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SEPTEMBER 3, 2019
The Wonder Years – Gene Therapy Enters the Age of Adolescence
Christopher J. RaymondSR. RESEARCH ANALYST
+1 312 267-5086 | [email protected]
Tyler M. Van BurenSR. RESEARCH ANALYST
+1 212 284-9488 | [email protected]
Danielle C. Brill, Pharm.D.SR. RESEARCH ANALYST
+1 212 284-5025 | [email protected]
Piper Jaffray does and seeks to do business with companies covered in its research reports. As a result, investors should be aware that the firm may have a conflict of interestthat could affect the objectivity of this report. Investors should consider this report as only a single factor in making their investment decisions. This report should be read inconjunction with important disclosure information, including an attestation under Regulation Analyst certification, found on pages 160 - 161 of this report or at the following site:http://www.piperjaffray.com/researchdisclosures.
David Amsellem
Sr. Research Analyst
Danielle Brill, Pharm.D.
Sr. Research Analyst
Joseph Catanzaro, Ph.D.
Sr. Research Analyst
Christopher Raymond
Sr. Research Analyst
Edward Tenthoff
Sr. Research Analyst
Tyler Van Buren
Sr. Research Analyst
Piper Jaffray Investment Research
At Piper Jaffray, our biopharma investment research team delivers to clients market-driven and
actionable insights across the biotech and pharmaceutical sectors. We build strong partnerships
with clients, and they trust our unique perspective to guide their investment strategies.
2 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Contents
01. Executive Summary
02. Introduction to Gene Therapy
03. Gene Therapy Product Design Considerations
04. Targeting Indications of Interest With Gene Therapy
05. Emerging Gene Therapies
06. Appendix
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 3
01.Executive Summary
4 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Executive Summary (Page 1/12): Viral Gene Therapy Company Landscape
Market Cap >$10B
Source: Company Websites. Piper Jaffray Research.
Market Cap $1–10B
Companies per GlobalData.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 5
Executive Summary (Page 2/12): Viral Gene Therapy Company Landscape
Market Cap <$1B
Source: Company Websites. Piper Jaffray Research.
Companies per GlobalData.
6 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Executive Summary (Page 3/12): Viral Gene Therapy Company Landscape
Private
Source: Company Websites. Piper Jaffray Research.
Companies per GlobalData.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 7
Gene therapy has experienced a renaissance in the last 5 years. It’s been
roughly five years since gene therapy as a field has re-entered the collective
conscience of biotech investors, as a deeper understanding of virology, advances
in vector and capsid design, and innovation in manufacturing all converged,
resulting in an explosion of promising data and concomitant regulatory
advancement. Indeed, after an almost 15 year “nuclear winter” (from ~1999 –
marked by the tragic death of Jesse Gelsinger as a result of gene therapy
treatment – to 2014), the industry had the first approved gene therapy (QURE’s
Glybera – approved by EMA in 2012), as well as meaningful human proof of
concept data across a number of disease indications. Since then, this innovation
has only accelerated, as the FDA and/or EMA have now approved five gene
therapies (QURE’s Glybera, ORTX’s Strimvelis, ONCE’s Luxterna, AVXS/NVS’
Zolgensma, and BLUE’s Zynteglo) and the number of annual AAV-based trial
initiations has ballooned from a handful in 2014 to ~40 today, with approximately
300 active programs ongoing (Exhibit 1). Despite this innovation and resultant
value creation, we still view the field as very early in terms of fulfilling its potential.
Sizeable value creation with likely more to come. While pure-play gene therapy
companies have been around for decades, as one might expect, the collective
market cap of these names has followed a trajectory very similar to that we would
expect for a space undergoing tremendous innovation.
Executive Summary (Page 4/12): As a Therapeutic Class, Gene Therapy Has Already Delivered a Great Deal
of Value, But in Terms of Potential, it’s Still Just an Adolescent
Source: Clinicaltrials.gov. Piper Jaffray Research.
EXHIBIT 1
Clinical Trial Initiations for AAV-based Treatments
EXHIBIT 2
Collective Market Cap of All Pure Play Gene Therapy Companies over Time
0
5
10
15
20
25
30
35
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Num
ber
of C
linic
al tr
ial In
itia
tio
ns
Year
Phase I Phase II Phase III
$0
$5,000
$10,000
$15,000
$20,000
$25,000
$30,000
$35,000
$40,000
$45,000
2005 2010 2015 2019
Mark
et C
ap (
in $
M)
Year
8 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
As one might expect, with innovation comes acquisition. As gene therapies have made their way out of academic institutions and into the hands of biotech companies
via licensing deals and academic spinouts, the field seems poised to enter a new era wherein the pace of gene therapy company acquisitions may begin to increase.
One could argue that it has already, as we've witnessed a number of large-cap names acquire public smid-cap and private gene therapy companies over the last 5 years.
These include Pfizer (Bamboo Therapeutics in 2016), Novartis (AveXis in 2018), Biogen (Nightstar Therapeutics this year), and Roche (Spark, in process), and as these
companies build out their manufacturing capabilities to support ongoing therapeutic development, it is likely only a matter of time before their BD teams get their hands on
more innovative assets.
Executive Summary (Page 5/12): Gene Therapy Company Acquisitions
Source: Goswami R et al. Front Oncol. 2019;24(9):297. Kaemmerer WF. Bioeng Transl Med. 2018;3(2):66–177. Piper Jaffray Research.
EXHIBIT 3
Acquisitions of Gene Therapy Companies Over The Past Five Years
0
1
2
3
4
5
6
7
8
2014 2015 2016 2017 2018 2019 (to date)
Num
ber
of A
cquis
itio
ns o
f G
ene T
hera
py C
om
panie
s
Year
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 9
Manufacturing – more than just a black box. Just as important as the vector design, the ability to manufacture high-quality GMP-grade, scalable, and cost-efficient gene
therapy product remains a challenge and a vast majority of companies rely on contract manufacturing organizations to fill this role. However, with the recent explosion of
gene therapy programs, a shortage of contract manufacturing capabilities and human capital has resulted, driving many companies to bring manufacturing in-house. While
this appears to be a hefty upfront investment, it allows companies to have more control over product quality, production schedules, capacity, and costs, while keeping
proprietary knowledge that contributes to the unique capabilities of each company’s platform close to the vest. But we note CMOs are trying to keep up with demand, and
we have seen these organizations beef up their gene therapy manufacturing capabilities through acquisitions with Thermo Fisher’s $1.7B acquisition of Brammer Bio in
March and Catalent’s $1.2B acquisition of Paragon Bioservices in April.
Executive Summary (Page 6/12): As a Therapeutic Class, Gene Therapy has Already Delivered a Great Deal
of Value, But in Terms of its Potential, it’s Still Just an Adolescent
Source: Pettitt D et al. Emerging Platform Bioprocesses for Viral Vectors and Gene Therapies. BioProcess International. April 2016. Piper Jaffray Research.
EXHIBIT 4
Typical Viral Vector Manufacturing Process Overview
Vector
Amplification
Vector
ExpansionPurification Polishing Fill-Finish
Thaw from master or
working cell bank
(eg, CHO)
Shake flask or spinner
Bioreactor
(5–15 L)
Bioreactor
(50–1000 L)
Transduction:
CHO + Vector
Cell lysis,
broth clarification
Filtration
Chromatography
(immunoaffinity,
ion exchange)
DNA removal
(eg, endonuclease)
Ultrafiltration
Sterile filtration
Transfer to
storage vessel
Cryopreservation
Labeling,
sterilization, storage
Se
ed
Tra
in
10 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
We’ve only scratched the surface. As we highlight in this report, a deeper understanding of, and the ability to manipulate and design viral vectors (specifically
adeno-associated viral vectors), advances in promotor technology and viral genome design, as well as improved manufacturing and process design, have all converged in
the past five plus years, creating an explosion of programs targeting an increasing array of tissues and disease targets. This includes diverse areas such as dermatology,
hematology, metabolic diseases, musculoskeletal, neurology, ophthalmology, and otology, to name a few.
In this report, we make mention of more than 100 gene therapy companies and profile 23 companies of particular interest – names which we think are best positioned to
capitalize on recent innovations in the field. While we don’t pretend to highlight every company or program, we think investors will do well to pay particular attention to these
names as the field advances further. Generally speaking, we look for future refinement of treatment options, including more diversified mechanisms for gene manipulation
(eg, virally delivered ASOs, CRISPR/Cas9), improved tissue targeting, and answers to the all-important question around re-dosing patients.
Executive Summary (Page 7/12): As a Therapeutic Class, Gene Therapy has Already Delivered a Great Deal
of Value, But in Terms of its Potential, it’s Still Just an Adolescent
Source: Goswami R et al. Front Oncol. 2019;24(9):297. Kaemmerer WF. Bioeng Transl Med. 2018;3(2): 66–177. Piper Jaffray Research.
EXHIBIT 5
Indications Being Targeted by Gene Therapies Covered in This Report
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 11
Executive Summary (Page 8/12): Key Public and Private Gene Therapy Players Profiled in This Report
Market Cap <$10BMarket Cap >$10B Private
Source: Company Websites. Piper Jaffray Research.
12 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Novel gene therapies have the potential to transform treatment landscapes for which huge unmet need remains. On the following four slides, we summarize the
available approaches and clinical trials of select companies profiled within this report. Further detail on these and additional companies is provided later in the report.
Executive Summary (Page 9/12): The Expanding Gene Therapy Landscape
Source: Piper Jaffray Research.
ADVM (Van Buren, OW). Adverum Biotechnologies’ lead candidate ADVM-022, is
an intravitreal gene therapy that produces Eylea. The ongoing ADVM-022 Phase I
OPTIC trial has already dosed 6 patients with a single intravitreal injection of 6E11
vg/eye of 022 and has also dosed the second cohort at a 2E12 vg/eye dose level
(n=6). Based on existing observations from the study, the company plans to
present initial 24-week data from the first cohort of 6 patients at the Retinal Society
meeting in September, 2019.
Akouos (Private). Akouos is a precision gene therapy company developing
treatments to restore and prevent monogenic hearing loss disorders. As the
company prepares for an IND submission in 2H20 for their lead Anc80 candidate,
management is engaging with multiple institutions to begin genetic screening in
newborns with confirmed deafness. Looking ahead, Akouos expects clinical
endpoints to include measurements of signal or noise detection, speech
perception, and QoL outcomes.
Amicus Therapeutics (FOLD, not covered). Amicus is a fully integrated, global
rare disease gene therapy company with one of the largest portfolios of gene
therapies to treat rare diseases in the field. Twelve children with Batten disease
have been dosed with lead candidate AAV-CLN6 to date, and remarkably, the
Hamburg motor and language score indicate no disease progression in children
30 months old at the time of treatment with AAV-CLN6. Data in 7 additional
patients at 2 years will be reported in 3Q19. In addition, the company plans to dose
3 additional Batten disease pediatric patients with AAV-CLN3 and is continuing to
develop AAV-GAA for the treatment of Pompe disease.
Asklepios BioPharmaceutical (Private). AskBio, a privately held AAV gene
therapy company founded in 2001, is engaged in the development, manufacture,
and delivery of novel gene therapies to treat a number of devastating diseases.
The company harnesses the scientific expertise of Dr Jude Samulski, the former
Director of the Gene Therapy Center at the University of North Carolina, and a
co-founder and current CSO of AskBio, to drive continued innovation in gene
therapy development with unique viral cassettes (i.e., self-complementary vectors,
synthetic promoters), next-generation chimeric capsids, and scaled up
manufacturing capabilities.
AVRO (not covered). AVROBIO is utilizing its proprietary commercial plato
platform which combines their lentiviral vector system with an automated, closed
cell manufacturing system for CD34+ gene therapy. AVRO’s lead asset,
AVR-RD-01, comprises autologous CD34+ HSCs transduced to express the
human α-galactosidase A (AGA) gene, and is in Phase I/II development for Fabry
Disease. Early efficacy data indicate durable AGA expression and an associated
reduction in lyso-Gb3 levels of 30%–40%. One patient treated in Phase II achieved
an 87% reduction from baseline in the average number of Gb3 inclusions per
kidney peritubular capillary (PTC) 1 year posttreatment. No treatment-related AEs
have been reported to date.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 13
Executive Summary (Page 10/12): The Expanding Gene Therapy Landscape
Source: Piper Jaffray Research.
AXGT (not covered). Axovant Gene Therapies has three clinical stage gene
therapy programs. Their most advanced program, AXO-LENTI-PD, is a lentivirus-
based gene therapy for Parkinson’s Disease (PD). Employing a lentiviral vector
allows for packaging of the 3 key enzymes involved in endogenous dopamine
synthesis and delivery in a co-localized fashion to neurons. Six-month follow-up
data from the dose-ranging portion of the ongoing Phase II trial showed improved
motor symptoms, lower oral levodopa dose requirements, and reduced
dyskinesias. Axovant is also developing AAV-based gene therapies for GM1 and
GM2 gangliosidosis and both programs are now in the clinic. We expect initial
3-month data from the ongoing GM1 trial with AAV-AXO-GM1and 3-month data
from the second dose cohort of the ongoing PD gene therapy trial (AXO-LENTI-
PD) in 4Q19. Data from two dosed patients in the ongoing GM2 trial with
AAV-AXO-GM2 is expected at a medical congress in 2H19.
BMRN (Raymond, OW). BioMarin has developed and commercialized a number of
biopharmaceuticals for rare diseases, and currently has two gene therapy
programs in development – valoctocogene roxaparvovec, or valrox (AAV5-F8) for
the treatment of hemophilia A, and BMN 307 (AAV5-PAH) for the treatment of
PKU. Phase I/II updates for valrox have been impressive, with the latest Year 3
update indicating a plateauing of FVIII activity (as measured by the chromogenic
assay) and demonstrating durable and clinically meaningful reductions in
annualized bleed rates (ABRs) and FVIII usage. These data, in combination with
recently disclosed interim data from a Phase III valrox study, will support FDA and
EMA regulatory filings in 4Q19.
BOLD (Raymond, OW). Audentes is an AAV-based genetic medicines company
focused on developing and commercializing innovative therapies for serious rare
neuromuscular diseases. The company focuses on developing AAV-based genetic
medicines for monogenic diseases where the underlying biology is well understood
and amenable to treatment using BOLD’s proprietary AAV gene therapy technology
platform. The company currently has six gene therapy programs in development,
with BLA filing for lead candidate AT132 for treatment of X-linked myotubular
myopathy (XLMTM) expected mid-2020.
BLUE (Van Buren, N). bluebird is developing a pipeline of gene therapies for
severe genetic diseases. Since its inception, the company has optimized an
industry-leading HSC platform which is being leveraged across the gene therapy
portfolio. The company’s lead candidates include Zynteglo for transfusion-
dependent β-thalassemia (TDT), Lentiglobin for severe sickle cell disease (SCD),
and Lenti-D for cerebral adrenoleukodystrophy (CALD). Zynteglo recently received
approval from the EMA for the treatment of non-β0/β0 TDT and European launch
preparation is currently ongoing with initial sales expected to be recorded in 1H20.
Lentiglobin efficacy in SCD has been positive and we expect the Phase III trial to
be initiated by the end of 2019.
14 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Executive Summary (Page 11/12): The Expanding Gene Therapy Landscape
Source: Piper Jaffray Research.
BBIO (Van Buren, OW). BridgeBio’s gene therapy pipeline includes two corporate
subsidiaries, Adrenas and Aspa, whose drugs target congenital adrenal
hyperplasia (CAH) and Canavan disease, respectively. The company plans to file
an IND for BBP-631 for the treatment of CAH in 1H20, following positive data in
non-human primates that demonstrated potential restoration of the natural
hormonal and steroidal cycle, which is disrupted in CAH patients. The company
also plans to complete route of administration and dose finding studies, as well as
IND-enabling toxicology studies in 2019 to support the submission of an IND for
BBP-812 for the treatment of Canavan disease in 2020.
MeiraGTx (MGTX, Van Buren, OW). MeiraGTx’s diverse pipeline spans several
ocular disorders, neurodegenerative disease, and salivary gland disease, and
incorporates a proprietary Riboswitch technology, which precisely controls target
gene protein production. The company plans to discuss registrational criteria with
the FDA for AAV-GAD in Parkinson’s disease, as well as AAV-RPE65 in RPE65
deficiency by YE19. In addition, the company expects data from ongoing Phase I/II
trials in achromatopsia (AAV-CNGB3 and AAV-CNGA3), X-linked retinitis
pigmentosa (XLRP, AAV-RPGR), and radiation-induced xerostomia (RIX,
AAV-AQP1) in the next couple of years.
Passage Bio (not covered). Passage Bio is partnering with UPenn’s Gene
Therapy Program and Orphan Disease Center to develop novel therapies for GM1
gangliosidosis, frontotemporal dementia (FTD) and Krabbe disease, which are
primed to enter the clinic throughout 2020. Preclinical biomarker data in AAV-GLB1
for GM1 and AAV-PGRN for FTD are early indicators of efficacy. Non-human
primate studies demonstrated improved HEX activity with AAV-GLB1, and
5–10-fold greater PGRN levels in the CSF following AAV-PGRN administration.
RARE (Raymond, OW). Once a wild card, Ultragenyx’s gene therapy platform has
continued to deliver on expectations with initial proof-of-concept data reported for
Phase I/II clinical programs DTX301 (OTC deficiency) and DTX401 (GSDIa), with
additional updates for patients treated at higher doses of both products expected in
3Q19. RARE has established non-GMP internal manufacturing platforms for both
HEK293 transient transfections and HeLa producer cell lines to develop these
processes to full scale before transferring them to CMOs for clinical and/or
commercial development, but plans to build out their own in-house GMP
manufacturing facility in the future.
RCKT (not covered). Rocket’s robust pipeline includes AAV- and LV-based gene
therapy programs with potential to be first-in-class for rare and devastating
pediatric disease indications. The company intends to enter registrational studies in
2020 for RP-A501 for the treatment of Danon disease (DD) and if successful,
approval may occur by the mid 2020s. Phase I RP-L102 data are expected by
YE19 in Fanconi Anemia and a registrational Phase II FA trial is expected to begin
by YE19. Finally, two Phase I studies in PKD and LAD are also expected to initiate
in the 2H19.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 15
Executive Summary (Page 12/12): The Expanding Gene Therapy Landscape
Source: Piper Jaffray Research.
SRPT (Brill, OW). Sarepta is currently the market leader in developing treatments
for Duchenne Muscular Dystrophy (DMD). In addition to their commercial product,
Exondys51, Sarepta has the most advanced microdystrophin (MD) gene therapy
program, which is currently enrolling DMD patients in a Phase III study.
The company also has a deep pipeline of gene therapy candidates for various
musculoskeletal and neurological disorders including Limb-Girdle Muscular
Dystrophy (LGMD). Sarepta’s LGMD-2E gene therapy is being evaluated in a
Phase I/II trial. Given overlap in disease manifestations across LGMD subtypes,
successful development for 2E should have positive read-through across the
LGMD gene therapy platform. Sarepta’s early stage gene therapies targeting
LGMD subtypes 2A, B, C, D, and L have overlapping constructs with 2E—all utilize
the same vector, and similar promotors. Pivotal data from the MD gene program is
anticipated by YE20 and an update from the LGMD-2E study is expected at World
Muscle Society in October 2019.
QURE (Brill, OW). uniQure’s gene therapies employ the AAV5 vector.
The company’s lead-candidate AMT-061 is the most advanced, and potentially best
in-class, Hemophilia B gene therapy (AMT-061) program in the clinic. AMT-061’s
pivotal Phase III trial is currently underway and topline data are expected by YE20.
QURE plans to introduce AMT-130, their gene therapy for Huntington’s Disease
(HD), into the clinic in 2019. We expect initial patient biomarker and safety data
around YE19 or early 2020. The company also has an in-house manufacturing
facility. All clinical trials are run with commercial-grade supply to expedite
CMC scale-up.
16 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Introduction to Gene Therapy
02.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 17
The concept of gene therapy originated ~60 years ago and has more recently
been driven by groundbreaking insights into our DNA discovered by the
human genome project. The human genome comprises ~25,000 genes, with
mutations, disruptions, or deletions in genes encoding altered and dysfunctional
proteins underlying a plethora of rare diseases. In fact, genetic dysfunctions are
reported to cause more than 5,700 rare diseases, and the global burden of genetic
diseases is immense, afflicting almost 30 million people in the US and
300 million globally.
The basic premise of gene therapy is to correct (repair), replace, or regulate
the dysfunctional gene that is responsible for causing disease. Ultimately,
durable expression of the functional gene and stable production of the therapeutic
protein are desired, to ideally achieve a one-time curative treatment.
Several gene therapy delivery approaches are under development:
• Ex vivo: genetic modification of isolated patient (autologous) or donor
(allogeneic) cells followed by re-introduction to the patient (eg, CAR-T cells)
• In situ: direct administration of genetic material to target cells or tissues to treat
localized conditions (eg, plasmid vector gene delivery directly to target tissues)
• In vivo: viral or non-viral vectors are employed to deliver therapeutic genes or
materials to defective cells or tissues (Exhibit 7)
This report focuses on in vivo viral vector-mediated gene therapies.
Ex vivo cellular therapies, including CAR-Ts, and gene-editing technology
landscapes have been covered in previous BioInsights reports, linked herein.
The Premise and Promise of Gene Therapy
Source: Goswami R et al. Front Oncol. 2019;24(9):297. Wikimedia Commons. Piper Jaffray Research.
EXHIBIT 6
Snapshot of Genetic Diseases Caused by Single Gene Mutations
EXHIBIT 7
In Vivo Gene Therapy Delivery Methods
18 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Genomic medicine is by no means a new concept. The ‘birth’ of gene therapy is
attributed to Professor William Szybalski, who performed the first virus-mediated
gene transfer to mammalian cells to correct a genetic defect in 1962. The first
patient was dosed with gene therapy in 1990 for the treatment of adenosine
deaminase severe combined immune deficiency (ADA-SCID), which resulted in
durable partial control of the disease. However, subsequent trial failures ensued,
with severe and fatal immune reactions and the emergence of leukemias due to
insertional mutagenesis. Around the same time as these safety concerns arose,
Gendicine (Shenzhen SiBiono GeneTech) became the first gene therapy to be
approved worldwide, when China approved its use for the treatment of head and
neck squamous cell carcinoma in 2003. The progression of gene therapy halted
over the next decade as research efforts shifted to focus on increasing the safety of
viral vectors used to deliver genes to patients, while maintaining transduction
efficiencies necessary for efficacy. FDA and EMA guidance was established to
govern gene therapy program development. The next gene therapy approval was
obtained in 2012, when Glybera (uniQure, no longer marketed) received approval
in Europe for the treatment of an ultra-rare blood disorder, hereditary lipoprotein
lipase deficiency.
The first in vivo muscle-specific gene therapy was approved by the FDA in
December 2017 – Spark Therapeutics’ Luxturna, for the treatment of vision loss
In patients with inherited retinal dystrophy caused by biallelic mutations in the
RPE65 gene. The AAV2 vector is administered via a single subretinal injection and
delivers a functional copy of the RPE65 gene to retinal pigment epithelial (RPE)
cells, regenerating RPE65 protein production and restoring the visual cycle.
Following this in May 2019, Novartis’ Zolgensma was the first systemic gene
therapy to receive FDA approval for pediatric patients <2 years of age with
infantile-onset spinal muscular atrophy (SMA). Zolgensma also employs an
AAV vector to deliver a functional copy of the human SMN1 gene, which encodes
survival motor neuron (SMN) protein production by target motor neuron cells,
improving muscle movement and function. It is administered via a one-time
IV infusion, currently priced at $2.1 million – a source of much debate.
In January 2019, the FDA described a “surge of cell and gene therapy
products entering early development”. More than 800 active gene therapy INDs
are currently on file, and the FDA anticipates approval of 10–20 gene therapies a
year beginning in 2025. The agency likens this innovative period for
gene therapies to that of the development and mainstreaming of monoclonal
antibody therapies.
A Brief History of Gene Therapy
Source: Goswami R et al. Front Oncol. 2019;24(9):297. Kaemmerer WF. Bioeng Transl Med. 2018;3(2): 66–177. Piper Jaffray Research.
EXHIBIT 8
Key Events In Vivo Gene Therapy Development
1990 1995 2000 2005 2010 2015 2020 2025
1990: First patient
treated with gene
therapy for ADA-SCID
1999: Jesse Gelsinger
dies following
gene therapy
2002: Leukemia
cases in children
treated for SCID
2003: China
approves Gendicine
for H&N cancer
2012: Europe approves
Glybera for ultra-rare
blood disorder (LPLD)
2017:
FDA approves
Luxterna
FDA anticipates
surge in gene
therapy approvals
2019:
FDA approves
Zolgensma
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 19
The scope of gene therapy clinical trials that are currently underway is vast.
ClinicalTrials.gov lists 4,032 gene therapy studies, nearly 1,700 of which are
active (planned, recruiting, or ongoing). A recently published analysis illustrated
the breadth of indications being targeted in gene therapy trials, which ranged from
communicable, dermatologic, immunologic, gastrointestinal, hematologic,
metabolic, and neurologic diseases, cancer, and other syndromes (Exhibit 9).
Viral vectors remain the most dominant gene delivery method, with adenovirus
(AV), adeno-associated virus (AAV), retrovirus (RV), and herpes simplex virus
(HSV) representing the most frequently used viruses in clinical trials (Exhibit 10).
Various types of therapeutic transgenes are being evaluated, ranging
from anti-angiogenic genes, cytokines, receptors, replication inhibitors,
tumor suppressors, vaccine antigens, and other therapeutic proteins of interest.
The recovery of the gene therapy field from the initial period of enthusiasm
followed by disillusionment, to the surge in trials and anticipation of future
gene therapy drug products, has been termed the “hype cycle”. As the hype
for gene therapies continues to escalate, we dive deep into the unique product
development considerations and the key companies shaping the space.
Critical gene therapy product design considerations, spanning vector, capsid,
and promoter selection and design, tissue tropism and targeting, transgene
delivery, transduction efficiency (TE), immunogenicity, and manufacturing will be
discussed in the next section of this report.
The Resurgence of Gene Therapy Today
EXHIBIT 9
Gene Therapy Clinical Trials by Disease Type
EXHIBIT 11
The Gene Therapy Hype Cycle
Source: Goswami R et al. Front Oncol. 2019;24(9):297. Kaemmerer WF. Bioeng Transl Med. 2018;3(2): 66–177. Piper Jaffray Research.
EXHIBIT 10
Use of Recombinant Viral Vectors in Gene Therapy Clinical Trials
14%
15%
8%
14%13%
8%
8%
10%
10%
Immune System
Cancer
Communicable
Gastrointestinal
Genetic
Hematologic
Metabolic
Dermatologic
Total Gene Therapy Syndromes
34%
32%
24%
10% Retrovirus
Adenovirus
Adeno-associated Virus
Herpes Simplex Virus
20 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
In the process of compiling this report, we have spoken with dozens of KOLs
and industry experts in the field of gene therapy. Along the way, we’ve learned
a few things. As such, we offer herein our view of where the field might be headed
in the near-to-intermediate term.
Increasing versatility & efficiency in terms of treatment options & modalities:
• Beyond gene replacement. Companies are already developing vectorized
ASOs (eg, BOLD, NVS/AXVS), and of course delivery of gene editing
machinery (CRISPR/Cas9) is a topic worthy of its own deep dive (which we
previously published).
• Cell/tissue targeting should continue to improve. Chimeric capsids should
see increased clinical use (many companies already possess libraries with
hundreds of thousands of potential capsids). We suspect these will only
improve over time with respect to specific cell/tissue targeting
• Better expression. We anticipate increased use of synthetic and inducible
promotors will allow for more regulated gene expression
• Ablation strategies. With parallels to oncolytic viruses, controlled and targeted
cell ablation technologies could be employed, delivering inducible “cell death”
receptors, which when exposed to specific drugs could drive a highly specific,
targeted cell death
• Redosing. While this concept appears to be anathema to the traditional notion
of “one and done” that generally accompanies gene therapy, it seems most
every gene therapy company is working on such approaches, but so far largely
demur when asked to discuss these programs in detail. Given pragmatic
challenges to durability of expression, we think this work makes sense, and
foresee a generation of novel capsids developed that can evade the immune
system to allow for efficient redosing
Manufacturing – we expect a Moore’s Law (of sorts) to apply here. More
companies are bringing gene therapy manufacturing in house, and refining
proprietary processes at an ever-increasing pace. While we liken this to Moore’s
Law (doubling of components per integrated circuit, and increasing computing
speed every 2 years), we believe that, directionally, manufacturing capabilities will
continue to advance at this rapid pace for the foreseeable future, with time from
vector development to full-scale production continuing to shrink, as well as
decreasing manufacturing costs.
• Speed and Cost (AskBio). As an example, we highlight work being conducted
by private company, AskBio, who recently partnered with Toughlight Genetics to
replace plasmids with closed-linear, double stranded DNA constructs known as
doggybone DNA (dbDNA), eliminating large plasmid backbones and antibiotic
resistant genes as selection vehicles, as well as large plasmid reactor volumes
• Scalability (RARE and BOLD). Many players use HeLa producer cell lines at
2,000 L scale today, but one company, RARE, indicates their “HeLa 2.0” cell
line can be easily scaled to 10,000L. BOLD utilizes a transient transfection
suspension system at a 500 L scale today, but management notes there is no
biological limitation to going beyond that capacity
A Look Forward – Where We Think the Field is Headed
Source: Max Roser. https://ourworldindata.org/uploads/2019/05/Transistor-Count-over-time-to-2018.png. May 2019. Piper Jaffray Research.
EXHIBIT 12
Moore’s Law: Transistor Count on Integrated Circuit Chips (1971–2018)
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 21
Gene Therapy
Product Design Considerations
03.
22 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
The premise of gene therapy is to correct (repair), replace, or regulate a
dysfunctional gene that is responsible for causing disease. The basic
mechanisms by which these goals can be achieved include A) gene replacement,
B) gene addition, C) gene silencing, and D) gene editing (A–C are illustrated in
Exhibit 13, below).
Gene replacement is the mechanism currently being tested in the majority of
advanced clinical trials, and provides a straightforward mechanism by which to
treat monogenic diseases caused by a single gene defect. Gene addition is more
appropriate for complex genetic disorders and infectious diseases. Finally, gene
silencing is used to treat diseases caused by gain-of-function or gain-of-toxicity
mutations, often using gene knockdown by RNA interference or reprogramming of
mRNA splicing by antisense oligonucleotides (AONs).
In order to express or silence the gene of interest, the genetic material must
be packaged into expression cassettes for delivery to the target cells.
Expression cassettes consist of the transgene (cDNA or genomic DNA), a
promoter to drive expression of the transgene, and a transcription stop codon.
Posttranscriptional response elements (PRE) may also be incorporated to enhance
gene expression. The cassettes are typically packaged into a vector (viral or
nonviral) for delivery to the target cells.
The core steps in the gene therapy development process are summarized in
Exhibit 15, below. Key product design considerations, spanning vector, capsid, and
promoter selection and design, transduction efficiency and payload, administration,
tissue tropism and targeting, transgene delivery, and immunogenicity will be
discussed in detail on the following pages.
Introduction: Process and Components
EXHIBIT 13
Gene Therapy Strategies
Source: Wang D and Gao G. Discov Med. 2014;18(98):151–161. Johnston J et al. InTech Open. 2011. ISBN: 978-953-307-617-1. Piper Jaffray Research.
Identification of
affected gene
Develop
expression
cassette with
therapeutic
transgene
Load
vector with
expression
cassette
Vector
administration
Integration of
genetic material
into DNA and
protein
production
Vector delivery of
gene into
nucleus of cells
EXHIBIT 15
Core Steps of Gene Therapy Development
EXHIBIT 14
Components of an Expression Cassette
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 23
Viral and non-viral vectors are employed to deliver therapeutic genes or materials to defective cells or tissues, mediating in vivo treatment of systemic genetic
diseases. While numerous physical and chemical methods of gene delivery are being explored in clinical trials, viral vectors remain the predominant method of gene
delivery, having shown the most efficient delivery of genetic material to target cells and tissues. Key features of the four major viral vectors that are currently under
evaluation in clinical trials are summarized below.
An ideal vector should deliver the therapeutic gene to a specific cell type (both dividing and non-dividing), accommodate foreign genes of sufficient size, transfer a precise
amount of genetic material into each target cell, and achieve the level and duration of transgenic expression sufficient to correct the defect. The vector should be safe and
tolerable – it should not be immunogenic, pathogenic, or inflammatory, or induce insertional mutagenesis. Greater than 70% of the viral vectors being used globally in
ongoing clinical trials are non-pathogenic and replication-defective. Large scale production capability is also desired. Vector options are reviewed in more detail on the
following slides.
Vector Selection and Design
EXHIBIT 16
Key Features of Commonly Used Viral Vectors
Source: Goswami R et al. Front Oncol. 2019;24(9):297. Piper Jaffray Research.
Vector Genome
Max Size of
Exogenous
DNA Insertion
Target Cells Integration Advantages Limitations
Adenovirus
(Ad)dsDNA >8 kb
Broad tissue
tropism
Dividing and
non-dividing
cells
Episomal
• High transduction efficiency
• Demonstrated clinical efficacy
• Short-term effect (1–2 weeks)
• High immunogenicity
• Complexity of engineering
Adeno-
Associated Virus
(AAV)
ssDNA 5 kb
Episomal
(0.1%
genomic)
• Low toxicity: non-inflammatory/pathogenic
• Efficient transduction
• Long-term, durable gene expression
(months – life long)
• Cost-efficient commercial scale
production
• Low packaging capacity (max 5 kb)
• Potential triggering of existing innate and
adaptive immune responses
• Preexisting host neutralizing antibodies
• Purification may be challenging
Lentivirus
(LV)RNA 8–12 kb Genomic
• Low immune response
• Efficient transduction
• Life-long transgene expression
• Large-scale clinical production
• Insertional mutagenesis
• Limited cassette size
Herpes Simplex
Virus (HSV)dsDNA
>30 kb
<50 kb
CNS, muscle,
heart, liverEpisomal
• Efficiently infect multiple cell types
• Large packaging capacity
• Transient gene expression
• Limited clinical experience
• Immune response
24 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Adenoviruses are non-enveloped, double-stranded DNA viruses with the
capacity to carry large genes, up to 7.5 kb in size. Over 50 serotypes of
adenovirus have been isolated.
Adenoviruses rapidly infect a broad range of human cells, both dividing
and non-dividing. The virus binds the coxsackie-adenovirus receptor (CAR)
on the host cell surface with high-affinity and enters the cell by receptor-
mediated endocytosis (RME). The endosome is uncoated, releasing the viral
DNA, which is transported into the nucleus. Within the nucleus, the viral DNA is
transcribed to produce mRNA, which is translated into the therapeutic protein
(Exhibit 18, right). Lack of integration into the host genome results in transient
gene expression, lasting ~1–2 weeks.
The major concern regarding use of adenoviral vectors is the strong
immunogenicity exhibited by the pathogenic virus. Pre-existing host
immunity may also exist. Attempts to circumvent immunogenicity include
modification of viral capsids and “sero-switch” gene transfer, a strategy that
involves the repeated administration of alternating adenovirus vectors that are
derived from different serotypes in order to avoid anti-adenovirus humoral
immune responses.
Adenoviral vectors are currently being evaluated only in very select
indications, including oncology and heart failure. The field has more broadly
shifted towards AAV and lentiviral vectors, which are discussed in more detail
on the following slides.
Focus on AV Vectors
EXHIBIT 17
Adenovirus Structure
EXHIBIT 18
Mechanism of Adenovirus-mediated Delivery of Therapeutic DNA
Source: Ip WWY & Qasim W. Adv Hematol. 2013;2013:176418. Goswami R et al. Front Oncol. 2019;24(9):297. Piper Jaffray Research.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 25
AAVs are small, single stranded non-pathogenic DNA viruses that contain
two genes (rep and cap), and only reproduce in the presence of a helper virus
(eg, Ad, HSV, or baculovirus). This requirement for a helper virus to proliferate,
along with the nonpathogenic nature and minimal immunogenicity of AAV,
renders it one of the safest vectors to use. It is therefore not surprising that
AAV is currently the most frequently used viral vector for gene therapy.
Thirteen serotypes of AAV have been isolated. Their diverse capsids
confer distinct tissue tropism, making the AAV system attractive for
selective and highly efficient gene transduction of a wide range of cell types.
Recombinant AAV (rAAV) vector production involves a 3-plasmid
co-transfection method performed in packaging cell line. The key
components and steps involved in this process are illustrated below.
1. Transgene-containing rAAV vector: the majority of AAV’s viral genome
is replaced with the therapeutic transgene (viral packing genes remain)
2. AAV rep (replication) and cap (capsid) genes: Contains the code for
regulatory proteins involved in AAV genome replication and capsid proteins
that determine tissue tropism, respectively
3. Helper virus genes: enable rAAV replication only during the
manufacturing process
A limitation of AAV vectors is their relatively limited packaging capacity.
Up to a 5 kb therapeutic expression cassette can be incorporated in an AAV
vector, beyond which the packaging efficiency drops significantly. Several
Dual-AAV vector approaches (overlapping, trans-splicing, and hybrid) that
involve “splitting” the therapeutic expression cassette between two independent
AAV vectors are being developed to increase the size of the transgene that
AAV vector can deliver.
Focus On Adeno-Associated Virus (AAV) Vectors (Page 1 of 2)
EXHIBIT 20
rAAV2 Vector Production
Source: Schultz BR and Chamberlain JS. Mol Ther. 2008;16(7):1189–1199. Trapani I. Genes (Basel). 2019;10(4):287. Piper Jaffray Research.
EXHIBIT 19
AAV Serotypes and Tissue Tropism
Serotype Tissue Tropism
AAV1 Muscle; Adipose; CNS; Heart
AAV2 CNS (particularly ocular); Kidney; Muscle; Testes
AAV3 Liver
AAV4 Brain; Retinal pigmented epithelium (RPE); Lung
AAV5 Liver; CNS; Ocular; Pancreas
AAV6 Striated muscle (heart); Respiratory epithelium (lung)
AAV7 Brain; Photoreceptors; RPE; Striated muscle
AAV8 Hepatocyte; Pancreas; RPE; Photoreceptors; Brain; Skeletal muscle
AAV9 Heart; Skeletal muscle; Lung; Brain; CNS
AAVrh10 Pleura; CNS
Purification
TransgeneITR ITR
Promoter
rep
cap
Encapsulated
rAAV vectors
1. 2. 3.
26 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
AAV vectors are able to infect both non-dividing and dividing cell types,
entering cells via RME. Following entry, virions traffic to the host cell nucleus,
where vector uncoating likely occurs. The vector genome is released, forming
episomes, or more rarely integrating into the host
genome (as has been observed with AAV2 integrating into chromosome 19),
resulting in durable long-term gene expression.
While the immunogenicity of AAV vectors is low compared with other
viral vectors, AAVs occasionally trigger innate and adaptive immune
responses. Although administration of AAVs to immune privileged sites
alleviates this concern, mitigation of AAV immunogenicity is an ongoing area of
research. Short-term immune suppression, coadministered during the initial
AAV treatment, may minimize activation of memory T and B cells, and
contribute to gene therapy persistence. Additional strategies include genetically
modifying AAV vectors to alter their capsid structure and to restrict transgene
expression to target tissues (using tissue-specific promoters).
An additional consideration for AAV vectors is the challenge commercial
scale production and purification has faced due to the requirement for
co-infecting helper virus for productive infection.
Both FDA-approved in vivo gene therapies (Luxterna and Zolgensma)
utilize AAV vectors. Additional clinical and preclinical success has been
observed in several diseases, including hemophilia B, neurological, and
heart disease.
Focus On Adeno-Associated Virus (AAV) Vectors (Page 2 of 2)
Source: Schultz BR and Chamberlain JS. Mol Ther. 2008;16(7):1189–1199. Trapani I. Genes (Basel). 2019;10(4):287. Piper Jaffray Research.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 27
Lentiviruses are spherical enveloped RNA viruses that belong to the
retrovirus family. With a larger genome than AAV, lentiviral vectors (LVVs) have
the capacity to incorporate therapeutic genes as large as 12 kb. They exhibit broad
cell tropism, infecting a wide range of somatic cells, including hematopoietic stem
cells (HSCs).
Unlike AAV, lentivirus incorporates its DNA directly into a cell‘s chromosome
upon infection. After the LV enters the host via fusion or RME, the RNA genome
is released into the cytoplasm of host cells and reverse transcriptase occurs,
creating viral DNA from the RNA. Viral DNA traffics to the nucleus and is
incorporated into the host genome via the viral enzyme integrase. Integrase
catalyzes both the cleavage of viral DNA and the joining of the cleaved viral DNA to
host cell DNA. After viral DNA is joined to the host DNA, post-integration repair is
conducted by the cell‘s own DNA repair proteins. Viral gene and therapeutic protein
expression subsequently occur outside the nucleus. The ability of lentivirus to
integrate into the host genome allows this vector to provide a sustained therapeutic
effect to dividing cells, such as HSCs, and effectively treat those diseases not
adequately addressed by AAV-based gene therapy.
As an integrating virus, lentivirus poses different safety risks than AAV.
Extensive research has been conducted over the last several decades to
characterize these risks, and has made great strides in improving the safety profile
of this class of viruses. The ability to integrate offers the benefit of sustained
transgene expression and these viruses can handle longer transgene cassettes.
Traditional retroviral vectors (gammaretroviruses) presented significant safety
concerns resulting from insertional mutagenesis and ensuing oncogenesis, as well
as the emergence of replication-competent virus. Lentiviruses exhibit more targeted
integration preferences, avoiding integration near promoters and genes that
regulate the cell’s growth, and favoring the bodies of transcription units, reducing
the risk for insertional mutagenesis. They have also been engineered to employ
self-inactivating (SIN) technology to prevent the formation of replication-competent
virus. In these ways, lentivirus provides significant improvements over traditional
retroviral vectors.
Focus On Lentiviral (LV) Vectors (Page 2 of 2)
Source: Applied Biological Materials, Inc. Dufait I et al. Lentiviral Vectors in Immunotherapy. InTech Open. 2013. DOI: 10.5772/50717. Piper Jaffray Research.
EXHIBIT 21
Lentiviral Structure
EXHIBIT 22
The Lentivirus Replication Cycle
Envelope
Envelope protein
RNA genome
Reverse
transcriptase
Proteinas
estruturais
28 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
The key components of the lentiviral genome are illustrated in Exhibit 23 below.
• LTRs, or long terminal repeats, act as a promoter, or “control center”, for the
expression of viral genes
• Gag, pro, pol, and env genes encode for the structural proteins of the capsid,
protease, reverse transcriptase, and envelope proteins, respectively
• The remaining genes perform regulatory functions (tat and rev) as well as alter
cellular function
To form a lentiviral vector, ~1/3 of the viral genome (encoding the virulence
factors) is deleted and the vector system is divided into several plasmids
(Exhibit 24). Plasmids are small, double-stranded DNA molecules that are used as
tools for transferring and manipulating genes. Separation of the various
components of the LV into these distinct plasmids is an important safety step
designed to prevent the resulting LV vector from replicating and causing infection.
1. Vector plasmid: contains the therapeutic transgene. One LTR is deleted,
which renders the other LTR transcriptionally inactive, resulting in a vector
which cannot replicate
2. Packaging plasmid: contains the gag, pro, pol, rev, and tat genes
3. Envelope plasmid: encodes the envelope protein and determines what
receptor the virus binds to when entering a cell
Lentiviruses can be pseudotyped with heterologous viral envelopes to direct
their tissue tropism. One popular example of this is the envelope glycoprotein
derived from vesicular stomatitis virus (VSV), which confers broad tropism and
facilitates transduction of many cell types.
Focus on Lentiviral Vectors (Page 2 of 2)
EXHIBIT 23
Key Component of the Lentivirus Genome
EXHIBIT 24
Lentiviral Vector Plasmids and Components
Source: Dufait I et al. Lentiviral Vectors in Immunotherapy. InTech Open. 2013. DOI: 10.5772/50717. Piper Jaffray Research.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 29
The viral capsid forms the protein shell that contains the viral genome and
differs in structure between serotypes. The viral proteins that make up the
capsid determine tissue tropism by their specificity for host cell surface receptors,
and further influence intracellular trafficking. The capsid also contributes to the
potential immunogenicity of a viral vector.
As reviewed in Exhibit 19 on slide 26, AAV serotype selection for gene therapy is
determined by these differences in tissue tropism. AAV2, 8, and 9 are the most
frequently used serotypes of AAV due to their abilities to infect a diverse array of
target tissues.
While AAV-based therapies have shown success with gene delivery, opportunities
exist to refine vector functionality, by improving transduction efficiency, specificity,
and immunogenicity. Capsid optimization can be achieved by implementing the cap
gene modification strategies illustrated in Exhibit 25, below.
• Amino acid point mutations can be employed to:
• Prevent posttranslational modifications that potentially lead to capsid
degradation, thereby enhancing transduction efficiency
• Increase gene delivery specificity
• Minimize immune recognition by preexisting neutralizing antibodies to AAV
in the host, enhancing transduction efficiency
• Peptide motif insertions:
• Transference or grafting of peptide domains (eg, receptor binding domains)
between serotypes to impart specific functions on a serotype of interest
• DNA shuffling to create capsid chimeras that possess functional domains
with specific properties of interest (eg, a ‘blood brain barrier traversing
footprint‘ that affords greater specificity and transduction efficiency)
• Insertion of nonviral motifs can be performed to selectively transduce target
cells and minimize off-target transgene expression; “peptide locks” can be
inserted to regulate transduction in response to endogenous or chemical
stimuli; mosaic capsids can be created for activateable peptide displays
• Chemical biology approaches:
• Precise capsid modifications such as insertions of tags, amino acids, or
motifs to specific subunits of the viral capsid facilitates site-specific addition
of moieties, vector retargeting, and improves transduction efficiency
Analogous to this is the process of pseuodtyping of lentiviral particles to
alter cellular tropism and intracellular trafficking. Envelope proteins (rather
than capsid proteins) determine viral entry into specific types of host cells and
the transduction efficiencies in quiescent vs differentiated cells. LVs can be
pseudotyped with heterologous viral envelopes or artificially engineered
envelope proteins that trigger transient activation of host cells, increasing TE.
Tissue Tropism and Targeting: Capsid Selection and Optimization
EXHIBIT 25
Rational Design Strategies for AAV Capsid Engineering
Source: Lee EJ et al. Curr Opin Biomed Eng. 2018;7:58-63. Durand S & Cimarelli A. Viruses. 2011;3(2):132–159. Piper Jaffray Research.
Amino Acid Mutation Motif Insertion Chemical Biology
30 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Promoters are regulatory units located upstream of the transgene that initiate
transcription of the transgene, driving both the level and durability of gene
expression. The regulatory unit encompasses the promoter itself (the RNA
polymerase binding site) and associated operators, or response elements.
Promoters are activated by transcription factors.
The promoter to be used in a when building a vector is chosen based on the
following criteria:
• Compatibility with the type of RNA to be produced (i.e., RNAP II promoter for
mRNA expression, RNAP III for small RNA)
• Host organism suitability: bacterial promoters for prokaryotic cells, eukaryotic
(endogenous), viral (exogenous), hybrid, or synthetic promoters
• Desired promoter activity: constitutive, inducible, regulated
Promoters may be native or composite in nature. Native, or minimal, promoters,
are single 5’ gene fragments that comprise a core promoter and its natural 5’UTR
(generally a weaker promoter). Composite, or hybrid, promoters may comprise
promoter elements from distinct origins or combine a distal enhancer with a
minimal promoter of the same origin. Hybrid promoters that comprise viral
enhancer/endogenous fusions may enhance the level, durations, and specificity of
the transgene expression.
Tissue-specific promoters are commercially available for a broad range of cells
and tissues, including bone, endothelial, hematopoietic, liver, lung, muscle, and
neuronal, to name a few. Tumor-specific promoters have also been identified and
are employed to drive targeted gene expression in tumor vs normal cells.
Synthetic promoters, novel DNA sequences, are also being developed to
optimize the size, selectivity, and activity of the promoter, specific for a given tissue
or cell type, or mode of delivery. Promoters can be designed to be constitutively
active, drug regulatable, or inducible, or active under specific conditions (i.e., in a
disease state, or in response to an infection or treatment). Companies are
developing proprietary platforms, such as Synpromics' (acquired by AskBio in
August 2019) PromPT "a unique, and multi-dimensional bioinformatics engine", to
create libraries of promoters that can be adapted per the above criteria.
Synthetic promoters may also play a role in bioprocessing and gene therapy
manufacturing by facilitating the development of stable producer cell lines with
greater productivity, which may remove the requirement for multiple transfections
per manufacturing run. Inducible promoters may be regulated with small molecules
to provide tight control over the manufacturing process.
The promoters most commonly used in viral vectors are summarized below:
• Chicken beta actin (CAG): universal promoter that drives constitutive
expression of mRNA; may be combined with a CMV enhancer
• Cytomegalovirus (CMV): strong mammalian promoter that constitutively
expresses mRNA. Initially drives high levels of transcription that may later
decline due to promoter inactivation
• The inducible H1 and constitutive U6 promoters may be used to drive
transcription of miRNAs by lentiviral vectors
Promoter Selection
Source: Zheng C & Baum BJ. Methods Mol Biol. 2008;434:205-19. Synpromics Company Website. Piper Jaffray Research.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 31
The transfer of a gene via a viral vector is termed transduction.
The delivery of the viral vector, or vehicle, may be performed by directly injecting
the virus into the body (in vivo) or by exposing a patient’s cells to the virus outside
the body, then re-introducing these cells to the body (ex vivo). The delivery method
selected is disease-specific and determined by the vector used and target cells.
Transduction efficiency (TE) is a measure of the percentage of target cells
transduced by the viral vector and expressing the gene of interest. The TE of
in vivo gene therapies can be influenced by several factors, including the number of
vectors reaching the target cell, vector affinity for target cells, target cell expression
of surface receptors for viral entry, target cell division activity, antiviral host immune
responses (nAbs), and ultimately, delivery of the genetic payload (transgene) and
expression of the therapeutic protein.
As such, the serotype of the viral vector, viral load, vector-specificity for target
tissues, and the promotor used can all affect TE and transgene expression.
Recombinant AAV (rAAV) are able to infect both dividing and non-dividing host
cells. Following host cell infection, the AAV genome is transformed into episomes,
circular double-stranded genetic elements that are stably maintained
extrachromosomally, and can replicate independently of the host, providing long-
term gene expression in non-dividing cells. However, episomes undergo enzymatic
degradation over time, and the gene becomes diluted as cell proliferation
continues, attenuating gene expression. The presence of pre-existing host nAb to
AAV is one of the biggest barriers to efficient transduction with rAAV vectors;
Capsid engineering of AAV vectors is an effective approach to evading the immune
response and augmenting transduction potential.
Lentiviral vectors exhibit enhanced TE compared with traditional retroviral-based
vectors due to their ability to also infect quiescent host cells. Upon host cell
infection, integration of lentiviral genetic information into the host’s genome occurs.
As the transgene replicates along with the host cell and is transferred to daughter
cells, more durable gene expression is theoretically achieved. The specific site of
the host’s genome at which the LVV integrates can affect the level of transgene
expression.
Efficient transduction is essential to optimize therapeutic outcomes.
Vectors with greater TEs can be administered at lower doses to achieve a
therapeutic benefit, minimizing risk for inflammatory host reactions and associated
safety concerns.
A number of processes may contribute to the potential decline or loss of transgene
expression over time, including gene silencing and deletion.
Transgene Delivery: Vector Administration, Transduction Efficiency, and Payload
EXHIBIT 26
Direct (In Vivo) vs Cell-based (Ex Vivo) Gene Therapy
Source: Collins M & Thrasher A. Proc Biol Sci. 2015;282(1821):20143003. Fischer L et al. Exp Clin Cardiol. 2002; 7(2-3): 106–112. Piper Jaffray Research.
32 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Manufacturing high-quality, scalable, cost-efficient gene therapy products is
challenging due to the complex multi-step processes involved in production
(Exhibit 27). While the exact steps of which differ according to the specific vector
used, the core goal of each process remains the same – to consistently produce
safe, pure, potent, and durable gene therapy products.
The recent explosion of gene therapy programs has resulted in shortage of
contract capabilities, with 12–18 month manufacturing wait times. As such,
pharmaceutical companies are increasingly developing their own gene therapy
manufacturing systems, leveraging their knowledge base of quality systems from
biologics manufacturing to create commercial-scale fully-integrated gene therapy
manufacturing facilities.
In-house manufacturing capabilities provide control over product quality,
production schedules, capacity, and cost, along with flexibility and business
continuity, while keeping proprietary knowledge in-house. Establishment of
such capabilities, and the production of commercial-grade gene therapy products,
prior to initiating Phase III trials de-risks clinical trial programs, reducing regulatory
concerns regarding changes in manufacturing processes or facilities between
Phase III and commercial production.
The quality and efficiency of the manufacturing process may become a
dividing factor among competitive programs. Investment in manufacturing at an
early stage is key for gene therapy’s commercial success. When evaluating gene
therapy companies - especially those developing their own manufacturing systems
- to fully understand the company’s logic behind:
• Cell line selection: The industry is split between two approaches to production,
insect (baculovirus) vs human cell lines. Insect lines are generally easier to
grow, achieving ~40-fold greater productivity in suspension, with a volumetric
benefit (2000 L vs 200–400 L scale), similar conditions of cell infection at low
and high volumes (supporting ease of scalability), and are less likely
contaminated with human pathogens. Human cell lines may be transiently
transfected with the transgene, an approach that uses a tremendous amount of
capsid and may be challenging to scale up
• Plasmid complexity: Human producer cell lines may generated by
incorporating rep, cap, and the transgene to the genome, to be banked and
used repeatedly – providing consistency and realizing cost reductions
• Purification validation: Techniques to isolate and remove empty capsids from
the end product are important for product purity and potency. Removal of
deamidated capsids is also crucial to ensure liberation of the transgene
following vector administration
Efforts to increase yields and improve purity and consistency should all help
maximize margins and minimize development/regulatory delays. As an increasing
number of gene therapy products enter the market and gene therapy manufacturing
processes become better validated and more established, regulatory comfort
around the quality and safety of manufacturing processes is likely to increase.
Gene Therapy Manufacturing (Page 1 of 3)
Source: Pettitt D et al. Emerging Platform Bioprocesses for Viral Vectors and Gene Therapies. BioProcess International. April 2016. Piper Jaffray Research.
EXHIBIT 27
Typical Viral Vector Manufacturing Process Overview
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 33
Gene Therapy Manufacturing – Diving into AAV Manufacturing Platforms (Page 2 of 3)
Source: Piper Jaffray Research.
General Overview of AAV Gene Therapy Manufacturing. Innovation and refinement of AAV gene therapy manufacturing approaches has rapidly progressed within the
last five years. Below, we highlight major differences between the commonly used manufacturing platforms. While challenges exist with each system, many companies
have made improvements to these platforms to reduce costs, increase scalability and production timelines, and improve quality control and safety. In our view, there is
no best platform, but instead believe there are certain considerations, which we highlight on the following slide, as guiding to the most appropriate system to utilize.
Transient Transfection Platform Producer Cell Line Platform
REP/CAP Plasmid Plasmid Integrated in cell line Integrated in cell line
ITR-transgene Plasmid Plasmid BEV* Integrated in cell line
Helper genes Plasmid Plasmid BEV WT adenovirus
Cell line HEK293 (adherent) HEK293 (suspension) Sf9 insect cells HeLa S3 (suspension)
Production system
examplesCellFactory, CellCube, iCELLis WAVE Bioreactor Stirred tank reactor Stirred tank reactor
Efficiency of DNA delivery ++ + +++ +++
Scalability -++
(500 L scale-up common)
+++
(2,000 L scale-up common)
+++
(2,000 L scale-up common)
Safety concerns None None NoneContaminating
helper virus
AdvantagesQuick to produce virus in small scale
Helper virus-free AAV
Added safety of insect cells/virus
Efficient large-scale production
Same helper virus for all
production runs
Efficient large-scale production
Challenges
Low scalability of triple transfection
Low % of full capsids
High plasmid costs
Potentially low BEV stabilityStable producer cell line to
produce for each project
Examples of companies
using the platformSarepta, Passage Bio
Audentes, Ultragenyx, Spark,
AveXis/Novartis, AskBio
BioMarin, MeiraGTx
uniQure, VoyagerBayer, Ultragenyx
EXHIBIT 28
Key Features of Commonly Used Viral Vectors
BEV=baculovirus expression vector.
34 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapy Manufacturing (Page 3 of 3)
Source: Piper Jaffray Research.
Everybody wants to rule the (manufacturing) world. But with respect to platform selection, beauty remains in the eye of the beholder. Manufacturing is a
key aspect for emerging gene therapies, not just in terms of COGS and margins, but for clinical development and commercialization, where reproducibility and safety
remain top concerns for regulators. With a number of companies bringing gene therapy manufacturing capabilities in-house, and confusion as to which AAV platform may
be king, we break down some important considerations for investors when thinking about the most appropriate platform for a company to develop and/or utilize.
• For ongoing programs, what’s the indication size? For many rare disease companies treating small numbers of patients a year with a certain gene therapy, there
may be no need to scale up to 2,000L+ capacity with a producer cell line. Rather, transient transfection systems may be the most efficient for producing sufficient
quantities of product
• What diseases is the company looking to treat in the future? Is the company planning to move into a larger indication that may require scale-up beyond the
capabilities of a transient transfection system? If so, how do they plan to do this, especially if they’ve already established a system in-house?
• For in-house manufacturing, what scale-up capacity can the current facility accommodate? Can the company add additional bioreactors into the facility, or
are there physical limitations?
• How quickly does the product need to be made? For companies competing to be first to market (but depending on the indication), it may be most appropriate to
produce a gene therapy product in a transient transfection system and bridge to product made by a producer cell line platform post-approval
• What are the timelines for scale up? For CMOs and companies producing product in-house, with ongoing enhancements to the capabilities of the platforms,
including speed and scalability of production, how quickly can these players establish a fully scaled-up GMP manufacturing process?
• Is the company using commercial material in preclinical and clinical studies? The FDA’s draft guidance on gene therapy development highlights the importance of
using “to be” commercial gene therapy product as soon as possible in preclinical and/or clinical development. It’s important to consider what process the company is
currently using to manufacture product and whether this will be the process used during commercialization. For companies that plan to switch platforms (eg, transient
transfection to producer cell line), bridging studies in preclinical and or small clinical studies may be needed and could be a source of delay or complication
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 35
Targeting Indications of Interest With
Gene Therapy
04.
36 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Indications of Interest Covered Within This Report
Source: Company Reports. Myotonic Dystrophy Foundation, NORD. Piper Jaffray Research.
Hematology
Inborn errors of
metabolism
Musculoskeletal
Ophthalmology
Otology
Dermatology
Neurology
Lysosomal storage disorders
• Becker Muscular Dystrophy (BMD)
• Myotonic Dystrophy Type 1 (DM1)
• Duchenne’s Muscular Dystrophy (DMD)
• Limb-Girdle Muscular Dystrophy (LGMD)
• Oculopharyngeal muscular dystrophy (OPMD)
• X-linked myotubular myopathy (XLMTM)
• Achromatopsia
• Choroideremia
• Retinitis pigmentosa
• Wet Age-Related Macular
Degeneration (AMD)
• X-Linked Rentinoschisis
(XLRS)
• Hearing loss
• Epidermolysis
bullosa
• ALS - C9ORF72
• Huntington's Disease
• Friedreich's Ataxia
• Frontotemporal dementia
• Parkinson's disease
• SCA-Type 3
• Alpha-1 Antitrypsin (A1AT) Deficiency
• Congenital Adrenal Hyperplasia
• Ornithine Transcarbamylase (OTC) Deficiency
• Phenylketonuria (PKU)
• Wilson disease
Neurological disorders
Other
• Danon Disease
• Fabry’s disease
• GM1
• GM2
• MPS IIIA
• MPS IIIB
• Pompe disease
• Batten Disease (CLN1)
• Batten Disease (CLN3)
• Cerebral
adrenoleukodystrophy
(CALD)
• β-Thalassemia
• Hemophilia A
• Hemophilia B
• Hereditary Angioedema
• Sickle Cell Disease
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 37
Dermatology
04.1
38 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Epidermolysis bullosa (EB) encompasses a family of rare inherited diseases
that are characterized by skin fragility and blistering in response to
mechanical trauma. The prevalence is estimated to be ~1 in 30,000–50,000
people, or 1,100–2,500 patients in the US. More than 30 clinical subtypes of EB
have been described to date, which can be distinguished based on patterns of
structural basement membrane alterations and underlying genetic mutations, 20 of
which are known. The four predominant forms of EB are summarized in Exhibit 29,
below. Clinical phenotypes are heterogeneous and range from mild to severe and
life threatening.
No cure exists for any subtype of EB. Current SOC focuses on skin protection,
constant wound care, and management of secondary comorbidities.
Elucidation of the pathogenetic mechanisms underlying each subtype has
facilitated the design of novel protein and gene therapies that aim to correct the
functional deficiencies that lead to this devastating collection of diseases.
For the purpose of this report, we will focus on novel gene therapies that are
currently in development for the treatment of recessive DEB (RDEB).
RDEB is caused by mutations in the COL7A1 gene that lead to a deficiency in
collagen VII gene and subsequent separation of the sublamina densa. This results
in painful blistering and epidermal erosion of the skin and mucous membranes.
Gene therapy approaches aim to deliver wildtype COL7A1 cDNA to the skin
to restore functional collage VII (C7) production and skin integrity. On the
following page we summarize gene therapies in Phase I/II clinical trials and beyond
for RDEB, some of which are described in more detail later in the report. A number
of additional companies are in preclinical stages of RDEB gene therapy
development, and are not covered by this report.
Gene Therapy for Epidermolysis Bullosa
Genetic Mutations and Splitting Sites Underlying EB
Source: Kiritsi D & Nyström A. F1000Res. 2018 Jul 17;7. pii: F1000 Faculty Rev-1097. Bhattacharjee O et al. Front Cell Dev Biol. 2019; 7: 68. Piper Jaffray Research.
EXHIBIT 30
Subtype Structural
Change
Gene
MutationProtein Deficiency
EB Simplex
(EBS)
Intraepidermal
split
KRT5
KRT14
Keratin 5 and keratin 14
Abnormal intermediate filaments
Junctional EB
(JEB)
Separation within
lamina lucida LAMB3
Laminen-332
Abnormal anchoring filaments
Dystrophic EB
(DEB)
Sublamina densa
separationCOL7A1
Collagen VII
Anchoring fibril deficiency
Kindler
Syndrome
Various split
levelsFERMT1
Kindlin-1
Focal adhesion/growth
deficiency
EXHIBIT 29
Main Subtypes of EB
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 39
All current clinical-stage therapies aim to deliver wildtype COL7A1 gene to patient keratinocytes in order to drive expression of normal Type VII collagen and
restore anchoring fibrils and skin function. The therapies differ in terms of vector employed (adenoviral, lentiviral, retroviral), target cell (keratinocytes, epidermal stem
cells, dermal fibroblasts) and mode of administration (skin graft vs intradermal injection). Key features of clinical stage RDEB assets are outlined below. Available clinical
data for select companies are described in Section 5 of the report.
Gene Therapies Landscape: Recessive Dystrophic Epidermolysis Bullosa (RDEB)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 31
Clinical Stage Companies Developing Gene Therapies for Recessive Dystrophic EB
Company Ticker Drug Vector (Gene) Mode of AdministrationDevelopment
StageNotes
Abeona
TherapeuticsABEO
EB-101Retrovirus
(COL7A1)
• Skin graft: autologous keratinocytes
• LZRSE-Col7A1 Engineered Autologous
Epidermal Sheets (LEAES)
Phase I/II• Initiating Phase III
mid-2019
EB-201AAV
(COL7A1)
• Skin graft: autologous keratinocytes
• AAV-mediated gene editing and delivery
approach
Preclinical• No data presented at
this time
Fibrocell Science FCSC FCX-007Lentivirus
(COL7A1)
• Intradermal injection: autologous
fibroblastsPhase I/II
• Phase III trial initiation
expected 2Q19
• If successful, BLA filing
expected 2021
Holostem Terapie
AvanzatePrivate Hologene 7
Retrovirus
(COL7A1)
• Skin graft: autologous cultured
epidermal grafts containing epidermal
stem cells
Phase I/II • Clinical trial recruiting
Krystal Biotech KRYS
KB103
(Bercolagene
Telserpavec)
HSV1
STAR-D platform
(COL7A1)
• Topical formulation: Off-the-shelf, non-
invasive modified HSV-1 therapyPhase II
• Pivotal Phase III trial to
initiate 2H19
• BLA filing expected
1H20
40 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Several lessons have been learned from initial clinical trials in both
RDEB and JEB.
The large size of the COL7A1 cDNA (8,833 nucleotide open reading frame) has
presented several challenges in terms of limiting transduction efficiency, virus
packaging, and viral titer.
Vector selection: Both lentiviral and retroviral vectors are being explored in
clinical-stage gene therapy trials for RDEB.
• Retroviral vectors still carry safety concerns relating to the risk for oncogenesis
due to random integration, especially given the tumor susceptible
microenvironment of DEB skin. However, this risk is somewhat alleviated by the
ease of monitoring the skin for, and excising, any carcinogenic effects.
Advantages include stable gene expression and low immunogenicity
• Replication-defective non-integrating HSV-1 vectors have a high payload
capacity to accommodate the large COL7A1 cDNA, efficiently penetrate skin
cells following topical application, and exhibit low immunogenicity
• Lentiviral vectors facilitate direct delivery of COL7A1 to skin cells via intradermal
injection of C7-expressing keratinocytes, which, unlike genetically-corrected
epidermal graft therapy, does not require anesthesia or hospitalization
Mode of administration. Three main modes of gene therapy delivery are currently
employed by assets in clinical trials, epidermal sheet graft, local intradermal
injection, and topical application to wounds. Transplantation of epidermal sheet
grafts requires immobilization of grafts for several days following placement, which
can be challenging depending on the wound location. Local intraepidermal injection
offers targeted delivery of gene therapy, but may be more likely to initiate
immunogenic reactions at the injection site. Topical application may be the simplest
approach, facilitating treatment by dermatologists vs specialists.
Durability: Preliminary data from small clinical trials of keratinocyte grafts suggest
that the durability of gene therapy responses in EB may be influenced by the
following factors:
• Transduction efficiency and successful delivery of stem cells to the skin
• Whether gene-corrected cells confer a selective advantage over nontransduced
resident skin cells
• Age-related decline in the regenerative potential of patient keratinocytes
• Pre-existing immunogenicity and alloreactivity to the therapeutic gene product
While initial data with keratinocyte grafts certainly suggest a clinical
advantage over the current SoC for RDEB, the relatively short half life of C7
points to an anticipated need for repeated grafts or other local treatments, a
far cry from a desired single-dose gene therapy. The need for repeated
treatments raises several concerns, such as a) repeated biopsying of patients to
collect autologous keratinocytes/skin cells for transduction, b) potentially increased
immunogenicity/development of neutralizing antibodies, c) repeated costs. Local
administration vs systemic correction of C7 also clearly lacks the potential to ‘cure’
DEB, as the approach is limited to treating existing wounds rather than preventing
their occurrence in the first place.
The factors described above provide a number of considerations for gene therapy
product design, mode of delivery, and potential patient inclusion criteria for
clinical trials. Specific trial information and data from select companies will be
discussed in the following section of this report.
Specific Considerations for RDEB Gene Therapy
Source: Marinkovich MP & Tang JY. J Invest Dermatol. 2019;139:1221e1226. Company Reports. Piper Jaffray Research.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 41
Hematology
04.2
42 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene therapy for the correction of inherited blood disorders. Similar to other
indications, inherited hematologic disorders or those blood disorders caused by a
single gene variant are the best candidates for treatment. Inherited genetic
alterations are responsible for a range of devastating hematological diseases
including β-thalassemia, sickle cell disease, and other hemoglobinopathies, as well
as bleeding disorders such as hemophilia. Correction of the causal single gene
defect could potentially provide a one-time, curative treatment approach rather than
the current lifelong, multidisciplinary disease management and treatment SOC.
Hemophilia is a group of inherited, genetic disorders that impairs the body’s
ability to clot blood. There are two forms of hemophilia that are caused by
mutations in genes that encode Factor VIII (F8, Hem A) and Factor IX (F9, Hem B),
with different mutations variably affecting levels of factor activity, blood clotting
ability, and severity of disease. While injuries/lacerations may cause potentially
life-threatening bleeding, patients may also experience spontaneous bleeds into
joints and other tissues, causing significant tissue damage. There is no cure for
hemophilia, but current treatment significantly improves patient outcomes, quality of
life (QoL), and life expectancy.
Hemoglobinopathies are a group of blood disorders that impair production of
hemoglobin by red blood cells (RBCs). These disorders fall into two main
categories – thalassemia syndromes and structural hemoglobin variants. Clinical
manifestations of hemoglobinopathies are highly variable and range from mild
hypochromic anemia to moderate hematological disease to severe, lifelong,
transfusion-dependent anemia with multiorgan involvement. In this section, we
highlight two hemoglobinopathies, β-thalassemia and sickle cell disease, for which
gene therapy development is currently ongoing.
Briefly, β-thalassemias are autosomal recessive diseases caused by the
insufficient production of β-globin chains, a key protein subunit of
hemoglobin. Generally, mutations are grouped as those that cause zero functional
β-globin production (β0) or reduced functional β-globin (β+). For severely affected
patients, the disease state requires chronic blood transfusions with healthy RBCs
every 3–5 weeks to maintain hemoglobin levels and control disease. However,
chronic use has the potential to induce iron overload, and results in significantly
increased mortality risk due to heart and liver toxicity.
Sickle cell disease is a life-threatening inherited hematological disorder
characterized by abnormally shaped RBCs which disrupt blood flow in small
blood vessels. A single point mutation in the beta-chain of hemoglobin causes
abnormal sickle hemoglobin (HbS) formation, leading to lower affinity for oxygen.
Over time repeated RBC sickling and ongoing hemolytic anemia result in organ
damage and substantial morbidity and mortality. Treatment is primarily geared
towards reducing symptoms and is not universally effective.
Thus, for both β-thalassemia and sickle cell disease, single gene replacement of
the non-functional or dysfunctional β-globin gene presents a compelling option to
life-long treatment.
Gene Therapy for Hematologic Disorders
Source: QURE R&D Day 2018. Company Reports. Piper Jaffray Research.
EXHIBIT 32
The Coagulation Cascade
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 43
Selected Gene Therapy-amenable Hematologic Disorders
Source: Company Reports. NORD. Piper Jaffray Research.
EXHIBIT 33
Rationale for Targeting Select Hematological Disorders With Gene Therapy: Blood Clotting Disorders
Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach
Hemophilia A ~15,000
• Bleeding disorder caused by
insufficient levels of the blood clotting
protein, factor VIII (F8)
• ~70% of cases are inherited, X-linked
recessive; ~30% occur spontaneously
• Patients are classified as mild
(6%–30% of normal F8 levels; 30% of
patients), moderate (1%–5% of normal
F8; 20% of patients), and severe
(<1% of normal F8; 50% of patients)
• Age of diagnosis depends on disease
severity – mild: 36 months, moderate:
8 months, severe: 1 month
• Clotting factor replacement treatment
is the current SOC for patients, but
treatment must be administered for
the life of the patient
• Maintaining a level of no or very low
bleeding rates is critically important,
but recurring bleeds, including joint
bleeds, do occur which can result in
debilitating disease and chronic pain
• Gene therapy reduces treatment
burden and improves QoL with a
one-time treatment
• Consistent levels of F8 provide better
protection from bleeding episodes due
to spontaneous or traumatic events
• Though F8 gene is large with over
200 disease alleles described in
HemA, disorder can be treated by
replacing the non-functional/
dysfunctional gene with a modified
version of F8 (B-domain deleted)
Hemophilia B ~6,000
• Bleeding disorder caused by defective
or insufficient levels of the blood
clotting protein, factor IX (F9)
• 70% inherited x-linked recessive;
30% spontaneous
• Classified mild/moderate/severe
(see above)
• Age of diagnosis depends on disease
severity – mild: 36 months, moderate:
8 months, severe: 1 month
• Gene therapy reduces treatment
burden and improves QoL with a
one-time treatment
• Consistent levels of F9 provide better
protection from bleeding episodes due
to spontaneous or traumatic events
• Disorder can be treated by replacing
the non-functional/dysfunctional gene
44 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Selected Gene Therapy-amenable Hematologic Disorders
Source: Company Reports. NORD. Piper Jaffray Research.
EXHIBIT 34
Rationale for Targeting Select Hematological Disorders With Gene Therapy: Hemoglobinopathies + Others
Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach
β-Thalassemia ~5,000
• Blood disorder that reduces the
production of hemoglobin, the iron-
containing protein in RBCs that carries
oxygen to cells throughout the body
• Caused by mutations in the HBB
gene, which encodes beta-globin, a
subunit of hemoglobin
• 60%–80% of patients require
regular red-cell transfusions and
iron chelation for proper treatment of
the disease (transfusions Q3–5 wks)
• Chronic transfusions may lead to
iron overload, significantly increasing
mortality risk due to heart and
liver toxicity
• A single treatment to genetically
modify a patient’s hematopoietic stem
cells to replace the dysfunctional
HBB gene
Sickle Cell Disease ~50,000
• An inherited disease caused by
defects in the beta-globin gene (HBB)
• ~65k patients with HbSS genotype
• Mutated hemoglobin polymerizes and
causes RBCs to form a “sickle” shape
which causes RBC aggregation –
restricts blood flow to organs, causes
pain, cell death, and organ damage
• Hydroxyurea is the current SOC
(promotes expression of normally-
repressed fetal hemoglobin), but
causes severe side effects – reduced
white blood cell and platelet counts
• Bone marrow transplant also an
option, but less than 10% of patients
are eligible due to donor
matching/availability
• A single treatment to genetically
modify a patient’s hematopoietic stem
cells to replace the dysfunctional
HBB gene
Hereditary
Angioedema~7,000
• Several types of HAE - Types I and II
caused by genetic mutations in C1NH
(aka SERPING1) which encodes C1
esterase inhibitor (C1-INH), a protein
that regulates kallikrein
• Lack of kallikrein regulation puts
patients at risk of uncontrolled
swelling attacks that can be life
threatening
• Inheritance of Types I and II are
autosomal dominant
• Age of onset varies, but most people
have first attack in childhood or
adolescence; frequency of attacks
increases after puberty
• Current SOC involves frequent
infusions or injections of plasma-
derived C1-INH to prevent swelling
• Response to treatment varies patient
to patient; long-term patient outlook
varies depending on the frequency
and location of attacks
• Replacement of the C1-INH gene
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 45
Early setbacks, but the science behind gene therapy has rapidly evolved.
As we've gained greater knowledge and a better understanding of viruses and their
underlying biology, researchers have continued to unlock ways to design safer and
more effective gene therapies. It wasn't that long ago that initial challenges were
encountered for Hem B AAV gene therapies, which drove immunological
responses, resulting in the clearance of functional protein product. Ex vivo gene
therapy for hemoglobinopathies has also met with its share of setbacks, with early
challenges of transplant-related toxicities and leukemia induced by viral vector
integration into the host genome. However, the field has made giant strides
forward, even in just the past few years, as we've gained more clinical experience,
created better recombinant viruses, and improved the design of gene
therapy cassettes.
Considerations for hemophilia treatments – durability is key. Though SOC for
patients with hemophilia has its limitations, in relation to many other diseases,
hemophilia patients have access to reasonably effective treatment options. In this
regard, while gene therapy is potentially transformative for these patients, products
need to demonstrate not only efficacy and safety, but also long-term duration of
expression to help support the price tag that comes along with these treatments.
Currently, most competitors in clinical development are taking similar approaches
for the treatment of Hem A and Hem B – targeting the liver with a recombinant AAV
gene therapy (eg, AAV5), and using a modified F8 (B-domain deleted) or
F9 (gain of function Padua mutation) gene to replace the underlying dysfunctional
protein. The design and manufacturing of these vectors is important for the safety,
efficacy, and durability of treatment, and while safety and efficacy have both been
demonstrated in clinical trials thus far, durability remains an unanswered question.
In the end, the gene therapy treatment that produces durable responses –
sustained expression of clotting factor, no or very few spontaneous bleeds, and
avoidance of arthropathy – will be crowned the winner.
Considerations for the treatment of hemoglobinopathies – is ex vivo gene
replacement the best strategy? Transplantation of autologous, genetically
corrected hematopoietic stem cells (HSCs) is one approach being developed by
multiple companies for the treatment of β-thalassemia and sickle cell disease.
Thus far, the strategy has been safe and effective, but key questions remain as to
the longevity of treatment as well as the cost and complexity of both the lentiviral
vector and ex vivo manufacturing process – the latter being a key concern as
patients affected by these disorders skew towards lower socioeconomic conditions.
However, companies continue improving this approach with innovation ongoing in
HSC procurement, transduction, and transplantation efficiency.
As an offset, we note that additional treatment strategies are currently being
developed for β-thalassemia and sickle cell disease including AAV delivery of
CRISPR/Cas9 to drive endogenous fetal hemoglobin production, as well as oral
compounds with disease modifying capabilities (eg, GBT’s voxelotor) that may
prove to be more durable or convenient approaches to disease management.
That said, it’s still too early in the game to know for sure who the winner will
be here.
Gene Therapy for Hematologic Disorders: Special Considerations for Select Indications
Source: Company Reports. Piper Jaffray Research.
46 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Hematological Disorders – Hemophilia A
Source: Company Reports. GlobalData. Piper Jaffray Research.
EXHIBIT 35
Companies Developing Gene Therapies for Hemophilia A
Company Ticker Disorder Asset Vector Target Gene Stage of Development
BioMarin
PharmaceuticalBMRN Hem A
Valoctocogene
roxaparvovec
(valrox, BMN 270)
rAAV5 F8 (B-domain deleted) Phase III
Spark
TherapeuticsONCE Hem A SPK-8011 Novel rAAV F8 (B-domain deleted) Phase III
Bayer/
Ultragenyx
BAYRY/
RAREHem A DTX-201 rAAV F8 Phase II
Sangamo
TherapeuticsSGMO Hem A SB-525 rAAV6 F8 (B-domain deleted) Phase I/II
Takeda
PharmaceuticalTAK Hem A TAK-754 rAAV F8 Phase I
UniQure QURE Hem A AMT-180 rAAV5FIX-FIAV
(activates FX in absence of FVIII)Preclinical
Expression
TherapeuticsPrivate Hem A Undisclosed Lentivirus F8 Preclinical
Expression
TherapeuticsPrivate Hem A Undisclosed rAAV F8 Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 47
Gene Therapies Landscape: Hematological Disorders – Hemophilia B
Source: Company Reports. GlobalData. Piper Jaffray Research.
EXHIBIT 36
Companies Developing Gene Therapies for Hemophilia B
Company Ticker Disorder Asset Vector Target Gene Stage of Development
Spark
TherapeuticsONCE Hem B
Fidanacogene
elaparvovec
(SPK-9001)
AAV F9 (Padua variant) Phase III
UniQure QURE Hem B AMT-061 AAV5 F9 (Padua variant) Phase III
Freeline
TherapeuticsPrivate Hem B FLT-180a AAVS3 F9 (Padua variant) Phase I/II
Expression
TherapeuticsPrivate Hem B Undisclosed AAV F9 Preclinical
Takeda
PharmaceuticalTAK Hem B SHP648 Undisclosed F9 Preclinical
Logicbio
TherapeuticsLOGC Hem B LB-101 AAV F9 Preclinical/Discovery
Catalyst
BiosciencesCBIO Hem B CB 2679d-GT AAV8 F9 (patented sequence) Preclinical
48 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Hematological Disorders – β-Thalassemia, Sickle Cell, Hereditary Angioedema
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 37
Companies Developing Gene Therapies for Hematological Disorders
Company Ticker Disorder Asset Vector Target Gene Stage of Development
bluebird bio BLUE β-thalassemia LentiGlobin LentivirusHBB
(Beta-globin, T87Q variant)Phase III
Orchard
TherapeuticsORTX β-thalassemia OTL-300 Lentivirus
HBB
(Beta-globin)Phase I/II
Aruvant
SciencesPrivate β-thalassemia ARU-1801 Lentivirus Modified fetal hemoglobin Phase I/II
Errant Gene
TherapeuticsPrivate β-thalassemia Thalagen Lentivirus
HBB
(Beta-globin)Preclinical
bluebird bio BLUE Sickle cell disease LentiGlobin LentivirusHBB
(Beta-globin)Phase II
Aruvant
SciencesPrivate Sickle cell disease ARU-1801 Lentivirus Modified fetal hemoglobin Preclinical
CSL Behring CSL:AUΒ-thalassemia,
sickle cell diseaseCAL-H Lentivirus Gamma-globin Preclinical
Adverum
BiotechnologiesADVM
Hereditary
angioedemaADVM-053 AAVrh.10 C1INH Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 49
Inborn errors of metabolism• Lysosomal storage disorders
• Neurological disorders
• Other
04.3
50 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Lysosomal storage disorders: A family of ~70 genetically distinct diseases
with a monogenic basis. LSDs are rare, inherited metabolic disorders primarily
characterized by dysfunction of lysosomes – membrane-enclosed organelles filled
with enzymes (>60) that function to break down different types of biological
products (eg, proteins, lipids, carbohydrates) within cells. When one of these
enzymes is dysfunctional or non-functional, progressive accumulation of biological
products occurs, driving cellular dysfunction, oxidative stress, inflammation, and
impaired organ function in tissues throughout the body, ultimately resulting in
death. While each LSD is individually rare, collectively these disorders are
common, with a frequency of ~1 in 7,000 births.
For a small number of LSDs, enzyme replacement therapy (ERT) provides a
disease modifying option, but the vast majority of disorders lack effective
therapies. ERTs are recombinant enzymes (proteins) that transiently replace the
missing or defective enzyme that causes the disease. The first ERT was approved
in 1991 for the treatment of Gaucher disease, and while additional ERTs have been
approved since that time, approved treatments have only been developed for eight
LSDs: Fabry disease, Gaucher disease, lysosomal acid lipase deficiency, MPS I,
MPS II, MPS IVA, MPS VI, and Pompe disease.
While ERTs reduce the severity of disease for many patients, recombinant
enzymes (generally) degrade rapidly and require frequent dosing (Q1W,
Q2W), which leads to fluctuations in enzyme levels over time, allowing the disease
to progress. In addition, ERTs are unable to cross the blood brain barrier (BBB),
presenting a challenge for LSDs that primarily affect the CNS, and though some
disorders can be treated by administering ERTs intra-cerebroventricularly or
intrathecally, a number of complications may arise. Since LSDs are monogenic
(single gene) disorders, and the enzymes are not subject to complex regulatory
mechanisms, these disorders are excellent candidates for treatment with
gene therapy.
There’s no one and done way to treat all LSDs; the approach to gene delivery
depends on the disorder. Though LSDs share a common feature (enzyme
dysfunction in lysosomes), the approach to delivering the functional gene of interest
depends on the underlying disease (i.e., affected tissues, need for episomal vs
integrated DNA). With >65% of LSDs having a neurological component, accounting
for the need to deliver genetic material to the CNS is one of the most important
considerations. Currently, there are three main approaches used in clinical
development for the treatment of LSDs using gene therapy: (1) systemically
delivered vectors, (2) direct delivery of vectors to the CNS, and (3) ex vivo gene
therapy. We describe these approaches in more detail on the following page.
Gene Therapy for Lysosomal Storage Disorders and Specific Considerations (Page 1 of 2)
Prevalence of Lysosomal Storage Disorders
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 38
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 51
Systemic administration using AAVs. This approach involves the direct delivery
of a gene into an organ so that the gene product will not only correct the locally
transduced cells, but will also be secreted at high levels and subsequently
recaptured by other cell types via the mannose-6-phosphate receptor (though we
do note that M6P receptor expression varies between tissues types, thus not all
tissues may be treated equally). The secreted enzyme cannot cross the BBB,
therefore the benefits of this approach are generally limited to the peripheral
organs. However, certain AAV serotypes (eg, AAV9) do penetrate the BBB and can
infect cells in both the CNS and in other tissues throughout the body when given
systemically. Thus, choosing the proper capsid allows for a potentially “one and
done” treatment strategy when administered via IV.
Direct CNS administration of AAVs. Alternatively, AAVs can be directly injected
into the CNS utilizing different types of delivery methods (eg, intra-parenchymal,
intrathecal). This method bypasses the viscera and generally keeps viral
transduction and enzyme expression restricted to the brain and spinal cord.
AAV serotype remains a key factor to ensure the proper transduction of cells
(i.e., neurons, oligodendrocytes, and/or astrocytes).
Additional ways to deliver functional enzyme to the CNS: Ex vivo lentiviral
treatment of hematopoietic stem cells. For LSDs affecting the CNS, modifying
hematopoietic stem cells (HSCs) also presents a viable option for gene therapy
treatment. In this approach, autologous CD34+ HSCs are isolated from a patient
and modified outside of the body (ex vivo) with a viral vector. Because these stem
cells will regraft in the bone marrow of the patient and be maintained long-term,
utilizing a virus that integrates into the host genome is the most effective approach
with this strategy. Thus, autologous CD34+ HSCs are transduced with a lentivirus,
and cells with a successfully integrated copy of the functional gene are infused
back into the patient. Following this, partially differentiated hematopoietic cells can
produce other immune cells within the body, but can also cross the BBB where
they subsequently differentiate into microglia. These resident CNS immune cells
then produce functional enzyme within in the brain.
Gene Therapy for Lysosomal Storage Disorders and Specific Considerations (Page 2 of 2)
Source: Company Reports. Piper Jaffray Research.
52 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Selected Gene Therapy-amenable Lysosomal Storage Disorders
Source: Company Reports. NORD. NIH Rare Diseases. Piper Jaffray Research.
EXHIBIT 39
Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy
Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach
Fabry Disease ~4,000-5,000
• Caused by mutations in α-
galactosidase A gene (AGA)
• Enzyme deficiency causes build up of
glycolipids in the body that particularly
affect small blood vessels, heart,
and kidneys
• X-linked dominant inheritance
• Age of onset varies by disease type
(Type 1: Classic; Type 2: Later Onset)
• Symptoms lead to renal failure,
cardiac disease, early death
• No cure or standard treatment for
patients; because disease causes
multi-organ dysfunction, patients need
individually tailored comprehensive,
multi-disciplinary treatment
• Enzyme replacement therapy (ERT) is
a cornerstone of treatment and must
be initiated early for best results
• Single gene replacement of AGA via
lentiviral or AAV gene delivery
MPS IIIA ~600
• Caused by mutation in SGSH
• Autosomal recessive inheritance
• Signs and symptoms usually begin in
early childhood (1-4 years) and
include severe neurological symptoms
such as progressive dementia,
aggressive behavior, hyperactivity,
seizures, deafness, and loss of vision
• No cure or standard treatment for
patients; medications are used to
relieve symptoms (eg, anticonvulsants
for seizures) and improve QoL
• Single gene replacement of SGSH via
lentiviral or AAV gene delivery
MPS IIIB ~400
• Caused by mutation in NAGLU
• Autosomal recessive inheritance
• Signs and symptoms the same as
MPS IIIA, but symptom onset slightly
less severe
• No cure or SoCs; medications are
used to relieve symptoms
(eg, anticonvulsants for seizures)
and improve QoL
• Single gene replacement of NAGLU
via lentiviral or AAV gene delivery
Pompe Disease ~3,000
• Caused by mutations in GAA
• Autosomal recessive inheritance
• Glycogen accumulation affects
muscles causing weakness and
diminished muscle tone; cardiomegaly
also common
• Symptom onset: infantile (after few
months of birth), non-classic infantile
(~1 year of age), late-onset (teenage
years or adulthood)
• Enzyme replacement therapy (ERT)
common, but therapy does not
produce stable GAA levels
• Relative instability of GAA requires
frequent dosing to maintain enzyme
levels
• Patients typically develop an immune
response to ERT
• Single gene replacement of GAA via
lentiviral or AAV gene delivery
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 53
Selected Gene Therapy-amenable Lysosomal Storage Disorders
Source: Company Reports. Mytonic Dystrophy Foundation. NORD. Piper Jaffray Research.
EXHIBIT 40
Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy
Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach
Danon Disease
(GSD IIb)
Unknown
(Est. range
from 1,000-
15,000)
• Caused by mutations in LAMP2, with
>160 different mutations identified
• X-linked dominant inheritance
• Key features are diseased heart
muscle (cardiomyopathy), weakness
of body muscles (skeletal myopathy),
and intellectual disability
• Symptoms of disease vary from
person to person and depend on
gender; boys tend to be more severely
affected than girls
• No curative treatments available
• No symptomatic SoC – treatments
need to be tailored to each individual
and their symptoms
• Current disease management requires
multi-disciplinary team of physicians
(cardiologist, neurologist,
ophthalmologist, geneticist, etc)
• In patients that progress rapidly,
heart transplantation may be need
almost immediately
• Gene replacement of LAMP2 via
AAV gene delivery
GM1
Gangliosidosis<500
• Caused by mutations in GLB1 gene
• Divided into three forms based on
disease onset: type 1 (infantile), type
2 (juvenile), type 3 (adult/chronic)
• Autosomal recessive inheritance
• Several tissue types are affected,
leading to developmental defects,
enlarged liver and spleen, skeletal
abnormalities, seizures, vision loss
• No curative or disease modifying
treatments available
• Symptomatic treatment for some
neurologic signs are available
(eg, anticonvulsants for seizures)
• Limited success with cord-blood
HSC transplantation in
presymptomatic patients
• Gene replacement of GLB1 via
AAV gene delivery
GM2
Gangliosidosis<500
• Caused by mutations in HEXA
(Tay-Sachs) or HEXB (Sandhoff
disease) that encode subunits of
beta-hexosaminidase
• Autosomal recessive genetic disorder
• Symptoms include motor delays,
mental deterioration, motor weakness,
heart murmurs, seizures, blindness,
splenomegaly
• Divided by age of disease onset:
infantile/juvenile (3-6 months of age)
and adult
• No curative or disease modifying
treatments available – only
symptomatic therapies
• Death from respiratory infections
usually occurs by age three for the
infantile form
• Symptomatic treatment for some
neurologic signs are available
(eg, anticonvulsants for seizures)
• Gene replacement of both HEXA and
HEXB via AAV gene delivery
54 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Lysosomal Storage Disorders
Source: Company Reports. GlobalData. Piper Jaffray Research.
EXHIBIT 41
Companies Developing Gene Therapies for Fabry Disease
Company Ticker Disorder Asset Vector Target Gene Stage of Development
AVROBIO AVRO Fabry Disease AVR-RD-01 LentivirusAGA
(alpha-galactosidase A)Phase I/II
Abeona
TherapeuticsABEO Fabry Disease Undisclosed AAV
AGA
(alpha-galactosidase A)Preclinical
Amicus
TherapeuticsFOLD Fabry Disease Undisclosed AAV
AGA
(alpha-galactosidase A)Preclinical
Freeline
TherapeuticsPrivate Fabry Disease FLT190 AAV
AGA
(alpha-galactosidase A)Preclinical
Sangamo
TherapeuticsSGMO Fabry Disease ST-920 AAV6
AGA
(alpha-galactosidase A)Preclinical
uniQure QURE Fabry Disease AMT-190 AAVAGA
(alpha-galactosidase A)Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 55
Gene Therapies Landscape: Lysosomal Storage Disorders
Source: Company Reports. GlobalData. Piper Jaffray Research.
EXHIBIT 42
Companies Developing Gene Therapies for MPS IIIA and MPS IIIB
Company Ticker Disorder Asset Vector Target Gene Stage of Development
Lysogene/
Sarepta
Therapeutics
LYS/
SRPTMPS IIIA LYS-SAF302 AAVrh10 SGSH Phase III
Esteve
PharmaceuticalsPrivate MPS IIIA EGT-101 AAV9 SGSH Phase II
Abeona
TherapeuticsABEO MPS IIIA ABO-102 AAV9 SGSH Phase I/II
Orchard
TherapeuticsORTX MPS IIIA OTL-201 Lentivirus SGSH Preclinical
Abeona
TherapeuticsABEO MPS IIIB ABO-101 AAV9 NAGLU Phase I/II
Orchard
TherapeuticsORTX MPS IIIB OTL-202 Lentivirus NAGLU Preclinical
Esteve
PharmaceuticalsPrivate MPS IIIB EGT-201 AAV9 NAGLU Preclinical
56 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Lysosomal Storage Disorders
Source: Company Reports. GlobalData. Piper Jaffray Research.
EXHIBIT 43
Companies Developing Gene Therapies for Pompe Disease
Company Ticker Disorder Asset Vector Target Gene Stage of Development
Actus
TherapeuticsPrivate Pompe Disease ACTUS-101 AAV2/8 GAA Phase II
Audentes
TherapeuticsBOLD Pompe Disease AT845 AAV8 GAA Preclinical
Spark
TherapeuticsONCE Pompe Disease
SPK-3006
(AAV-sec-GAA)AAV GAA Preclinical
AVROBIO AVRO Pompe Disease AVR-RD-03 Lentivirus GAA Preclinical
Abeona
TherapeuticsABEO Pompe Disease Undisclosed AAV GAA Preclinical
Amicus
TherapeuticsFOLD Pompe Disease Undisclosed AAV GAA Preclinical
Sarepta
TherapeuticsSRPT Pompe Disease Undisclosed AAV GAA Discovery
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 57
Gene Therapies Landscape: Lysosomal Storage Disorders
Source: Company Reports. GlobalData. Piper Jaffray Research.
EXHIBIT 44
Companies Developing Gene Therapies for Danon Disease and GM1/GM2 Gangliosidosis
Company Ticker Disorder Asset Vector Target Gene Stage of Development
Rocket Pharma RCKTDanon Disease
(GSDIIIb)RP-A501 AAV9 LAMP2 Phase I
Axovant
SciencesPrivate
GM1
GangliosidosisAXO-AAV-GM1 AAV9
GLB1
(B-galactosidase 1)Phase I/II
Lysogene LYSGM1
GangliosidosisLYS-GM101 AAVrh10
GLB1
(B-galactosidase 1)Preclinical
Passage Bio PrivateGM1
GangliosidosisAXO-AAV-GM1 AAV
GLB1
(B-galactosidase 1)Preclinical
Axovant
SciencesPrivate
GM2
GangliosidosisAXO-AAV-GM2 AAVrh8
HEXA
(Β-hexosaminidase A)Phase I/II
58 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene replacement tends to be the modality of choice for in-born metabolic
errors with neurological manifestations. In-born metabolic errors impact a wide
range of physiological systems, including the CNS. In many of these conditions,
neurological function is disrupted when genetic mutations in enzymes lead to
irregular processing of biological compounds. Since these mutations cause loss of
function in enzymes, gene replacement strategies are optimal for functional
restoration. However, certain conditions already have enzyme replacement
therapies that may be effective for disease treatment, so developing gene therapies
for these disorders would need to be justified in terms of efficacy and cost-savings
to be a commercially viable option.
With some exceptions, considerations for gene therapy for in-born metabolic
conditions that affect the CNS are similar to other neurological conditions.
Various factors involved in gene therapies for neurological conditions have been
discussed elsewhere in this report; metabolic conditions that affect the CNS must
also consider the same aspects as these neurological conditions, such as the site
of administration. However, a few factors are not as challenging to address, making
gene therapy development for in-born metabolic errors with neurological
manifestations less complicated. For example, many of the mutated enzymes and
proteins involved in these conditions are soluble and capable of being secreted and
taken up by cells. This characteristic lowers the viral load required from gene
therapy since fewer cells need to be transduced for a system-wide impact. Intrinsic
obstacles of gene therapies, like the risk of immune response, still exist but are not
as high due to the lower viral load.
Treatments must be designed for pediatric patients with these types of
disorders. Onset of disorders of metabolic errors typically occurs at birth or during
childhood. In metabolic disorders with neurological manifestations, this generally
leads to progressive, systemic loss of normal body function during the childhood
and adolescent years. Many of these disorders eventually lead to full dependence
on caregivers and eventual death due to respiratory or cardiac issues. With the
early age of onset and rapid progression of diseases, gene therapies within this
sector must be designed to be administered to a young population.
Many of these disease are ultra-rare, leading to limited interest but also
additional opportunities. While the ultra-rare nature of some these conditions
keeps companies from developing gene therapies for them, the high unmet need
also makes them ideal candidates to provide proof-of-concept of their potential in
treating some of the most devastating diseases. For example, bluebird bio is
developing its Lenti-D therapy for the ultra-orphan indication, cerebral
adrenoleukodystrophy (CALD), which to date has demonstrated meaningful benefit
to patients and highlights the power of their HSC technology platform (see below).
Gene Therapy for In-born Metabolic Errors (Neurological Disorders) & Related Considerations
bluebird bio’s approach to gene therapy for CALD
Source: bluebird bio Company Reports. Piper Jaffray Research.
EXHIBIT 45
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 59
Selected Gene Therapy-amenable In-born Metabolic Errors (Neurological Disorders)
Source: NINDS. GHR. Company Reports. Piper Jaffray Research.
EXHIBIT 46
Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy (1 of 2)
DiseaseUS
PrevalenceDisease Background Unmet Need
Potential Gene Therapy Rationale &
Approach
Batten Disease
(CLN1 - infantile)~3,000
• Mutation in CLN1 gene leads to build up of
lipids and proteins
• Onset by 1 year, some at 5 or 6 years
• Symptoms include loss of motor function,
seizures, blindness
• No cure, antiepileptics for seizures
• Feeding tube after 3–4 years
• Death by early-to-mid childhood
(except for juvenile form)
• Gene replacement of CLN1 gene
(PPT1 protein) via gene therapy
Batten Disease
(CLN3 - juvenile)~5,000
• Mutation in CLN3 gene leads to build up of
lipids and proteins
• Onset at 4–7 years
• Symptoms include blindness, learning and
behavioral problems, dementia, seizures,
loss of balance, and stiffness
• No cure, antiepileptics for seizures
• Caregiver-dependent by teenage
years
• Death by age 15–30 years
• Gene replacement of CLN3 gene
(batennin protein) via gene therapy
Cerebral
Adrenoleuko-
dystrophy
(CALD)
<500
(worldwide)
• X-linked recessive condition caused by
mutation in the ABCD1 gene that leads to
rapid neurological function loss and death
• Onset in early childhood
• Symptoms include hormonal deficiencies
and downstream affects like abnormal
blood pressure, heart rate, and sexual
development
• No cure, QoL treatments
• Six major functional disabilities:
communication loss, cortical
blindness, total incontinence,
wheelchair dependence, and
complete loss of voluntary movement
• Death within 1–10 years after onset
• Gene replacement of ABCD1 gene
(ABCD1 protein) via gene therapy
60 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Selected Gene Therapy-amenable In-born Metabolic Errors (Neurological Disorders)
Source: Company Reports. Piper Jaffray Research.
Source: Company Reports. Myotonic Dystrophy Foundation, NORD. Piper Jaffray Research.
Companies Developing Gene Therapies for Inborn Errors of Metabolism (Neurological)
Company Ticker Disorder Asset Vector Target Gene Stage of Development
Abeona
TherapeuticsABEO Batten Disease ABO-201 AAV9 CLN3 Phase I/II
Abeona
TherapeuticsABEO Batten Disease ABO-202 AAV9 CLN1 Phase I/II
Amicus
Therapeutics FOLD Batten Disease AAV-CLN6 AAV9 CLN6 Phase I/II
Amicus
Therapeutics FOLD Batten Disease AAV-CLN8 AAV9 CLN8 Phase I/II
Amicus
Therapeutics FOLD Batten Disease AAV-CLN3 AAV CLN3 Phase I/II
Amicus
Therapeutics FOLD Batten Disease AAV-CLN1 AAV9 CLN1 Preclinical
bluebird bio BLUE
Cerebral
Adrenoleukodystrophy
(CALD)
ALD-102
ALD-104Lenti-D ABCD1 Phase II/III
EXHIBIT 47
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 61
Other Selected Gene Therapy-Amenable Inborn Errors of Metabolism
Source: Company Reports. NORD. Piper Jaffray Research.
EXHIBIT 48
Rationale for Targeting Other Select Metabolic Disorders With Gene Therapy
Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach
Alpha-1 Antitrypsin
(A1AT) Deficiency~100,000
• Autosomal codominant disorder
caused by mutations in the
SERPINA1 gene that leads to
dysfunctional alpha-1 antitrypsin
• Onset of lung disease at 20–50 years;
liver disease occurs in infants
• Symptoms: Shortness of breath,
fatigue, emphysema, jaundice,
cirrhosis
• Emphysema is managed with
bronchodilators, steroids, or oxygen,
but QoL is greatly impaired
• Treatment for liver disease is limited
due to lack of approved therapies
• A1AT patients may have normal life
expectancy. However, smoking may
exacerbate lung symptoms and result
in faster decline
• AAV delivery of functional A1AT gene
to liver cells aims to replace
dysfunctional neutrophil elastase
activity in the lungs. The goal of this
treatment is to protect the lung against
proteolytic damage and restore lung
health in A1AT patients
Congenital Adrenal
Hyperplasia (CAH)~30,000
• Autosomal recessive disorder caused
by mutations in the CYP21 gene,
encoding 21-hydroxylase (21OH)
• Onset typically during adolescence
• Symptoms: Adrenal crisis due to
cortisol deficiency, salt-wasting
disease due to aldosterone
imbalance, excess testosterone leads
to virilization, infertility
• Steroid supplementation is the SoC
to improve basal cortisol and
suppress ACTH
• Standard steroids offer a marginal
benefit to patients and carry serious
toxicities related to long-term use
• Patient mortality is three times higher
than healthy peers
• AAV delivery of the CYP21A2 gene
to adrenal cortex cells restores
homeostatic control of adrenal
hormones
• 21OH increases aldosterone and
cortisol production, while reducing
testosterone, thereby mitigatin the risk
of adrenal crisis
Ornithine
Transcarbamylase
(OTC) Deficiency
~2,500
• X-linked recessive disorder caused
by mutation in the OTC gene, which
encodes a liver enzyme responsible
for detoxification of ammonia
• Onset occurs during childhood
• Symptoms: excessive levels of
ammonia in their blood can potentially
result in neurological deficits
• Arginine-rich, protein-restricted diets
are used to manage OTC disease
• Ammonia concentrations may still
persist despite dietary changes
• Patients with <2% of normal OTC
activity die within one week;
14% activity leads to normal
development with diet restriction
• AAV delivery of the OTC gene with
the goal of reducing the occurrence
of cognitive and neurological
complications associated with
ammonia buildup due to OTC
deficiency
Phenylketonuria
(PKU)~15,000
• Autosomal recessive disorder caused
by mutations in the PAH gene
encoding phenylalanine hydroxylase
• Onset occurs within months of life
• Symptoms: Drowsiness, listlessness,
and difficulties feeding. Severe infants
develop intellectual disability,
seizures, and psychiatric disorders
• Brain phenylalanine levels mainly
controlled by diet; may also be treated
with Kuvan or Palynziq (BioMarin,
covered by Chris Raymond)
• Treatment must be started at a very
young age (under 3 months)
• Life expectancy may be normal if diet
is maintained indefinitely
• Hematopoietic stem cell-derived AAV
delivery of a functional copy of the
PAH gene to liver cells aims to
restore the normal phenylalanine
metabolic pathway
62 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Other Selected Gene Therapy-Amenable Inborn Errors of Metabolism
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 49
Rationale for Targeting Other Select Metabolic Disorders With Gene Therapy
Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach
Wilson’s Disease ~10,000
• Autosomal recessive disorder
caused by mutations in the ATP7B
gene encoding a copper-transporting
ATPase
• Onset as early as 2 years old
• Symptoms: Toxic accumulation of
copper in the liver and CNS,
resulting in chronic cirrhosis, tremors,
and migraines
• Decoppering is achieved with copper
chelators (D-penicillamine), and a low
copper diet, maintained indefinitely
• Up to 50% non-compliance to
treatment and up to 24% of patients
with neurological or liver disease
progression despite treatment
• Without treatment, life expectancy is
estimated to be 40 years
• AAV delivery of APT7B gene to the
liver to restore physiological copper
metabolism, optimize adherence to
treatment, and prevent disease
complications such as neurological
deterioration, psychiatric
manifestations and progressive
liver diseases
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 63
Gene Therapies Landscape: Other Inborn Errors of Metabolism
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 50
Select Companies Developing Gene Therapies for Other Inborn Errors of Metabolism
Company Ticker Disorder Asset Vector Target Gene Stage of Development
BridgeBio
(Adrenas)BBIO
Congenital Adrenal
Hyperplasia (CAH)BBP-631 AAV5 CYP21A2 (21OH) Preclinical
Ultragenyx RARE
Ornithine
Transcarbamylase
(OTC) Deficiency
DTX301 AAV8 OTC Phase I
Homology
MedicinesFIXX Phenylketonuria (PKU) HMI-102 AAVHSC PAH Phase I/II
BioMarin BMRN Phenylketonuria (PKU) BMN 307 AAV5 PAH Preclinical
Ultragenyx RARE Phenylketonuria (PKU) UX-501 AAV8 PAH Preclinical
Pfizer (Vivet) PFE Wilson’s Disease VTX-801Proprietary liver-trophic
AAVAPT7B Phase I/II
Ultragenyx RARE Wilson disease UX701 AAV APT7B Phase I/II
64 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Musculoskeletal
04.4
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 65
Musculoskeletal diseases are uniquely suited for gene therapies. Genetic
musculoskeletal diseases are of particular interest as targets for gene therapies
due to a multitude of factors. Skeletal muscles do not divide after they are formed,
which protects against durability loss from the transient transduction of vectors.
Additionally, many of these disorders are monogenic with well-known
pathophysiologies but have a high unmet need for treatments. Since the
pathophysiologies can overlap for these disorders, this presents the possibility of
viral vectors and constructs being useful in multiple indications.
Many musculoskeletal disorders amenable to gene replacement are related to
the dystrophin-associated glycoprotein (DAG) complex. The DAG complex is
responsible for connecting the cytoskeleton to the extracellular matrix. The complex
houses key sub-complexes and proteins that maintain structural integrity of the
musculature and facilitate signaling from the external musculoskeletal junction into
the cell. Malfunctioning proteins normally involved in the DAG complex can
generate several types of muscular dystrophies (see Exhibit 51, right) by disrupting
proper formation and function of the complex. Gene therapies targeting these
disorders are ultimately aiming to restore DAG complex functionality by replacing
the effected protein within it.
Other musculoskeletal disorders require different modalities of action
through gene therapy. Certain musculoskeletal disorders result from progressive
nucleotide repeats within a gene. These repeats cause build up of protein and
RNA aggregates that cannot be broken down. Unlike DAG complex-related
dystrophies, these conditions are better suited for exon-skipping or target
knockdown gene therapies, which can reduce the amount of toxic protein, instead
of gene replacement.
Gene Therapy for Musculoskeletal Disorders
The DAG Complex & associated musculoskeletal disorders
Source: Company Reports. Sarepta R&D Day Presentation 2018. Piper Jaffray Research.
EXHIBIT 51
Sarcoglycan sub-complex contains α, β, γ, δ
subunits and is responsible for stabilizing the
sarcolemma; dysfunction in the subunits lead
to Limb-Girdle Muscular Dystrophies
Dystroglycan links the
cytoskeleton to the
extracellular matrix to
provide structural integrity to
muscles and facilitate cell
signaling; dysfunction leads
to various dystrophies like
Walker-Warburg Syndrome
and Fukuyama
Congenital Dystrophy
Dystrophin connects actin
filaments to the
cytoskeleton and creates a
scaffold for cell signaling;
malfunction results in
Duchenne Muscular
Dystrophy (DMD) or Becker
Muscular Dystrophy (BMD)
66 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Selected Gene Therapy-amenable Musculoskeletal Disorders
Source: Company Reports. Myotonic Dystrophy Foundation. NORD. Piper Jaffray Research.
EXHIBIT 52
Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy (1 of 3)
DiseaseUS
PrevalenceDisease Background Unmet Need
Potential Gene Therapy Rationale &
Approach
Becker Muscular
Dystrophy
(BMD)
10,000
• X-linked recessive disorder caused by
mutations in the DMD gene, encoding
dysfunctional dystrophin
• Symptoms: progressive weakness and
wasting of skeletal and cardiac muscles, with
onset often observed between 8–25 years old
• Exondys51 available for DMD patients
with exon 51 mutation, Translarna
available for nonsense mutations in EU
• All other treatments symptomatic
• Life expectancy to mid-to-late
adulthood; normal life expectancy if
there are no cardiac issues
• Microdystrophin (shortened, functional
dystrophin) gene therapy to replace
dysfunctional gene
• Exon-skipping gene therapy to correct
native dysfunctional dystrophin transcript
into functional form
Myotonic
Dystrophy 1
(DM1)
30,000
• Autosomal dominant disorder caused by
expansion of CTG repeats in DMPK gene that
leads to protein aggregates
• Age of onset ranges from 20 to 70 years
• Symptoms include progressive weakness and
wasting of skeletal muscles
• Severity based on age of onset
(congenital being most severe)
• Minimal impact on life expectancy
• No cure available; treatment is
symptomatic
• Potential of utilizing gene knockdown
methods to reduce mutated DMPK levels
• Possibility of delivering exon-skipping
technology via gene therapy to produce
functional DMPK variants
Duchenne’s
Muscular
Dystrophy
(DMD)
10,000
• X-linked recessive disorder caused by
mutations in the DMD gene, encoding
dysfunctional dystrophin
• Symptoms include progressive muscle
weakness with onset at age 6–7 years,
leading to loss of ambulation by 12–15 years
• Exondys51 available for DMD patients
with exon 51 mutation (low efficacy)
• No other treatments available
• Life expectancy ~24–27 years
• Microdystrophin (shortened, functional
dystrophin) gene therapy to replace
dysfunctional gene
• Exon-skipping gene therapy to correct
native dysfunctional dystrophin transcript
into functional form
OPMD~3,000 –
4,000
• Autosomal dominant disorder caused by
mutation in the PABPN1 gene that leads to
PABPN1 aggregates
• Onset typically around 40 years of age
• Symptoms include muscle weakness, ptosis,
dysphagia
• No cure available
• Treatment centers around addressing
symptoms (plastic surgery, orthopedic
devices, cricopharyngeal myotomy)
• Replacement of PABPN1 by gene
therapy
• Potential of utilizing gene knockdown
methods to reduce mutated PABPN1
• Possibility of delivering exon-skipping
technology via gene therapy to produce
functional PABPN1 variants
XLMTM~2,700 –
3,000
• X-linked recessive disorder caused by
mutation in the MTM1 gene
• Onset evident at birth
• Symptoms include myopathy, hypotonia, and
fragile bones
• No cure available
• Most severe-form is most common
• Symptomatic treatment
• Average life expectancy is 29 months
• Replacement of MTM1 via gene therapy
• Exon-skipping gene therapy to correct
native dysfunctional myotubularin
transcript into functional form
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 67
Selected Gene Therapy-amenable Musculoskeletal Disorders
Source: Chu et al. J Exp NeuroThera. 2018. NORD.
EXHIBIT 53
Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy (2 of 3)
DiseaseUS
PrevalenceDisease Background Unmet Need Potential Gene Therapy Rationale & Approach
LGMD-2A NR
• Autosomal recessive disease caused by mutations
in Calpain 3 gene
• Age of onset 2–53 years
• Symptoms defined by phenotype (Leyden-Mobius,
Erb LGMD, HyperCKermia)
• No cure exists
• Cardiac and respiratory issues
are rare
• Gene therapy to replace dysfunctional gene
with full-length calpain 3
• Exon-skipping gene therapy to correct
native dysfunctional calpain 3 transcript into
functional form
LGMD-2B 2,600
• Autosomal recessive disease caused by mutations
in dysferlin protein that disrupts sarcolemma
resealing
• Age of onset between 15–30 years
• Symptoms characterized by muscle wasting in the
proximal limbs; progression is slow
• No cure exists
• Symptomatic treatment
• Patient remain ambulatory
• No respiratory or cardiac issues
• Gene therapy to replace dysfunctional gene
with full-length or shortened (micro) dysferlin
• Exon-skipping gene therapy to correct
native dysfunctional dysferlin transcript into
functional form
LGMD-2C 640
• Autosomal recessive disease caused by mutations
in γ‐sarcoglycan, part of the sarcoglycan
subcomplex of DAG
• Symptoms characterized by muscle wasting in the
proximal limbs
• No cure exists
• Symptomatic treatment
• Patients wheel-chair bound
by teenage years
• Cardiomyopathy is common
• Gene therapy to replace dysfunctional gene
with full-length γ‐sarcoglycan
• Exon-skipping gene therapy to correct
native dysfunctional γ‐sarcoglycan transcript
into functional form
LGMD-2D 1,100
• Autosomal recessive disease caused by mutations
in α‐sarcoglycan, part of the sarcoglycan
subcomplex of DAG
• Symptoms characterized by muscle wasting in the
proximal limbs
• No cure exists
• Symptomatic treatment
• Patients wheel-chair bound
by teenage years
• Rare to see cardiomyopathy
• Gene therapy to replace dysfunctional gene
with full-length α‐sarcoglycan
• Exon-skipping gene therapy to correct
native dysfunctional α‐sarcoglycan transcript
into functional form
68 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Selected Gene Therapy-amenable Musculoskeletal Disorders
Source: Chu et al. J Exp NeuroThera. 2018. NORD.
EXHIBIT 54
Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy (3 of 3)
DiseaseUS
PrevalenceDisease Background Unmet Need Potential Gene Therapy Rationale & Approach
LGMD-2E 1,100
• Autosomal recessive disease caused by mutations
in β‐sarcoglycan, part of the sarcoglycan
subcomplex of DAG
• Symptoms characterized by muscle wasting in the
proximal limbs
• No cure exists
• Symptomatic treatment
• Patients wheel-chair bound
by teenage years
• Cardiomyopathy is common
• Gene therapy to replace dysfunctional gene
with full-length β‐sarcoglycan
• Exon-skipping gene therapy to correct native
dysfunctional β‐sarcoglycan transcript into
functional form
LGMD-2G NR
• Autosomal recessive disease caused by mutations
in TCAP protein
• Age of onset between 9–15 years
• Symptoms characterized by muscle wasting in
the proximal limbs with significant variation
in phenotype
• No cure exists
• Symptomatic treatment
• Males more severely affected
• ~50% of cases have cardiac
issues
• Gene therapy to replace dysfunctional gene
with full-length or shortened telethonin gene
• Exon-skipping gene therapy to correct native
dysfunctional telethonin transcript into
functional form
LGMD-2L 1,800
• Autosomal recessive disease caused by mutations
in anoctamin 5
• Age of onset between 10–20 years
• Symptoms include distal leg phenotype,
asymmetric thigh atrophy
• No cure exists
• Symptomatic treatment
• Males more severely affected
• No respiratory or cardiac issues
• Gene therapy to replace dysfunctional gene
with full-length anoctamin 5
• Exon-skipping gene therapy to correct native
dysfunctional anoctamin-5 transcript into
functional form
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 69
The biology of the musculoskeletal disorder may dictate which modality of
gene therapy is best. As previously discussed, certain musculoskeletal diseases
may be able to be addressed by simply replacing the dysfunctional gene with a
functional copy via gene therapy. However, certain genes are too large to fit into
viral capsids and other genetic approaches may need to be taken. One such
method would be to deliver an engineered abridged variant of the gene that still
retains its functionality. Another method would be to utilize exon-skipping
technology via gene therapy to deliver oligonucleotides can help “skip” mutated
exons to generate a functional, slightly shortened version of the protein product
from the original, native DNA transcript.
Vector and promoter selection is usually based on indication and goals of the
gene therapy. Special considerations are given to the selection and design of a
vector for gene therapy in musculoskeletal disorders based on the specific
indication. Certain indications, like Duchenne Muscular Dystrophy, are known to be
fatal due to cardiac failure and improvements in cardiac function are highly sought-
after – thus, promoters with high cardiac muscle activity are typically selected for
such indications. Transduction efficiency of viral capsids can differ between tissue
types and so viral capsids must be selected based on whether they have suitable
transduction (eg, AAV9 is known to be able to cross the blood-brain barrier and is
frequently selected for musculoskeletal diseases with a CNS component).
Immunogenicity is a major concern for any vector but is heightened for
musculoskeletal gene therapy. Given the high doses of vector that a patient may
receive in musculoskeletal gene therapy, the possibility of an immune response is
always a major risk. This risk is increased in the presence of neutralizing antibodies
and so gene therapy clinical trials traditionally screen patients for preexisting host
antibodies against the vector. In order to maximize the patient pool and lower
safety risk, vectors chosen for gene therapy tend to have relatively lower
prevalence of neutralizing antibodies within the patient population. Musculoskeletal
disorders typically have a higher gene therapy vector burden that further
exacerbates the risk of immune responses, so proper safety management is
paramount for development of gene therapies in this sector.
Considerations for Gene Therapy in Musculoskeletal Disorders
Tissue Tropism And Neutralizing Antibody Prevalence In AAV Serotypes
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 55
AAV
SerotypeTissue Tropism
Prevalence of
Pre-existing nAbs
AAV1 Muscle; Adipose; CNS; Heart 67%
AAV2CNS (particularly ocular); Kidney;
Muscle; Testes72%
AAV3 Liver
AAV4Brain; Lung;
Retinal pigmented epithelium (RPE)40%
AAV5 Liver; CNS; Ocular; Pancreas 46%
AAV6Striated muscle (heart);
Respiratory epithelium (lung)
AAV7Brain; Photoreceptors; RPE;
Striated muscle38%
AAV8Hepatocyte; Pancreas; RPE;
Photoreceptors; Brain; Skeletal muscle47%
70 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Musculoskeletal Disorders
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 56
Companies Developing Gene Therapies for Musculoskeletal Disorders
Company Ticker Disorder Asset Vector Target Gene Stage of Development
Audentes BOLD DM1 AT466 AAV8 (potentially)DMPK (knockdown)
DMPK (exon-skipping)Preclinical
Audentes BOLD DMD
• AT702 (exon 2)
• AT751 (exon 51)
• AT753 (exon 53)
AAV8 (potentially) DMD (exon-skipping) Preclinical
Sarepta SRPT DMDSRP-9001
microdystrophinAAVrh74
Microdystrophin
(replacing dystrophin)Phase II
Solid Bio SLDB DMD SGT-001 AAV9Microdystrophin
(replacing dystrophin)Phase I/II
Pfizer PFE DMD PF-06939926 AAV9Minidystrophin
(replacing dystrophin)Phase Ib
AskBio Private Limb Girdle 2i Unnamed AAV FKRP (replacement) Preclinical
Sarepta SRPT LGMD-2A LGMD2A or Calpain 3 AAVrh74 (potentially) Calpain 3 Preclinical
Sarepta SRPT LGMD-2B MYO-201 AAVrh74 Dysferlin Clinical
Sarepta SRPT LGMD-2C SRP-9005 AAVrh74 (potentially) Gamma-sarcoglycan Preclinical
Sarepta SRPT LGMD-2D SRP-9004 AAVrh74 Alpha-sarcoglycan Clinical
Sarepta SRPT LGMD-2E SRP-9003 AAVrh74 Beta-sarcoglycan Clinical
Sarepta SRPT LGMD-2L SRP-9006 AAVrh74 (potentially) Anoctamin 5 Preclinical
Audentes BOLD XLMTM AT132 AAV8 MTM1 (replacement) Phase I/II
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 71
Neurology
04.5
72 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Neurological diseases present distinctive challenges for gene therapy.
Many neurological diseases have multiple causes, involve the malfunction of
multiple proteins within biochemical pathways, or their pathophysiologies have not
been fully elucidated. Additional complexity in developing neurological disease
gene therapies lies within determining the optimal route of administration
(eg, intrathecal vs intracranial). As will be discussed later, selecting the route and
site of administration may have significant impact on the efficacy of gene therapy
since neurological conditions can be localized to certain areas of the brain or be
systemic. There are, of course, exceptions to these limitations, such as spinal
muscular atrophy 1 (SMA1). Zolgensma became the first gene therapy to be
approved for SMA1, which is monogenic in nature and affects the motor neurons in
the spinal cord.
Unique strategies are sometimes required to address unique neurological
conditions. In developing gene therapies for neurological disorders, companies
often have to develop novel workarounds to overcome the diverse etiologies found
in these disorders and the specific hurdles described above. However, the high
unmet need in many of these conditions makes them prime candidates for novel
solutions that can address even a few aspects of the disease, if not cure it outright.
One salient example of this is Parkinson’s disease (PD), which is known to have
multiple etiologies and no known cure. Levodopa is used in PD for symptomatic
treatment but has a well-known side effect of dyskinesia at peak-dose, which can
drastically lower QoL. To address this, Axovant Gene Therapies (AXGT, not
covered) has taken a novel approach for PD in which three different genes are
delivered using a lentiviral vector (Exhibit 57). The goal of this therapy is to produce
tonic levels of dopamine, which may reduce the dyskinesia brought on by variability
in levodopa and dopamine levels.
Another difficult-to-treat neurological condition is Huntington’s Disease (HD),
caused by the mutated HTT protein (mHTT). mHTT is known to aggregate and
induce progressive neurodegeneration. Since the toxicity is being driven by
aggregation, gene replacement therapy is not a viable option. Instead, companies
are developing a gene therapy to supplement a downregulated gene in HD,
CYP46A1. The gene encodes an enzyme that plays a neuroprotective role in the
brain. The goal of this approach is to slow the progression of HD by replenishing
down-regulated levels of the protein.
Gene Therapy for Neurological Disorders
Axovant’s Gene Therapies Strategy for Parkinson’s Disease
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 57
Tyrosine
hydroxylase (TH)
& cyclohydrolase
(CH1)
Aromatic
L-amino acid
decarboxylase
(AADC)
All 3 genes in
one lentiviral
capsid
TH and CH1
fused together to
promote
co-localizaton
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 73
Selected Gene Therapy-amenable Neurological Disorders
Source: Company Reports. Young et al. Ther Adv Psych Pharm. 2017. NIH. Curts et al Gene Reviews. 2015.
EXHIBIT 58
Rationale for Targeting Select Neurological Disorders With Gene Therapy
DiseaseUS
PrevalenceDisease Background Unmet Need
Potential Gene Therapy Rationale &
Approach
ALS
(ΔC9ORF72)
15,000(Total)
600(C90RF72)
• Condition with deterioration of neurons
resulting gradual neurodegeneration
• 10% inherited (~4% C90RF72 mutation)
• Age of onset typically between 55–75 years
• No cure
• Death within 2–5 years
• Riluzole & Radicava approved to slow
progression to paralysis
• Gene silencing of C90RF72 to slow
aggregation of protein
• Gene silencing of SOD1 to slow the
aggregation of mutant protein
Huntington’s
Disease30,000
• Autosomal dominant condition in the HTT
gene that results in CAG repeats and leads
to progressive degeneration due to
aggregation
• Onset typically between 30–50 years of age
• Symptoms include chorea, depression, and
cognitive impairment
• No cure to-date
• Death usually 20 years after
diagnosis
• Severity and speed of disease
progression correlated with number of
CAG repeats
• Gene silencing of mHTT to slow
aggregation of mutant protein
• Gene replacement of CYP46A1 to
enhance neuroprotective features
Friedrich’s Ataxia 8,000
• Autosomal recessive condition in the FXN
gene that cause triplet repeats.
• Age of onset: 5–15 years
• Symptoms include ataxia, spasticity, and
loss of strength & sensation
• No cure; symptom management &
physical therapy
• Wheel-chair bound in 10–20 years
• Cardiac issues common; some live to
60+ years
• Gene replacement of FXN to restore
frataxin functionality
Frontotemporal
Dementia
20,000 –
30,000
• Disease of unknown cause that results in
gradual loss of cognitive function
• Age of on-set between 40–60 years
• Mutated progranulin has been shown to be
associated as a biomarker
• No cure; treatment involves lifestyle
changes
• Death typically ~10 years after onset
• Gene replacement of PGRN to
enhance progranulin functionality
Parkinson’s
Disease60,000
• Disease with multiple causes (recessive &
dominant mutations); not fully understood
• Age of onset: ~60 years
• Symptoms include trembling, stiffness, slow
movement with gradual decline
• No cure, levodopa & dopamine
receptor agonists used to treat
symptoms
• Levodopa treatment causes L-DOPA-
induced dyskinesia
• Gene replacement of CH1, TH, AADC
genes to enhance dopamine
biosynthesis from tyrosine/levodopa
SCA-Type 3 10,000
• Autosomal dominant condition that causes
CAG repeat expansion in ATXN3 gene,
leading to neurodegeneration in the
cerebellum & brain stem
• Onset typically in mid-adulthood
• Symptoms: ataxia, dystonia, spasticity
• No cure
• 10–20 years of survival after
diagnosis
• Gene silencing of ATXN3 to slow
aggregation of mutant protein
74 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Identifying the appropriate target genes to treat neurological conditions can
be challenging. Neurological conditions are prone to having multiple causes –
genetic and non-genetic, which makes them especially difficult to treat. Companies
developing gene therapies for these conditions are faced with the challenge of
identifying which sub-group of patients with the disorder they would be treating to
generate the most impact from their gene therapy. For example, in a condition like
ALS, only a small subset of patients have mutations in specific genes such as
SOD1 or C90RF72 that may be amenable for gene therapy; a company
developing a gene therapy in ALS would have to consider commercial and
clinical development viability aspects in selecting which target gene to use.
Gene therapies for neurological disorders can be difficult to administer, with
many requiring transduction directly into brain cells. There are several routes of
administration that can be used to achieve this, with various benefits/drawbacks.
Intrathecal administration may be implemented for a relatively safe delivery;
however, this mode of administration is best suited for diseases that affect the
spine and cortical neurons, since vector penetration to internal regions of the brain
may be limited. Multiple diseases, including HD and PD, originate in the internal
portions of the brain and spread towards the external cortices as the disease
progresses to later stages (Exhibit 59). In order to deliver genes to these internal
regions, an intracranial procedure targeting specific regions of the brain, may result
in high transduction rates than IV or intrathecal (Exhibit 60). There are obvious
risks related to the surgical procedure, such as intracranial hemorrhaging, and
considerations must be made about the site of delivery to ensure optimal
transduction. For example, uniQure (QURE, covered by Danielle Brill) is delivering
their gene therapy for HD directly to the striatum, where the putamen resides and is
known to be most significantly affect portion of the brain in early-stage HD patients.
Considerations for Gene Therapy in Neurological Disorders
Huntington’s Disease Progression from Early Stage to Late Stage
Source: Company Reports. uniQure R&D Day Presentation 2018. Piper Jaffray Research.
EXHIBIT 59
Neurodegenerative effects of
Huntington’s Disease are most
visible in the putamen and
caudate of the striatum, where
mHTT aggregation is most
prevalent. As aggregates build
up, the degenerative effects
progress to the cortical
portions of the brain in
later-stages of the disease.
Speed of progression depends
on number of repeats within
the mHTT gene.
Neurological Gene Therapy: Various Routes of Administration
EXHIBIT 60
Gene therapies can be
delivered via 4 major routes of
administration depending on
target region, safety profile of
gene therapy and target effect.
IV administration may also be
possible for neurological
conditions but would need to
overcome lower transduction
efficiency issues that result
from lack of blood-brain barrier
penetration.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 75
Gene Therapies Landscape: Neurological Disorders
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 61
Companies Developing Gene Therapies for Neurological Disorders
Company Ticker Disorder Asset Vector Target Gene Stage of Development
Voyager
TherapeuticsVYGR Monogenic ALS VY-SOD102 AAV2 SOD1 RNAi Preclinical
AskBio Private Epilepsy Unnamed AAV Undisclosed Preclinical
Voyager
TherapeuticsVYGR Friedreich’s Ataxia VY-FXN01 AAV2 FXN Preclinical
Passage Bio Private Frontotemporal dementia Unnamed AAV9 PGRN Preclinical
uniQure QURE Huntington’s Disease AMT-130 AAV5mHTT exon1 targeting
miRNAClinical (2H19)
AskBio Private Huntington’s Disease Unnamed AAV Undisclosed Preclinical
Voyager
TherapeuticsVYGR Huntington’s Disease VY-HTT01 AAV2 mHTT RNAi Preclinical
Voyager
TherapeuticsVYGR Parkinson’s Disease VY-AADC AAV2 AADC Phase II
Axovant Gene
TherapiesAXGT Parkinson’s Disease AXO-LENTI-PD Lentiviral AADC/TH/CH1 Phase I/II
MeiraGTx MGTX Parkinson’s Disease NLX-P101 AAV GAD Phase I/II
AskBio Private Parkinson’s Disease Unnamed AAV Undisclosed Clinical
Gene Therapy
Research
Institute
Private Parkinson’s DiseaseAAV2-AADC
AAV2-TH-GCHAAV.GTX AADC/TH/CH1 Preclinical
Gene Therapy
Research
Institute
Private Sporadic ALS AAV.GTX-AADR2 AAV.GTX AADR2 Preclinical
76 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Ophthalmology
04.6
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 77
The eye presents advantages for gene therapy: accessibility and ease of
evaluation. Ophthalmic disorders, particularly retinal disorders, result from genetic
mutations in genes that are essential for retinal health, such as CHM or RS1, and
genes that lead to inherited degeneration of the retina. However, they can also be
caused by non-genetic factors including age in the case of wet age-related macular
degeneration (wet AMD). Ocular diseases are of particular interest as targets for
gene therapies due to their often monogenic nature, as well as the isolated, fluid-
filled and privileged space of the eye, which is easily accessible by injection.
Gene therapy for ocular disease is clinically validated. Luxturna (Spark
Therapeutics, which was acquired by Roche, uncovered) is a serotype 2 adeno-
associated virus (AAV2)-based vector encoding the RPE65 gene. The goal of this
therapy is to replace dysfunctional RPE65 in patients with Leber congenital
amaurosis type 2 (LCA2), an inherited retinal disease caused by mutations in this
gene. Luxturna is administered in the subretinal space following vitrectomy
(removal of the vitreous humor gel that fills the eye). Preclinical and clinical studies
have shown that the AAV2-RPE65 vector is safe and effective, as patients
demonstrated improvements in light sensitivity and in navigating dim lighting
conditions. Importantly, these effects were sustained over a 3-year follow-up period
in most of the studies. This initial success with gene therapy for an ocular disease
has provided proof of concept and given hope to the thousands of patients with the
various retinal diseases for which there are no approved therapies. It also paved
the way for several companies to develop other AAV vectors targeting different
retinal gene mutations. In fact, there are currently >30 ocular clinical trials studying
gene replacement in ocular/retinal disease using AAV vectors, including studies in
choroideremia, age-related macular degeneration (AMD), X-linked retinitis
pigmentosa (XLRP), and X-Linked Rentinoschisis (XLRS). With established
evidence now in place that the delivery of a gene to the retina can safely restore
visual acuity and retinal health in LCA2, additional genes may be delivered
accordingly in various disease settings.
Ocular gene therapies may potentially treat non-inherited retinal disorders.
As previously mentioned, diseases such as wet AMD are not caused by inherited
mutations in retinal genes, and are instead caused by age, or behavioral and
environmental factors. Anti-VEGF therapy is used in treating AMD, as the disease
is characterized by vascular overgrowth in the retina. Several therapies are in use,
including EYLEA (Regeneron Pharmaceuticals, covered by Chris Raymond),
Lucentis (Roche/Genentech, uncovered), Macugen (Pfizer, uncovered), and
Avastin (Roche/Genentech). Anti-VEGF is effective initially after injection;
however, “real-world” data from long-term clinical trials showed a surprising lack of
durability in the response to therapy. After one year of treatment, patients no longer
had meaningful improvement in visual acuity like that seen in pivotal trials for these
drugs. This may be due to the number of injections that are required (1 injection
per month) leading to non-compliance, among several other reasons associated
with injection of this protein. Therefore, gene therapy may be a favorable
alternative to repeated Intravitreal injection of recombinant anti-VEGF or other
recombinant proteins with the potential to (1) avoid peak and trough levels
associated with protein injection, (2) avoid potential safety issues with repeated
injections, and (3) to lower the burden on patients. We see from previous
experience with Luxturna and the myriad trials currently ongoing that gene therapy
is capable of achieving high levels of protein and long-term expression.
Gene Therapy for Ophthalmic Disorders
Source: Company Reports. Piper Jaffray Research.
78 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Selected Gene Therapy-Amenable Ophthalmic Disorders
Source: Company Reports. NORD. Piper Jaffray Research.
EXHIBIT 62
Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy
Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach
Choroideremia ~5,000
• X-linked recessive disorder caused by
mutations in the CHM gene, encoding
dysfunctional Rab-escort protein-1
(REP1), which leads to the death of
the retinal epithelium, photoreceptors,
and the choroid
• Symptoms: progressive loss of vision
• No approved treatments
• Symptom management includes
visual aids
• Significantly impaired QoL due to
vision loss
• AAV delivery of functional CHM gene
to retinal cells aims to replace REP1,
reducing the accumulation of waste
products to reduce cell death. The
ultimate goal of gene therapy in this
disease is to slow or halt vision loss
that result from CHM mutations
Wet Age-Related
Macular Degeneration
(Wet AMD)
1.2M
• Non-genetic retinal disease brought
on by age, inflammation,
hypertension, or by smoking
• Symptoms: abnormal vascular growth
on the retina that results in severe
vision loss, which may be rapidly
progressive
• EYLEA, Lucentis, Macugen, and
Avastin are all anti-VEGF therapies
designed to stop the growth of new
blood vessels by blocking the effects
of VEGF growth signals
• Anti-VEGF treatment requires monthly
injections, which is burdensome
• AAV delivery of aflibercept (anti-VEGF
antibody) aims to minimize the
treatment burden of repeated anti-
VEGF injection. This therapy restores
physiological angiogenic balance in
the retina, thereby halting or slowing
the progression of retinal damage
Retinitis Pigmentosa
(RP)~10,000
• Autosomal or X-linked disorder
caused by various mutations across
several chromosomes, and may even
be polygenic in some cases
• Symptoms: progressive vision loss,
dim light sensitivity, night blindness
• No approved treatments
• Dietary vitamin A supplements have
been shown to restore partial vision;
however, vitamin E leads to rapid
progression of disease, therefore
multivitamins may be dangerous
• AAV delivery of the functional RPGR
gene, which encodes the retinitis
pigmentosa GTPase regulator that is
responsible for protein transport in
photoreceptors. The aim of gene
therapy in XLRP is to restore vision
X-Linked
Rentinoschisis (XLRS)~15,000
• X-linked recessive disorder caused by
mutations in the rentinal-specific RS1
gene which encodes dysfunctional
retinoschisin protein
• Symptoms: reduced visual acuity,
retinal detachment, retinal bleeding
• No approved treatments
• Retinal detachment may be treated
surgically, but splitting or schisis of the
retina cannot be corrected
• Low vision aids are often provided
• AAV delivery via Intravitreal injection
of the functional RS1 gene targets the
therapy to retinal cells in XLRS
patients. The goal of this therapy is to
achieve a functional cure and prevent
further retinal damage
Achromatopsia ~10,000
• Autosomal recessive disorder caused
by mutations in CNGB3 and CNGA3
encoding a subunit of the cone
photoreceptor cyclic nucleotide-gated
(CNG) channel
• Symptoms: day blindness, reduced
visual acuity and color discrimination
• No approved treatments
• Tools are available for symptom
management, including deep red
tinted glasses or contact lenses, and
magnifying lens to deal with poor
visual acuity
• AAV delivery of the functional CNGB3
or CNGA3 gene targets the cone
receptors at the back of the eye where
they are most focused via subretinal
injection in achromatopsia patients.
The goal of this therapy is to restore
cone function
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 79
Vector selection is dependent upon disease etiology and gene size.
Viral vectors are the most common gene delivery systems for ocular diseases.
However, viral specificity is a challenge due to tissue tropism. Moreover, AAV
vectors have limited capacity. Some genes, such as TIMP3, which causes
Stargardt’s hereditary maculopathy (an inherited macular disease), are too large
(6.2 kb) to be carried to the retina by the AAV virus, as they only have a <5 kb
capacity. Lentiviral vectors may be used to carry larger genes. Alternatively, non-
viral gene therapy approaches offer the benefit of the same sustained, fine-tuned
expression of desired proteins and can address more common non-genetic retinal
diseases, such as age-related macular degeneration (AMD). In general, non-viral
vectors have better safety profiles, as they are less immunogenic, and can
therefore be administered repeatedly, if needed. They also have a lower risk of
insertional mutagenesis than viral vectors.
Surgical considerations remain an important issue to focus on for ocular
gene therapy. Subretinal dosing of a gene therapy requires an invasive surgical
procedure that can only be performed following vitrectomy by a trained surgeon.
During this procedure, a subretinal “bleb” is formed, resulting in transient
detachment of retinal pigment epithelium from the photoreceptors, which could
aggravate the already ongoing degenerative process that several patients are
already experiencing. Complications from the surgical process can arise, including
the creation of macular holes, unresolved retinal detachment (this will require an
additional surgery), choroidal effusions (accumulation of fluid in the suprachoroidal
space), and retinal tears. Importantly, it is also crucial to understand that cellular
transduction using subretinal injection is restricted only to the bleb location, which
limits the treatment area. It is for these reasons that companies like Adverum are
developing intravitreal injection (IVI) administered gene therapy. This process is
less invasive and is considered by some physicians to be safer due to reduced risk
of retinal damage. However, KOLs have noted that subretinal injection can be
100–1000x more efficient at targeting retinal cells than IVI. In fact, there are data
supporting the notion that IV only transduces cells in the fovea due to the presence
of the internal limiting membrane (ILM), which acts as a barrier between the retina
and the vitreous space. Moreover, IVI administration of gene therapy can lead to
high neutralizing antibody titers (which would increase the immune-mediated
elimination of drug), whereas almost no antibody response is seen following
subretinal injection. Therefore, it is clear that both IVI and subretinal injection have
their drawbacks. However, as 88% of retinal specialists believe that a surgical
procedure is warranted if a therapy offers a durable benefit of 6–12 months, we
note that it is extremely important to consider on a disease basis which route of
administration is required for effective delivery of gene therapy to the eye.
Long-term expression and efficacy in patients are still open questions.
There is a chance, as with any gene therapy, that it may not be possible to turn off
therapeutic gene expression once it is delivered to the eye. It is therefore
imperative to study the long-term safety of these gene therapies once injected into
the eye. Fortunately, the first gene therapy trials for Luxturna in LCA2 have not
shown any long-term safety issues. We believe this is de-risking for the field.
AAV gene therapies are expensive. Costs of production of AAV gene therapies
are exorbitant. Manufacturing of these low-yield vectors will have to drastically
improve to make economic sense for developers. Moreover, the prices of these
therapies are a significant burden. For example, Luxturna is marketed in the US at
$425,000 per eye. Questions regarding reimbursement and patient access remain.
Specific Considerations for Gene Therapy in Ophthalmic Disorders
Source: Company Reports. Piper Jaffray Research.
80 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Ophthalmic Disorders
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 63
Companies Developing Gene Therapies for Neurology Disorders
Company Ticker Disorder Asset Vector Target Gene Stage of Development
agtc AGTCAchromatopsia
(ACHM-A3)AAV-CNGA3 AAV CNGA3 Phase I/II
agtc AGTCAchromatopsia
(ACHM-B3)AAV-CNGB3 AAV CNGB3 Phase I/II
MeiraGTx MGTX Achromatopsia AAV-CNGA3 AAV CNGA3 Phase I/II
MeiraGTx MGTX Achromatopsia AAV-CNGB3 AAV CNGB3 Phase I/II
Biogen BIIB Choroideremia BIIB111 AAV2 Choroideremia (CHM) Phase III
MeiraGTx MGTX Retinitis Pigmentosa (RP) AAV-RPE65 AAV RPE65 Phase I/II
REGENXBIO REGX Wet AMD RGX-314 AAV8
Gene encoding
anti-VEGF monoclonal
antibody fragment
Phase I/IIa
Adverum
Biotech ADVM Wet AMD ADVM-022 AAV.7m8 Aflibercept (anti-VEGF) Phase I
agtc AGTCX-Linked Retinitis
Pigmentosa (XLRP)AAV-RPGR AAV RPGR Phase I/II
Biogen BIIBX-Linked Retinitis
Pigmentosa (XLRP)BIIB112 AAV8 RPGR Phase II/III
MeiraGTx MGTXX-Linked Retinitis
Pigmentosa (XLRP)AAV-RPGR AAV RPGR-ORF15 Phase I/II
agtc AGTCX-linked retinoschisis
(XLRS)AAV-RS1 AAV RS1 Phase I/II
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 81
Otology
04.7
82 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Source: Company Reports. Mytonic Dystrophy Foundation. NORD. Piper Jaffray Research.
EXHIBIT 64
Rationale for Targeting Hearing Loss With Gene Therapy
Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach
Hearing Loss ~300,000
• Roughly 50% of congenital hearing
loss has a genetic etiology, and more
than 300 different gene mutations
have been implicated
• The same genes responsible for
monogenic deafness may also
contribute to environmental hearing
loss due to drug exposure, noise,
and aging
• There are currently no FDA-approved
therapies to address hearing loss
• SoC includes hearing aids that offer
sound amplification and cochlear
implanted electrodes that stimulate
the auditory nerve
• These treatments only offer partial
recovery of function, only work in a
limited patient population, and do not
fully restore natural hearing
• Daily activities are significantly
impacted by hearing loss
• AAV or Adenoviral vectors are used to
deliver functional versions of genes
responsible for the loss of hearing,
including ATOH1, which encodes the
atonal transcription factor. This gene
is essential in the development of
inner ear hair cells. The aim is to
replace dysfunctional genes that
impair hearing and restore
dysfunctional or absent hearing ability
in individuals with a genetic basis
of disease
EXHIBIT 65
Companies Developing Gene Therapies for Hearing Loss
Company Ticker Disorder Asset Vector Target Gene Stage of Development
Akouos PrivateSensorineural
hearing lossAnc80AAV AAV Undisclosed Preclinical
Novartis NVSSevere to profound
hearing lossCGF166 Ad5
Atonal transcription factor
(Hath1)Phase I/II
Genetic hearing loss is caused by mutations affecting over 300 different loci
in many different ear cell types. Hair cells of the inner ear are the most common
target of gene therapy studies, most likely due to the fact they express that more
than 50% of the mutations leading to deafness. However, hair cells are postmitotic
and therefore do not divide, and are also organized within the inner ear hair bundle
in a compact arrangement – making them slightly more difficult targets for even
localized gene therapy. Other ear cells with known mutations causing hearing loss
that may be viable targets include the spiral ganglion neurons and support cells.
The inner ear is an attractive target for gene therapy. Similar to the eye, the
inner ear is an enclosed, fluid-filled space, offering several advantages and
disadvantages in the development of gene therapies. For example, the blood-
labyrinthine barrier within the inner ear provides a significant physical and diffusion
barrier which may make it difficult to treat inner ear hair cells systemically.
Conversely, this barrier allows therapeutic agents injected directly into the cochlea
to remain isolated there at elevated concentrations, which would reduce systemic
toxicity due to off-target effects.
Gene Therapy for Otological Disorders
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 83
Emerging Approaches in
Gene Therapy
05.
84 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
We believe that following our below checklist for valuating gene therapy companies mitigates some of the risk of investing in gene therapy, thereby creating compelling
investment opportunities with a more favorable risk/ reward ratio.
Our Checklist for Valuing Gene Therapy Companies
Source: Piper Jaffray Research.
Despite much recent progress in the field there are still more questions than answers when it comes to gene therapy. And in our view,
how gene therapies will pan out once they reach the clinic is highly unpredictable. For that reason, we prefer companies that have
generated compelling clinical efficacy and safety data, or at least clinical POC.01 CLINICAL DATA
02 UNMET NEED
03 COMPETITION
04 MARKET
OPPORTUNITY
05 PIPELINE
We look for companies developing gene therapies where existing therapies are limited and there is a high degree of unmet need.
We think physicians and patients will generally prefer other available treatment modalities (if efficacy/safety are comparable) over
gene therapy, because no one wants to be a guinea pig. However, for diseases with no alternatives, or suboptimal treatments with a
high morbidity/mortality, we expect broad utilization of gene therapies.
Many companies are developing gene therapy products for the same indications. We have two different approaches to picking stocks
in this situation. 1. Attempt to pick the winner and assign them majority of market share (most compelling data, most advanced,
cleaner safety profile, less invasive administration). 2. Assume they divide the market. If competing programs are too early to identify
areas of differentiation, we assume they share the market.
In our view, a deep pipeline is especially important when considering companies developing products targeting ultra-rare indications.
With that said, we are cautious about ultra-orphan indications. We worry about products in development targeting worldwide
population numbers in the hundreds. We think there is a cap on pricing, even if overall impact to health systems would be small.
As such, we worry about sustainability.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 85
Companies Covered
4D Molecular Therapeutics (Private)
Abeona Therapeutics (ABEO)
Adverum Biotech (ADVM; OW)
Akouos Therapeutics (Private)
Amicus Therapeutics (FOLD)
AskBio (Private)
Audentes Therapeutics (BOLD; OW)
AVROBIO (AVRO)
Companies Covered Within This Report
Source: Piper Jaffray Research.
In this section of the report, we dive into 22 companies that are developing novel gene therapies for the treatment of the conditions described previously. The companies
range from small private companies to large cap pharmaceutical companies, with assets that are currently being evaluated in preclinical and clinical stages
of development.
Please refer to the hyperlinked list below to jump to a company of interest.
Axovant Sciences Ltd (AXGT)
Biogen (BIIB; N)
Biomarin (BMRN; OW)
bluebird bio (BLUE; N)
BridgeBio (BBIO; OW)
Gemini Therapeutics (Private)
Gene Therapy Research Inst Co (Private)
Krystal Biotech (KRYS)
MeiraGTx (MGTX; OW)
Orchard Therapeutics (ORTX)
Passage Bio (Private)
Rocket Pharma (RCKT)
Sarepta Therapeutics (SRPT; OW)
Ultragenyx (RARE; OW)
UniQure (QURE; OW)
86 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Company overview. 4D Molecular is a next-generation gene therapy platform
company that uses therapeutic vector evolution to create optimized and proprietary
AAV vectors specifically tailored to the treatment of specific rare diseases.
The current pipeline spans four therapeutic areas including ophthalmology, heart,
muscle, and lung disorders.
Therapeutic vector evolution. To design next-gen AAV vectors, 4DMT works
with physicians/scientists to design optimized vector profiles for a given disease,
and then creates a highly complex and unique vector capsid library for
high-throughput screening. Using the power of natural selection in primates,
vectors with desirable profiles are enriched and isolated, and then further
engineered to carry specific therapeutic transgenes of interest. These optimized
vectors allow for highly efficient gene uptake and delivery, have increased tissue
specificity, and are less immunogenic than first generation AAV vectors.
Enhanced transduction efficiency of next-gen AAV vector, 4D-C102 vs AAV1
and AAV9 vectors. Relevant to Fabry disease, which affects heart tissue,
human pluripotent stem cell-derived cardiomyocytes were transduced with 4D-
C102, a next-gen AAV optimized to transduce the heart, or first-generation
AAV1 or AAV9 vectors encoding CAG-EGFP at multiple MOIs. Six days post-
infection, cardiomyocytes were analyzed for GFP fluorescence, with 4D-C102
transduced cells showing a statistically significant dose-dependent increase in
transduction efficiency compared to first-generation vectors. 4DMT will use 4D-
C102 as the novel vector for its Fabry product candidate, 4D-310, which is
expected to enter the clinic in 2020. The company presented these findings at
the 6th International Update on Fabry Disease held in May 2019.
4D Molecular Therapeutics (Private)
Source: 4D Molecular Therapeutics. Piper Jaffray Research
EXHIBIT 66
4DMT’s Gene Therapy Pipeline
EXHIBIT 67
Upcoming Catalysts
Indication Drug Catalyst
Choroideremia 4D-110 Initiation of P1 study expected in 2019
Choroideremia 4D-110 Natural History study (ongoing, n=50)
Fabry disease 4D-310 Anticipated FIH clinical trial initiation in 2020
Stage of Development
Indication Program DiscoveryPre-IND
Candidate
IND
Candidate
Choroideremia 4D-110
Retinal
Rare Disease4D-125
Fabry Disease 4D-310
Muscle
Rare Disease4D-510
Cystic Fibrosis 4D-710
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 87
Upcoming Catalysts
A fully-integrated gene and cell therapy company rapidly advancing genetic
medicines. Abeona Therapeutics (ABEO) is a biopharmaceutical company
focused on developing gene therapy products to treat severe, life-threatening rare
diseases. The company has three ongoing clinical programs with additional gene
therapies in preclinical development (Exhibit 68). ABEO is currently preparing to
initiate a pivotal Phase III trial for lead product candidate, EB-101 (ex vivo
autologous gene therapy of patient keratinocytes), for the treatment of Recessive
Dystrophic Epidermolysis Bullosa (RDEB) in 4Q19. In addition, the company has
two AAV gene therapy candidates in Phase I/II clinical development for the
treatment of Sanfilippo Syndrome (MPS III), a lysosomal storage disorder primarily
affecting the CNS, including ABO-102 (rAAV9-SGSH) for the treatment of MPS
IIIA, and ABO-101 (rAAV9-NAGLU) for the treatment of MPS IIIB.
Abeona Therapeutics (ABEO): Not Covered
Source: ABEO. Piper Jaffray Research
EXHIBIT 68
ABEO’s Gene Therapy Pipeline
EXHIBIT 70
Indication Drug Upcoming Catalyst
RDEB EB-101 Initiation of pivotal multi-center P3 trial in 4Q19
MPS IIIA ABO-102Pursuing an RMAT meeting with FDA in 2H19 to
determine development path forward
MPS IIIB ABO-101 Interim data update expected 2H19
Infantile
BattenABO-202
Guidance on timing of first clinical study
expected in 2019
EXHIBIT 69
Cognitive Benefits in Young Children with MPS IIIA Treated with ABO-102
Stage of Development
Indication Program Preclinical Phase I/II Phase III
RDEB EB-101
MPS IIIA ABO-102
MPS IIIB ABO-101
Infantile Batten
DiseaseABO-202
Juvenile Batten
DiseaseABO-201
Cystic Fibrosis ABO-401
Retinal Diseases ABO-50X
(Above) While all patients in the ongoing Phase I/II study for ABO-102 have shown
reductions in CSF and urine heparan sulfate levels and also shown reductions in
liver volume, the three youngest patients treated with ABO-102 have maintained
normal neurocognitive development within the range of unaffected children.
These data support the need and potential approach to treating MPS III children as
early as possible in the course of disease, prior to symptom onset when significant
neuronal loss has occurred.
88 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Adverum Biotechnologies, is a clinical stage gene therapy company targeting
ocular and rare disease. The company’s lead candidate is ADVM-02, a
proprietary AAV.7m8 vector driving the expression of aflibercept (anti-VEGF
antibody) for the treatment of wet AMD, for which we expect initial data from the
first cohort of patients treated in the OPTIC Phase I study on September 12, 2019.
ADVM-022 is Adverum’s lead AAV-based candidate for the treatment of
wet AMD. There are several approved anti-VEGF therapies for the treatment of
wet AMD including Avastin (Genentech, uncovered), Lucentis (Genentech), and
Eylea/aflibercept (Regeneron, covered by Chris Raymond). We know these drugs
work well and the anti-VEGF approach is well-validated. However, these therapies
lack meaningful durability after one year of treatment because of non-compliance
due to the frequency of injections required for efficacy (1 per month).
ADVM-022 does not require sub-retinal surgery and has demonstrated robust and
stable intraocular expression of aflibercept well beyond a year, which resulted in
reductions of CNV lesions and complexes comparable to the standard bolus
administration of aflibercept. The ongoing ADVM-022 Phase I OPTIC trial has
already dosed 6 patients with a single intravitreal injection of 6E11 vg/eye of 022
and a preliminary review of safety data from this cohort by the independent data
monitoring committee (DMC) revealed no serious adverse events (SAEs) or
dose-limiting toxicities (DLTs) associated with treatment for up to 5 months.
Adverum has also dosed the second cohort at a 2E11 vg/eye dose level (n=6).
Based on existing observations from the study, the company plans to present initial
24-week data from the first cohort of 6 patients at the Retinal Society Meeting in
London on September 12, 2019. Importantly, in addition to primary safety data, we
now expect to see secondary efficacy data, including an analysis of rescue
injections. We believe this suggests there may be early signs of efficacy at the
initial 6E11 dose level, which would be encouraging. Recall that with the final
dataset at optimal dose levels, we hope to see: (1) at least a 50% reduction in the
need for rescue injections; (2) maintenance of best corrected visual acuity (BCVA);
and (3) maintenance of central retinal thickness (CRT) by OCT. The initial 6E11
dose appears clinically relevant (and higher than ADVM's direct competitor), and if
data are positive, the company will meet with the FDA to discuss a development
path moving forward, which may potentially be expedited given 022’s Fast
Track status.
The company’s AAV vector manufacturing process is based on the
Baculovirus Expression Vector System (BEVS), which is a well-validated
approach that can accommodate large, high-yielding batches of AAVs due to the
use of insect cells grown in suspension cultures. This is differentiated from typical
mammalian cell-based approaches, which produce lower yields and are less
cost-effective. We anticipate Adverum’s manufacturing protocol to be highly
scalable for commercial use.
Adverum (ADVM): Van Buren, OW
Source: Company Reports. Piper Jaffray Research.
Upcoming Catalysts
EXHIBIT 72
Indication Drug Upcoming Catalyst
Wet AMD ADVM-022Initial Phase I data from
first 6 patients expected 3Q19
Adverum Pipeline
EXHIBIT 71
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 89
Akouos is a precision gene therapy company developing treatments to
restore and prevent hearing loss. 360 million people worldwide experience
hearing loss and there are currently no approved therapies to treat it. The company
is developing AAV-based gene therapies for sensorineural hearing loss that is
characterized by dysfunctional sensory cells and nerve fibers in the inner ear. It is
the leading cause of newborn deafness, and ~25% of adults over the age of 65
develop this condition, making it the most common of sensory disorders in general.
Sensorineural hearing loss is a great candidate for gene therapy as most cases are
monogenic in nature. Monogenic sensorineural hearing loss affects ~300,000
individuals in the US alone, and millions worldwide.
The company is developing a novel AAV-based platform technology to target
the gene therapy to the sensory cells of the inner ear. This platform is an
Ancestral AAV (Anc-AAV) technology that was originally developed by one of the
company’s co-founders at Massachusetts Eye and Ear. The lead vector for use in
gene therapy for hearing loss is Anc80, which was chosen out of over 40,000
ancestral vectors. The process behind the development of Anc80 and the broader
AncAAV portfolio involved predicting ancestors of AAV9. To achieve this, the
company used the sequence of AAV1-9 to phylogenetically predict where ancestral
nodes would be, synthesize them, and apply selective pressures to the ancestors.
It was serendipitous that one of these novel, created ancestors—the Anc80
library—transduced cochlear cells more potently than other AAV capsids. Akouos
plans to announce the identity of the target gene for the lead therapy later this
month at the American Neurotology Society annual meeting on September 14,,
2019. To prepare for target selection, Akouos has performed a systematic analysis
of 150 genes implicated in hearing loss, including STRC and GLB2.
The Anc80 gene therapy is delivered via minimally-invasive surgery to the
inner ear. Sensory cells sit upon an epithelial membrane that is suspended
between two fluid-filled spaces that are encapsulated in bone (Exhibit 73). Similar
to the eye, this portion of the ear is a prime target for gene therapy as local delivery
can achieve a high local concentration of gene of interest, which can overcome
efficiency challenges experienced with systemically delivered gene therapies.
Local injection also limits the possibility of systemic or off-target toxicities. Another
added benefit of targeting sensory cells is that they are post-mitotic, which means
there is a higher probability of achieving transduction of the gene of interest.
Akouos has a well-established, experienced team of leading experts in inner ear
drug delivery and pharmacokinetics. This team has significant experience
developing novel gene therapy technology for delivery to the inner ear.
Akouos (Private, Page 1 of 2)
Source: Akouos Company Reports. Piper Jaffray Research.
Inner Ear Delivery of Anc80 Gene Therapy
EXHIBIT 73
90 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Non-human primate data provided confidence to select Anc80 as the lead
program vector. Akouos presented data in 3 different NHPs at ASGCT in May of
this year, showing that treatment with the Anc80 vector expressing GFP for
visualization purposes achieves up to 100% transduction of its target hair cells in a
dose-dependent fashion (Exhibit 74). Moreover, the pattern of transduction within
the inner ear was consistent across a large part of the cochlea in several cell types,
including fibrocytes and support cells. This level of transduction is important, as the
company notes that 30%–40% restoration of WT levels of protein will likely be
sufficient to achieve clinically meaningful responses. Although we have not seen
data expressing protein quantity for a target gene of interest, management believes
the Anc80 vector can achieve a therapeutic level of protein expression based on its
ability to transduce inner ear cells to this extent. Also of note is the remarkable level
of hair cell survival following treatment with Anc80-GFP and the low levels of
neutralizing antibodies that the macaques developed against the vector up to
21 days following treatment. Together, these data suggest that high levels of
transduction are achieved with Anc80 in inner ear cells, without inducing cell death
or triggering a CNS immune response.
As the company prepares for an IND submission in 2H20 for their lead Anc80
candidate, management is engaging with multiple institutions to begin genetic
screening in newborns with confirmed deafness. The company estimates initial
studies in infants younger than 1 year old will initially take place outside of US
since there is higher potential for benefit and less risk for long, slow degeneration
over time in infants due to the health of hair cells being greater with younger age.
Moreover, the company notes that language plasticity is reduced after 3 years of
age, so they expect some children may be able to develop language skills following
treatment with the Anc80 gene therapy. Looking ahead, Akouos expects clinical
endpoints to include measurements of signal or noise detection, speech
perception, and QoL outcomes. Management has also scheduled a pre-IND
meeting with the FDA in September, and will have more clarity on the exact timing
of the IND submission thereafter (currently estimated for 2H20).
In addition, the company stated that it potentially has 3 programs that may enter
the clinic over the next 5 years, which includes work across 15 different types of
hearing loss. Management is setting up an internal research network as well as
strategic collaborators to establish proof of concept in mouse models to accelerate
lead programs that show early viability. Importantly, the company has an ongoing
manufacturing collaboration with Lonza that should provide supply for preclinical
and clinical needs in the near-term.
Akouos (Private, Page 2 of 2)
Source: Akouos Company Reports. Piper Jaffray Research.
Upcoming Catalysts
EXHIBIT 75
Indication Drug Upcoming Catalyst
Sensorineural Hearing Loss UndisclosedAnnounce target gene selection in
September 2019
Sensorineural Hearing Loss Undisclosed IND submission in 2H20
Dose-dependent Transduction with Anc80 Vector and Cochlear Frequency
EXHIBIT 74
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 91
Amicus is a fully integrated, global rare disease gene therapy company
that has the largest portfolio of gene therapies for rare diseases in the field.
Amicus’ lead gene therapy candidates include:
• AAV-CNL6: an AAV-based viral vector expressing the CLN6 gene that
encodes the linclin protein for the treatment of Batten disease
• AAV-CLN3: AAV-based viral vector expressing the CLN3 gene that encodes
the battenin protein for the treatment of Batten disease
• AAV-GAA: AAV-based viral vector expressing the GAA gene that encodes the
alpha glucosidase enzyme for the treatment of Pompe disease
Amicus’ main Batten disease asset in AAV-CLN6. Batten disease with the
CLN6 variant is characterized by late-infantile onset of disease and symptoms
including developmental delay, seizures, and eventual loss of mobility before
death. 12 children have been dosed with AAV-CLN6 to date, and to date, there is
no disease progression in children 30 months old at the time of treatment with
AAV-CLN6. Data in 7 additional patients at 2 years will be reported in 3Q19.
Amicus is also developing AAV-CLN3, an AAV-based gene therapy that
replaces the protein battenin. Batten disease caused by CLN3 mutations is also
rapidly progressive and leads to vision impairment, movement problems, and
seizures before death. Amicus has completed dosing of AAV-CLN3 in three
children in the low dose cohort and expects to dose three more in a higher dose
cohort in H2:2019. Preclinical data showed AAV-CLN3 improved motor function,
cognitive behavior, and survival in a Batten disease mouse model.
The company also has a preclinical gene therapy candidate for Pompe
disease. Amicus is developing hAAV-GAA to treat Pompe patients, who
experience symptoms including weak muscles, enlarged livers, failure to gain
weight, and respiratory issues. Preclinical data showed that hAAV-GAA reduced
glycogen levels in the central nervous system, as shown by glycogen Luxol/PAS
staining, in GAA knockout mouse spinal cord tissue.
Amicus Therapeutics (FOLD): Not Covered
Source: Company Reports. Piper Jaffray Research.
Upcoming Catalysts
EXHIBIT 77
Indication Drug Upcoming Catalyst
Batten Disease AAV-CLN62-year data from 7 patients
in 3Q19
Batten Disease AAV-CLN3Dosing of 3 additional children
in 2H19
Pompe Disease AAV-GAA Continued preclinical development
Amicus’ Pipeline
EXHIBIT 76
Stage of Development
Indication Program Preclinical Phase I/II
Fabry Disease AAV-GLA
Batten Disease AAV-CLN6
Batten Disease AAV-CLN3
Batten Disease AAV-CLN8
Batten Disease AAV-CLN1
Pompe Disease AAV-GAA
CDKL5 Deficiency AAV-CDD
Niemann-Pick Type C AAV-NPC
MPS IIIB Undisclosed
MPS IIIA Undisclosed
92 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
AskBio: Advancing the therapeutic boundaries of clinical gene therapies.
Asklepios BioPharmaceutical (AskBio) is a privately held AAV gene therapy
company founded in 2001, engaged in the development, manufacture, and delivery
of novel gene therapies to treat a number of devastating diseases. The company
harnesses the scientific expertise Dr Jude Samulski, the former Director of the
Gene Therapy Center at the University of North Carolina, and a co-founder and
current CSO of AskBio, to drive continued innovation in gene therapy development
with unique viral cassettes (i.e., self-complementary vectors, synthetic promoters)
and next-generation chimeric capsids with enhanced properties including improved
tissue selectivity and immune system evasion.
A differentiated business model. AskBio acts as a project incubator by internally
developing drug candidates and after a certain successful point, establishes a new
therapeutically-focused subsidiary special purpose entity (SPE) to continue
development. This model has a proven track record of success, with AskBio
successfully spinning out two SPE’s – Chatham Therapeutics (acquired by Baxter
in 2014) and Bamboo Therapeutics (purchased by PFE in 2016).
Scaled-up manufacturing. AskBio is a pioneer in vector manufacturing, and has
developed a proprietary gene therapy manufacturing system with the Pro10 cell
line, a suspension-adapted, HEK293 cell-based platform. The system requires no
up-front development (transient transfection system), and produces some of the
highest viral yields in the field. The system has been optimized to produce fewer
empty capsids and is universal so that it can produce all serotypes and chimeric
forms of AAV, and is currently scalable to 2000 L.
Asklepios BioPharmaceutical (Private)
Source: AskBio. Piper Jaffray Research.
EXHIBIT 78
AskBio’s Gene Therapy Pipeline
Stage of Development
Indication Program Discovery Preclinical Phase I/II
Pompe disease AAV2/8-GAA
Limb Girdle 2i AAV
Huntington’s AAV
Epilepsy AAV
Parkinson’s
DiseaseAAV
Congestive Heart
FailureAAV
Clinical programs ongoing. Though we don’t have much clarity on future clinical
updates, AskBio currently has Phase I/II programs ongoing for Pompe disease
(ACTUS-101; first patient dosed January 22, 2019) and Parkinson’s disease, with
additional programs potentially moving into the clinic in 2019 and 2020.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 93
Developing AAV-based therapies to treat rare neuromuscular disorders.
Audentes (BOLD) is an AAV-based genetic medicines company focused on
developing and commercializing innovative therapies for serious rare
neuromuscular diseases. The company focuses on developing AAV-based genetic
medicines for monogenic diseases using BOLD’s proprietary AAV gene therapy
technology platform. The company currently has six gene therapy programs in
development, with BLA filing for lead candidate AT132 expected mid-2020.
A robust pipeline with a number of candidates brimming to enter the clinic
soon. Lead candidate AT132 has continued to show impressive results in children
with X-linked myotubular myopathy (highlighted in more detail on the following
page), and after recent discussions with FDA and EMA, BOLD is enrolling
8 additional patient in a pivotal expansion cohort to generate final data requested
by regulators to support regulatory filings next year. Beyond AT132, BOLD expects
two additional programs to enter the clinic this year – AT845 (AAV8-GAA) in
Pompe disease and AT702 (AAV9-ASO) a vectorized approach to drive exon
skipping of the mutant dystrophin gene in Duchenne muscular dystrophy.
In-house gene therapy manufacturing has its perks. BOLD invested early on in
internal large scale cGMP manufacturing, with a state-of-the art facility located in
San Francisco, and is currently manufacturing at 1,000 L scale (2 x 500 L
bioreactors) with capacity to increase to 8,000 L if needed. The company uses a
transient transfection platform with a mammalian (HEK293) serum-free suspension
culture system for gene therapy product production, and recently brought internal
plasmid manufacturing in-house to improve supply chain control, reduce costs, and
accelerate production timelines for key starting material.
Audentes Therapeutics (BOLD): Raymond, OW (Page 1 of 2)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 79
BOLD’s Gene Therapy Pipeline
EXHIBIT 80
Upcoming Catalysts
Indication Drug Upcoming Catalyst
Pompe AT845 Expected IND submission 3Q19
XLMTM AT132 Phase I/II ASPIRO update at WMS Oct. 1–5, 2019
XLMTM AT132Complete dosing in pivotal expansion cohort by
Fall 2019
DMD AT702 P1/2 trial initiation 4Q19
DMD AT702 Submit IND-amendment for new AT702 product 1Q20
XLMTM AT132 Expected BLA filing mid-2020
Stage of Development
Indication Program Discovery Preclinical Phase I/II
XLMTM AT132
Pompe AT845
DMD
(Exon 2, 1-5)AT702
DMD
(Exon 51)AT751
DMD
(Exon 53)AT753
Myotonic
DystrophyAT466
94 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Spotlight on AT132 for the treatment of XLMTM. XLMTM is a rare genetic
disorder that primarily affects boys, and is characterized by severe muscle
weakness resulting in feeding difficulties and breathing complications, with only
~50% of affected children surviving to their 2nd birthday. AT132 is an AAV-based
gene therapy designed to deliver a functional copy of the myotubularin gene
(MTM1) to patients. In May, BOLD presented updated results for Cohorts 1
(1E14 vg/kg) and 2 (3E14 vg/kg) in the ongoing Phase I/II ASPIRO trial for AT132,
with continued clinical benefits observed in all patients in Cohort 1, and initial
(~6 month) positive data for Cohort 2, with accelerated muscle recovery
demonstrated.
• Impressive muscle recovery in Cohort 2 patients. As highlighted by a study
histologist, the muscle in XLMTM recovers in a two-step process. First, the
cellular machinery must return to its proper position in a cell, which is measured
through organelle localization. Following this, muscle fibers can begin to grow
and recover. In Cohort 1 (Exhibit 81), patients had improved organelle
localization at 6 months, and fiber growth was observed in the 1-year muscle
biopsy samples. Cohort 2 had a more rapid time to recovery, with more normal
organelle localization and fiber growth observed at 6 months in these patients.
• Cohort 2 hit expectations; Cohort 1 patients continued to improve.
For Cohort 2 (n=3), functional benefits were observed across the board, with an
average increase in CHOP-INTEND (measure of neuromuscular function) of
~56%. For patients in Cohort 1, patients tended to improve the longer they’re
monitored after AT132 treatment, and the trend continued with improvements in
CHOP-INTEND scores and reductions in ventilator use noted (Exhibit 82).
Audentes Therapeutics (BOLD): Raymond, OW (Page 2 of 2)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 82
Rapid Reductions in Ventilator Use in All Treated Patients
EXHIBIT 81
Improvements in Histopathological Hallmarks of XLMTM
Cohort 1 (1E14 vg/kg) Cohort 2 (3E14 vg/kg)
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 95
AVROBIO is a clinical stage company developing ex vivo lentiviral-based
gene therapies to potentially cure rare genetic diseases with a single dose of
gene therapy. The technology underpinning these therapies is the company’s
proprietary commercial plato platform, which combines their lentiviral vector system
with an automated, closed cell manufacturing system for CD34+ gene therapy.
The system is designed to consistently produce potent cells with enhanced gene
activity and long-term durability.
Each drug product comprises autologous CD34+ cell-enriched fractions of
HSCs transduced with a lentiviral vector containing a transgene encoding for
the following protein of interest:
• AVR-RD-01: human α-galactosidase A (AGA) for Fabry disease
• AVR-RD-02: glucocerebrosidase (GCase) for Type 1 Gaucher Disease
• AVR-RD-03: acid alpha-glucosidase (GAA) for Pompe disease
• AVR-RD-04: CTNS gene encoding cystinosin, for patients with cystinosis
AVRO’s gene therapy treatment protocol involves mobilization of a patients
CD34+ hematopoietic stem cells (HSC) from their peripheral blood stem cells
(PBMC). CD34+ cells are then transduced with the relevant lentiviral vector.
Patients undergo myeloablative preconditioning with busulfan prior to the infusion
of the drug product to enhance engraftment.
In July 2019, AVRO provided a data update on its lead asset, AVR-RD-01, with
8 patients dosed across Phase I and II trials. In the Phase I trial, a
30%–40% reduction in plasma lyso-Gb3 levels compared with baseline ERT was
observed in four patients. The reduction in leukocyte and plasma AGA enzyme
activity has been sustained >2 years in Patient 1, coincident with stable VCN
(~5%–10% of all nucleated cells average 1–2 copies of the transgene). AEs were
generally consistent with myeloablative conditioning, underlying disease, or
pre-existing conditions. No SAEs related to the drug product were reported. A mild
increase in anti-AGA antibody titer was observed in one patient.
AVROBIO (AVRO): Not Covered (Page 1 of 2)
Source: AVROBIO Investor Presentations. Piper Jaffray Research.
EXHIBIT 83
AVROBIO’s Pipeline
EXHIBIT 84
AGA Enzyme Activity in Phase I Trial of AVR-RD-01 for Fabry Disease
Note: Enzyme measurements are taken at ERT troughs; Dotted line illustrative onlyPatient #5’s Day 12 data point was utilized since the one month data was not obtained
96 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
The ongoing Phase II FAB-201 trial of AVR-RD-01 for Fabry Disease has
reported promising early data. The first patient dosed achieved an
87% reduction from baseline in the average number of Gb3 inclusions per
kidney peritubular capillary (PTC) 1 year post treatment (the primary efficacy
endpoint). Reductions in substrate inclusions were also recorded in skin endothelial
cells. These clinical improvements coincided with sustained leukocyte and plasma
AGA enzyme activity at 1 year, and VCN stability.
Kidney and cardiac function remained stable in this patient at 1 year, and no
unexpected safety events have been identified among the 3 patients dosed in the
Phase II trial to date. Secondary efficacy endpoints will evaluate kidney and cardiac
function, GI distress, pain, QoL, and various biomarkers. The study continues to
enroll (N=8) and is estimated to complete in December 2020.
AVROBIO’s beginning-to-end manufacturing platform, plato, provides the
foundation for worldwide commercialization. In 2019, plato obtained regulatory
clearance for Fabry disease in the US, Canada, and Australia. It is also cleared for
use in Gaucher disease in Canada. The proprietary vector toolbox has driven
improvements in VCN, transduction efficiency, and enzyme activity, with transgene
distribution shown in the kidney, brain, bone, muscle, and heart. Therapeutic drug
monitoring informs optimal balancing of engraftment with potential toxicity.
AVROBIO (AVRO): Not Covered (Page 2 of 2)
Source: AVROBIO Investor Presentations. Piper Jaffray Research.
EXHIBIT 85
FAB-201: Substrate Reduction in Kidney Biopsy 1 Year Post Treatment
EXHIBIT 87
Upcoming Catalysts
Indication Drug Upcoming Catalysts
Fabry AVR-RD-01FAB-201 Phase II trial recruitment continues;
plato to be incorporated
Gaucher AVR-RD-02
Initiate GAU-201 Phase I/II clinical trial in patients
with Type 1 Gaucher Disease in 2H19,
incorporating plato from the outset
Cystinosis AVR-RD-04Initiate Phase I/II investigator-sponsored clinical
trial and dose first patient in 2H19
Pompe AVR-RD-03 Initiate preclinical IND-enabling study 2H19
Unpaired t test for
difference between n=55
PTCs at baseline vs n=101
PTCs at 1 year; p < 0.0001
Error bar represents the
standard deviation
EXHIBIT 86
Scalability of the plato Platform for Commercial Supply
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 97
Company Overview. Axovant is a clinical stage company that focuses on
developing gene therapies for serious neurological conditions. The company has
three gene therapy candidates in their pipeline for the treatment of Parkinson’s
Disease, GM1 gangliosidosis, and GM2 gangliosidosis. All three programs are in
the clinic and data for the PD and GM1 programs are expected later in 2019.
Lead candidate AXO-LENTI-PD is in Phase II development for Parkinson’s
Disease. AXO-LENTI-PD is a lentivirus-based therapy that delivers all three genes
required for endogenous dopamine synthesis – tyrosine hydroxylase (TH),
cyclohydrolasae (CH1), and aromatic L-amino acid decarboxylase (AADC).
The therapy is administered directly into the brain (putamen) by MRI-guided
stereotactic delivery. The goal of therapy is to reduce variability and restore steady
dopamine levels in the brain, which should translate to motor function improvement
with less dyskinesia. AXO-LENTI-PD was acquired from Oxford Biomedica in
June 2018. The construct was modified to enhance co-localization of the TH and
CH1 proteins (with the goal of tonic generation of dopamine). The company is
currently running a Phase II trial of the gene therapy (“SUNRISE-PD”). The 2-part
trial includes a dose-escalation and dose-expansion phase. Part A (or dose-
escalation) is open-label, and includes 3 dose levels. Once the optimal dose is
selected, it will be moved into Part B, where patients will be randomized 1:1 to
treatment vs sham control for primary endpoint evaluation.
Initial clinical data with AXO-LENTI-PD show signals of efficacy. In June 2019,
Axovant announced 6-month data from SUNRISE-PD’s first dose cohort
(4.2 x 106 TU). The results showed increases in “ON” times (when levodopa
treatment is working) without any dyskinesia – a common side effect of levodopa
treatment. There was a reduction of ~21% in average levodopa dose requirements
(Exhibit 89). Patients also showed a 17-point improvement from baseline in the
UPRDS III Motor score (FDA-recognized scale measuring motor function in PD).
Positioning of gene therapy in PD treatment paradigm. Axovant will initially
target the ~10,000 PD patients who currently undergo deep brain stimulation
(DBS). These patients are generally in the later stages of the disease, and DBS is
an equally invasive procedure as that required for gene therapy delivery. Data from
their 2nd dose cohort (4Q19E), is expected to guide future program directions.
Axovant Gene Therapies (AXGT): Not Covered (Page 1 of 2)
Source: Axovant Gene Therapies. Piper Jaffray Research.
EXHIBIT 88
Axovant’s Clinical Pipeline
EXHIBIT 89
Phase II SUNRISE-PD Dose Cohort I Data
98 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Axovant is also developing gene therapies for GM1 and GM2 gangliosidosis.
Both GM1 and GM2 are fatal pediatric lysosomal storage disorders.
GM1 gangliosidosis is caused by deficiency in beta-galactosidase (lactase) while
GM2 gangliosidosis (Tay-Sachs/Sandhoff) is caused by deficiency in
beta-hexosaminidase (HexA). There are no approved disease modifying therapies
available for either indication.
Axovant dosed a 30 month-old baby with Tay-Sachs disease with AXO-AAV-GM2
via intrathecal and intrathalamic injections (Exhibit 90, top right). Natural history
data suggest HexA enzyme activity correlates with severity of disease and
restoration of HexA activity to 0.5% of normal could produce a clinically meaningful
effect. This therapeutic threshold appears achievable, as CSF HexA activity in the
first treated patient increased by ~3-fold vs baseline (see top right).
Axovant is also dosing patients with GM1 gangliosidosis with AAV-AXO-GM1 in a
registrational study. Part A of the two-part adaptive design trial is evaluating safety
and efficacy of 1.5 x1013 vg/kg of the vector in 4 GM1 patients. Efficacy will be
assessed by monitoring developmental changes using the VINELAND-3 scale and
physiological changes via MRI visualization. AAV-AXO-GM1 is administered by
IV infusion in order to address both systemic manifestations (osteoporosis and
blindness) and CNS-specific aspects of the disease. Initial clinical data are
expected in 4Q19 and will include safety/tolerability, CSF and serum biomarkers,
clinical and development changes, and MRI visualizations.
Manufacturing partnership in place. The company recently announced a
partnership with Yposkesi (a spinout from Genethon) to manufacture cGMP grade
viral vector for their gene therapy programs. The arrangement provides preferred
access and reserved capacity for vector production to Axovant that is sufficient to
meet the expected demand for the gene therapy. Under the agreement, Yposkesi
will provide process development expertise, technology transfer, manufacturing
scale-up, quality control, and quality assurance services.
Axovant Gene Therapies (AXGT): Not Covered (Page 2 of 2)
Source: Axovant Gene Therapies. Piper Jaffray Research.
EXHIBIT 91
Upcoming Catalysts
Indication Gene Upcoming Catalyst
PD TH-CH1-AADC 3-month update on Cohort 2 in 4Q19
GM1Beta-
galactosidase3-month data from patients in 4Q19
GM2 HexA Interim data expected in 2H19
EXHIBIT 90
AAV-AXO-GM2 Appears Safe and Shows Signals of Efficacy in First GM2
(Tay-Sachs) Patient Dosed
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 99
Growing the ophthalmology portfolio with recent acquisition of Nightstar
Therapeutics. Biogen, a biopharmaceutical company focused on developing
therapies for serious neurological and neurodegenerative diseases, recently
accelerated their ophthalmology efforts with the acquisition of Nightstar
Therapeutics in mid-2019, bringing in up to seven new programs to the pipeline –
clinical candidates NSR-REP1 (now BIIB111), an AAV2 for choroideremia (CHM),
and NSR-RPGR (now BIIB112), an AAV8 for X-linked retinitis pigmentosa, as well
as five additional preclinical candidates including NSR-ABCA4 for Stargardt
disease, and NSR-BEST1 for Best disease.
Biogen (BIIB): Raymond, N
Source: BIIB. Piper Jaffray Research.
EXHIBIT 92
BIIB’s Gene Therapy Pipeline
EXHIBIT 93
Upcoming Catalysts
Indication Drug Upcoming Catalyst
CHM BIIB111 Phase III data expected in 2H20
XLRP BIIB112 Phase II/III data expected in 2H20
EXHIBIT 94
Evidence of Maintained Visual Acuity in Phase I/II Studies
Stage of Development
Indication Program Preclinical Phase I Phase II Phase III
Choroideremia BIIB111
XLRP BIIB112
Stargardt
diseaseNSR-ABCA4
Best disease NSR-BEST1
Additional
programsUndisclosed
Compelling Phase I/II proof-of-concept data in CHM. Based on measurements
of visual acuity, initial studies of NSR-REP1 (BIIB111) demonstrated a higher rate
of maintained vision (loss of <5 letters) with only 8% of patients receiving high dose
gene therapy treatment losing ≥5 letters on the ETDRS chart compared to 13% of
patients in the NIGHT natural history study over a one year period. At 20 months,
22% of patients in NIGHT had lost five or more letters compared to a consistent
8% of patients treated with gene therapy at 24 months.
In addition, 21% of patients treated with NSR-REP1 demonstrated a meaningful
improvement in visual acuity (gain of ≥15 letters on ETDRS chart) at one year post-
treatment compared with only 1% of patients in the NIGHT study.
NSR-REP1 is currently in a randomized, open-label Phase III study (n=111)
assessing two doses of gene therapy (low vs high dose) in patients with
choroideremia, with data expected in 2H 2020.
100 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
A diversified rare-disease growth story with a soon-to-be validated gene
therapy platform. BMRN has developed and commercialized a number of
biopharmaceuticals for rare diseases, and currently has two gene therapy programs
in development – valoctocogene roxaparvovec, or valrox (AAV5-F8) for the
treatment of hemophilia A, and BMN 307 (AAV5-PAH) for the treatment of PKU.
Phase I/II updates for valrox have been impressive, with the latest year 3 update
(Exhibit 96) indicating a plateauing of FVIII activity (as measured by the
chromogenic assay) and demonstrating durable and clinically meaningful reductions
in annualized bleed rates (ABRs) and exogenous FVIII usage. These data, in
combination with recently disclosed interim data from the Phase III (additional
details on next page) will support FDA and EMA regulatory filings through an
accelerated approval pathway, with submissions expected in 4Q19.
Valrox launch will be supported by in-house gene therapy manufacturing.
BMRN utilizes an insect producer cell line platform to manufacture product with the
current setup supporting multiple 2000 L bioreactors and treatment of 4000+
patients per year. BMRN has conducted Phase III studies with material
manufactured at scale in the “to be” commercial facility, which simplifies process
validation efforts, avoids the need for conducting large, time consuming
bioequivalence bridging studies, and reduces potential regulatory concerns.
The platform has been optimized to increase viral titers (~30x more productive than
human cell lines in their hands), reduce the number of empty capsids produced,
and drive transduction efficiency that is on par with, if not better than, mammalian
cell platforms.
BioMarin Pharmaceutical (BMRN): Raymond, OW (Page 1 of 2)
Source: BMRN. Piper Jaffray Research.
EXHIBIT 95
BMRN’s Gene Therapy Pipeline
Stage of Development
Indication Program Preclinical Phase I/II Phase III Registration
Hem A Valrox
PKU BMN 307
UndisclosedSeveral
undisclosed
EXHIBIT 96
Phase I/II Update: Durable Efficacy Benefits Continue to Year 3
FV
III A
cti
vit
y (
IU/d
L)
Annualized Bleed Rate Control Reductions in FVIII Usage
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 101
Recap of Phase III valrox data. Prior discussions with FDA indicated valrox
would be eligible for regulatory review using an accelerated approval pathway if
initial data from a subset of patients in the ongoing Phase III study met a
pre-specified number of patients achieving FVIII levels above 40 IU/dL by
23 weeks. The company hit the pre-specified interim analysis endpoint, and plans
to submit regulatory filings for valrox to FDA and EMA in 4Q19.
• Phase III hits on pre-specified FDA expectations. As of the April 30, 2019
cut-off, 16 subjects had reached the 26 week post-treatment timepoint, and
seven had mean FVIII levels above 40 IU/dL. It was noted that an eighth
subject met this pre-specified criteria after the data-cut off and three more
subjects are expected to be evaluated. Though three patients were
unevaluable, we anticipate seeing data from these subjects during the next
tranche of updates expected in 2020.
• Efficacy demonstrated on other measures, too. In regard to annualized
bleed rates (ABRs, episodes/year) and FVIII usage (infusions/year), patients in
the interim analysis cohort demonstrated dramatic reductions in ABRs from
~10/year on SoC to ~1.5/year within 6 months of treatment, and mean FVIII
usage meaningfully decreased by ~95%. These data, in combination with
longer-term follow up in patients from the Phase I/II study will be used to
support regulatory filings to FDA and EMA in 4Q19.
BioMarin Pharmaceutical (BMRN): Raymond, OW (Page 2 of 2)
Source: BMRN. Piper Jaffray Research.
EXHIBIT 97
Phase III Update: FVIII Activity Hits on Pre-Specified FDA Expectations
EXHIBIT 98
Upcoming Catalysts
Indication Drug Upcoming Catalyst
Hem A Valrox FDA and EMA regulatory filings expected 4Q19
Hem A Valrox Potential FDA and EMA approvals in 2020
PKU BMN 307 Potential IND filing expected by YE19
Annualized Bleed Rate Control Reductions in FVIII Usage
102 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
bluebird bio is developing a pipeline of gene therapies for severe genetic
diseases. bluebird’s pipeline includes several drug candidates that have the
potential to transform the way clinicians treat patients.
Lenti-D, one of bluebird’s first products to reach the clinic, is an autologous
HSC therapy for patients with cerebral adrenoleukodystrophy (CALD), a rare
hereditary neurological disorder. This therapy provides functional
adrenoleukodystrophy protein (ALDP) to the brain to prevent life-threatening
disease progression, which includes severe myelination degradation and
cerebral inflammation.
The next most-advanced candidate is Zynteglo/LentiGlobin, which is being
developed as a therapy for transfusion-dependent β-thalassemia (TDT) and
severe sickle cell disease (SCD). This product corrects the defective globin gene
by the patient’s HSCs, which when reintroduced to the patient, can produce red
blood cells (RBCs) with functional and anti-sickling hemoglobin. The company
currently has five clinical studies to evaluate the efficacy and safety of LentiGlobin
in these indications.
Recently, bluebird made significant improvements to the HSC protocol which
have increased HSC quality and, importantly, improves the patient
experience by eliminating the need for bone marrow harvest. These changes
have led to better drug product characteristics which should increase clinical
efficacy – not only for this product – but for future candidates as well. The improved
protocol has been implemented in ongoing LentiGlobin clinical studies and the
learnings can be applied across the HSC platform.
smIR approach offers another way to edit HSCs. As an alternative strategy to
the company’s gene therapy approaches, we note that gene editing has the
potential to offer effective treatment options in the future. This product utilizes
bluebird’s lentiviral vector delivery technology to introduce a microRNA- (miRNA)
embedded short hairpin RNA (shRNA), referred to as shRNAmiR, to knock down
the enhancer of BCL11a. Suppression of this target is intended to upregulate fetal
hemoglobin and provide potential relief to patients with severe SCD.
bluebird bio (BLUE): Van Buren, N (Page 1 of 3)
Source: Company Reports. Piper Jaffray Research.
Upcoming Catalysts
EXHIBIT 100
Indication Drug Upcoming Catalyst
β-thalassemia (TDT) Zynteglo Ongoing
LentiGlobin LentiGlobin Phase III Initiation By YE:2019
CALD Lenti-D BLA/MAA Submission By YE:2019
bluebird bio Severe Genetic Disease Pipeline
EXHIBIT 99
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 103
Zynteglo is bluebird’s most-advanced gene therapy product for
hemoglobinopathies. bluebird is developing a potential one-time curative gene
therapy, Zynteglo, for patients with transfusion-dependent thalassemias (TDTs).
This approach uses a self-inactivating lentiviral vector to introduce a single codon
variant (T87Q) of the normal β-globin gene into the patient’s HSCs to induce the
production T87Q-globin and incorporation of it into normal functioning hemoglobin
A in the RBCs. Thus, the final drug product is the patient’s own genetically-
modified HSCs, and the T87Q mark can serve as a biomarker for in vivo production
of functional hemoglobin in patients. Zynteglo has been granted Orphan Drug
status by the FDA and EMA for β-thalassemia. Additionally, the FDA has granted
Breakthrough Therapy designation and the EMA has granted Priority Medicines
(PRIME) eligibility for the treatment of TDT patients.
Latest data overview in TDT. The company has initiated companion international
Phase I/II clinical studies to evaluate the safety and efficacy of Zynteglo using the
BB305 vector – an improved but similar vector similar to HPV569. The goal of the
studies is to observe increases in hemoglobin production that eliminate or reduce
dependency on chronic transfusions after treatment. bluebird believes that an
increase in hemoglobin levels could reduce or eliminate the need for chronic
transfusions in TDT patients. In the Phase I/II Northstar study (HGB-204), one of
the company’s longest running trials, patients have achieved up to 3.8 years of
transfusion independence. In the Phase III Northstar-2 study (HGB-207), which
utilizes a refined manufacturing process, the median total hemoglobin level at
6 months post-infusion was 11.9 g/dL with 9.5 g/dL being that from T87Q (n=11).
Patients who achieved transfusion-independence (TI, n=4) achieved an average
total hemoglobin level of 12.4 g/dL. In both of these studies, all patients who
achieved TI have maintained TI. Based on these results, bluebird believes that
once TI has been achieved, it is possible that the effects of Zynteglo will be lifelong.
The ongoing Northstar-3 (HGB-212) study is evaluating Zynteglo in patients with
the β0/β0 genotype (n=15). Currently, for the 5 patients who are 3 or more months
post-infusion, hemoglobin levels are between 10.2–13.6 g/dL. All studies described
above are intended to serve the basis of regulatory filings in both the US and EU.
bluebird bio (BLUE): Van Buren, N (Page 2 of 3)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 101
HGB-204: 8/10 Patients With Non-β0/β0 Have Achieved TI
EXHIBIT 102
HGB-212: Gene Therapy-Derived T87Q Significantly Contributes To Hb Levels
104 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
HGB-206: Median HbS ≤50% of Total Hb in Patients With ≥6 Months Follow-Up
bluebird is seeking to provide relief to SCD patients through their LentiGlobin
product. As described previously, the self-inactivating lentiviral vector encodes the
T87Q variant, which in addition to providing the formation of functional hemoglobin,
also inhibits hemoglobin polymerization, which is critical to reducing the symptoms
in SCD patients. Therefore, this product has the potential to provide a long-term
and potentially curative treatment for SCD. Similar to LentiGlobin for use in
β-thalassemia, it has also been granted Orphan Drug status by the FDA and EMA
for SCD, and Fast-Track designation by the FDA for the treatment of severe SCD.
The FDA has also granted Regenerative Medicine Advanced Therapy (RMAT)
designation for the treatment of severe SCD. Bluebird is actively engaged with
these regulatory agencies in regards to their proposed development plans for
LentiGlobin in severe SCD.
Latest data overview. The benefits of LentiGlobin in SCD patients are indisputable
and potentially offer a cure for patients who are suffering from severe SCD.
In Group A patients with 30–36 months follow-up (ASH 2018), patients achieved
T87Q levels of 0.7–2.8 g/dL, total Hb of 7.6–11.8 g/dL, 6/7 patients achieved RBC
TI (n=6/7), and VOEs declined by 71.5%. In Group B patients with 15–18 months
follow-up (ASH 2018), 2 patients achieved T87Q levels of 3.4 and 6.5 g/dL, total Hb
of 11.0 and 12.3 g/dL, and experienced 84% and 100% reductions in VOEs.
In Group C patients (EHA 2019) the refined manufacturing procedure yielded drug
product that at ≥6 months provides robust HbA-T87Q production between 4.5 and
8.8 g/dL, total Hb of 10.2–15.0 g/dL, decreased reduction in hemolysis, and
pan-cellular distribution of T87Q. Median HbS for these patients was ≤50% of total
Hb in patients with ≥6 months follow-up. No serious ACS or VOCs occurred in any
Group C patient post-LentiGlobin treatment to date (n=6).
Based on the increases in the Hb/HbS ratios, total Hb levels, and reduction in
VOEs observed in patients thus far, we believe the HGB-206 trial is likely to meet
both primary and secondary endpoints, especially given the fact that these
endpoint criteria have been met in patients who received a less-optimal drug
product. The HGB-210 Phase III study is expected to launch this year and with the
primary endpoint being T87Q and total hemoglobin levels.
bluebird bio (BLUE): Van Buren, N (Page 3 of 3)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 103
Hypothesis For LentiGlobin In Severe Sickle Cell Disease
EXHIBIT 104
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 105
Adrenas is a corporate subsidiary of BridgeBio (BBIO; Tyler Van Buren, OW)
and is one of the four key value drivers of the company. Adrenas is developing
BBP-631, a gene therapy for congenital adrenal hyperplasia (CAH), which is
expected to be IND-ready by early 2020.
CAH is a rare, inherited, autosomal recessive disorder that is debilitating and
life-threatening. Over 90% of CAH cases are caused by inactivating mutations in
CYP21, the gene which accounts for the production of 21-hydroxylase enzyme
deficiency (21OH). 21OH deficiency sends cortisol/ACTH homeostasis into
disarray, where uninhibited ACTH primarily directs androgen production through
17OHP. This renders the patient unable to produce cortisol and aldosterone, while
producing an excess of testosterone, which can lead to fatal adrenal crises.
BBP-631 is an adeno-associated virus-5, or AAV5, gene therapy with a codon-
optimized CYP21A2 transgene and a constitutively active CAG promoter designed
to allow patients to achieve homeostatic control of adrenal hormones by treating
the root cause of the disease, 21OH deficiency. By expressing the CYP21
transgene, it replaces the 21OH defective gene in transduced adrenal cortex cells,
which then produce and replace the essential enzyme. 21OH, once restored, will
activate the natural hormonal and steroidal cycle by increasing aldosterone and
cortisol production, while reducing testosterone levels, and therefore minimizing the
risk of adrenal crisis.
BBP-631 has demonstrated the ability to transduce adrenal cortex cells and
produce 21OH in nonhuman primates (NHPs), which suggests that it can
potentially restore the natural hormonal and steroidal cycle that is disrupted in CAH
patients. RNA levels increased dramatically (>10x) in BBP-631-treated NHPs from
4 to 12 weeks at all three doses used (5E12, 1.5E13, and 4.5E13). Unsurprisingly,
the highest RNA expression was seen with the highest dose at 12 weeks. Overall,
data provided thus far suggest that there is significant transduction in the adrenals
with sufficient vector genome counts and mRNA expression three months following
a single dose of BBP-631. 24-week data will be key to assessing durability moving
forward, and should be reported soon. While we haven’t seen the data, the
company noted that durability is still being observed at this time point.
BridgeBio (Aspa) is also developing BBP-812, a self-complementary adeno-
associated viral vector 9 (scAAV9) gene therapy, to restore functional ASPA gene
expression in the brain. This is a potentially curative treatment for Canavan
Disease as it directly addresses the underlying genetic cause of disease. BBP-812
will deliver a functional copy of the ASPA gene using a brain-penetrant AAV9
delivery vector, which will be GMP manufactured in partnership with
Paragon Biosciences.
BridgeBio (BBIO): Van Buren, OW
Upcoming Catalysts
Source: Company Reports. Piper Jaffray Research.
BridgeBio Gene Therapy Pipeline
EXHIBIT 105
EXHIBIT 106
Indication Drug Upcoming Catalyst
Congenital Adrenal
Hyperplasia (CAH)BBP-631 IND filing by 1H20
106 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Company Overview. Gemini Therapeutics is a biotechnology company focused
on developing treatments for genetically-defined dry age-related macular
degeneration (AMD) and associated ocular diseases. The company deems itself a
product engine that can utilize three different modalities (recombinant proteins,
monoclonal antibodies, and/or gene therapies) to treat diseases by finding the best
therapeutic solution for patients. Their main asset, GEM103, is a recombinant CFH
protein replacement currently in preclinical development for dry AMD, with
development ongoing for GEM104 (preclinical, rCFI protein replacement) and up to
three gene therapies (CFH, CFI, and one undisclosed target).
Precision medicine for dry AMD. AMD is the leading cause of irreversible
blindness in the US and EU, with currently no approved therapies. Genetic variants
identified within CFH, the gene that encodes Complement Factor H, have been
shown to increase the risk of developing dry AMD (some variants by 20x or more)
and also play a role in the severity of clinical phenotypes. Thus, restoring functional
CFH in certain patient subsets could be therapeutically meaningful, and the
company believes developing a recombinant protein and gene therapy could
provide an integrated solution to patient treatment.
Gemini Therapeutics (Private)
Source: Gemini Therapeutics. Piper Jaffray Research.
EXHIBIT 107
Gemini’s Gene Therapy Pipeline
EXHIBIT 109
Upcoming Catalysts
Indication Drug Upcoming Catalyst
Dry AMD GEM103 CFH protein replacement; IND expected Q419
Dry AMD GEM103 Clinical data including pharmacological POC, 2020
EXHIBIT 108
Preclinical Data Limited, but Initial Recombinant Protein Data Interesting
Stage of Development
Indication Program Discovery Preclinical Phase I/II Phase III
AMD CFH
AMD CFI
Other
ocular
Not
Disclosed
(Above) CFH is a complement control protein that functions by regulating both the
decay of C3 convertase and complement Factor I mediated C3b cleavage. In the
first panel, reduced CFH activity as a result of CFH mutations increases the time to
degrade C3 convertase, which drives complement pathway upregulation. In the
second panel, GEM103, the company’s recombinant CFH protein demonstrates
equivalent activity to endogenous FH in a cleavage assay. In the far right panel,
injection of GEM103 into the eye in NHP results in the stable expression of
supra-physiological levels of CFH in the primate eye.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 107
Company Overview. Gene Therapy Research Institute (GTRI) is a Japanese
biotechnology company developing gene therapies for neurological disorders.
They have two lead programs: sporadic ALS (AAV.GTX-ADAR2) and Parkinson’s
Disease (AAV2-AADC, AAV2-TH-GCH). Both programs are currently in preclinical
testing, with Phase I/II studies expected to begin in 2020. GTRI also has earlier
stage preclinical programs in Spinocerebellar Degeneration Type 1 (SCA1),
Alzheimer’s Disease, GLUT1 Deficiency and Tay-Sachs Disease (a type of
GM2 Gangliosidosis).
The company has developed 2 novel vectors. AAV.GTX is designed for CNS
diseases and penetrates the blood-brain barrier. Preclinical testing has shown
better expression in nerve cells than the current gold-standard vector for CNS,
AAV9. Their AAV.GT5 vector is designed for metabolic diseases, and exhibits
higher expression in hepatocytes compared with other AAV vectors. No immune
reactions to neutralizing antibodies have been detected.
.
AAV.GTX entering the clinic for sporadic ALS in 2020. The company’s planned
Phase I/II study in sporadic ALS will employ the AAV.GTX vector and will deliver
the ADAR2 protein through an intrathecal injection. ADAR2 is an RNA-editing
enzyme that is involved in proper editing of glutamate receptors; mutation or
downregulation of the gene is thought to result in the glutamergic deficit and
calcium influx that is classically seen in ALS patients and implicated in motor
neuron death. The company is plans to use this study to apply for approval in
Japan under its conditional approval system around the middle of 2022.
GTRI’s PD gene therapy packages three proteins in two recombinant vectors
for administration as a single injection. GTRI’s unique method will have one
AAV2 vector housing the tyrosine hydrolase (TH) and cyclohydrolase (GCH) genes
and another AAV2 vector housing the larger aromatic amino acid decarboxylase
(AADC) gene. The three genes contribute to the biosynthesis of dopamine.
The distinct vectors will be delivered as a mixture via one intracranial injection into
the striatum. The goal of therapy is to generate tonic dopamine production that may
reduce involuntary movements and decrease oral levodopa usage. GTRI plans to
initiate a Phase I/II study in 2020 and believes the results will support conditional
approval in Japan by the end of 2022.
Gene Therapy Research Institute (Private)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 110
GTRI’s Clinical Pipeline
EXHIBIT 111
Upcoming Catalysts
Indication Drug Upcoming Catalyst
Sporadic ALS AAV.GTX-ADAR2Phase I/II trial initiation in 1H20
Potential approval in mid-2022 (JPN)
Parkinson’s
Disease
AAV2-AADC,
AAV2-TH-GCH
Phase I/II trial initiation in mid-2020
Potential approval by YE22 (JPN)
108 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Krystal Biotech is developing novel “off-the-shelf” non-invasive modified
HSV-1 gene therapy products for the treatment of severe monogenic skin
diseases, aesthetic conditions, and chronic skin diseases (Exhibit 112).
The company developed a fully-integrated vector platform that employs
non-integrating, replication-incompetent HSV-1 vectors to directly deliver
transgenes of interest to the skin via topical application with high transduction
efficiency. The ~150 Kb genome of HSV-1 confers a large payload capacity,
accommodating multiple genes and effectors.
The company’s pipeline includes the following gene therapy products:
• KB103: Bercolagene telserpavec delivers a functional copy of the COL7A1
transgene to the compromised skin of patients with dystrophic epidermolysis
bullosa (DEB) to restore expression of functional collagen VII protein
• KB105: Delivers the wildtype TGM1 gene to keratinocytes for the treatment of
Autosomal Recessive Congenital Ichthyosis (ARCI) associated with TGM1
• KB301: Modified vector platform containing the human collagen gene is
formulated into an intradermal solution for the treatment of aesthetic defects
• KB104: Modified vector encoding optimized human SPINK5 for the treatment of
Netherton Syndrome
• KB5XX: The KB500 series includes vectors modified to carry anti-inflammatory
antibody effectors (full length and Ab fragments), formulated into a topical gel
for the treatment of chronic skin diseases such as atopic dermatitis
and psoriasis
KB103, KRYS’ lead pipeline candidate, is currently in Phase I/II development
for DEB. KB103 met the primary efficacy endpoints of functional COL7 expression
(observed as early as 2 days post treatment) and observation of NC1 and NC2
reactive anchoring fibrils in the two patients treated in the Phase I trial.
Combined analysis of Phase I and II efficacy data of KB103 in DEB
demonstrated complete closure of 7/8 KB103-treated wounds. The average
time to 100% wound closure was 20 days. Two patients in the Phase I study
achieved durable wound closure of 184 days and 174 days; preliminary Phase II
data indicate a 101 day duration of wound closure at the 120-day time point.
No treatment-related adverse events, immune responses, or blistering were
reported following initial or repeat doses of KB103. Analysis of blood and urine
samples confirmed the absence of viral shedding, clinical lab abnormalities, and
antibodies to COL7.
Preliminary in vitro and preclinical proof-of-concept and safety data with KB105
further support the notion that the proprietary off-the-shelf HSV-1 platform has the
flexibility to be adapted across multiple target genes of interest for the treatment of
a variety of dermatologic conditions.
Krystal Biotech (KRYS): Not Covered (Page 1 of 2)
Source: Krystal Biotech Q3 2019 Corporate Presentation. Bustos M et al. 2019 SID Annual Meeting. Piper Jaffray Research.
EXHIBIT 112
Krystal Biotech’s Pipeline
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 109
Krystal’s off-the-shelf system is differentiated from the majority of
competitive approaches that employ autologous, ex vivo genetically modified
cell therapies to treat severe skin diseases on multiple levels, including:
• Streamlined treatment approach is less invasive, expensive, and
time-consuming for patients and providers
• Reduced costs associated with manufacturing and supply chain
• Readily available for use in multiple patients
• Relative ease of administration by dermatologists in outpatient settings
Drug product preparation is conducted in-house at Krystal’s end-to-end GMP
manufacturing facility using upstream production and downstream purification
processes that are scalable from clinical phases to commercial production, and
compliant with global regulatory requirements.
Krystal Biotech (KRYS): Not Covered (Page 2 of 2)
Source: Krystal Biotech Q3 2019 Corporate Presentation. Bustos M et al. 2019 SID Annual Meeting. Piper Jaffray Research.
EXHIBIT 114
Off-the-shelf vs Autologous Ex Vivo Cell Therapy Production and Administration for Dermatologic Diseases
EXHIBIT 113
Upcoming Catalysts
Indication Drug Upcoming Catalysts
DEB KB103
• Commence pivotal Phase III trial in 2H19
• Commence EU trial in 1H20
• File BLA in 2H20
ARCI KB105• Commence phase I/II trial in 2H19; interim data
• Initiate pivotal trial in 1H20
Aesthetics KB301/302 • File IND in 2H19
Netherton KB104 • File IND in 1H20
- -• Break ground on second GMP manufacturing
facility in 1H20
110 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
MeiraGTx is a clinical stage gene therapy company with a diverse pipeline
that spans several ocular disorders, neurodegenerative disease, and salivary
gland disease, and incorporates a proprietary Riboswitch technology, which
precisely controls target gene protein production.
The pipeline includes:
• AAV-RPE65: AAV vector containing the RPE65 gene for the treatment of
RPE65-deficiency
• AAV-CNGB3 and AAV-CNGA3: AAV vector containing the CNGB3 gene or
CNGA3 gene for the treatment of achromatopsia
• AAV-RPGR: AAV vector containing the RPGR gene for the treatment of XLRP
• AAV-GAD: AAV vector containing the GAD gene for the treatment of PD
• AAV-AQP1: AAV vector containing the AQP1 gene for the treatment of
radiation-induced xerostomia
AAV-RPE-65 is the company’s lead ophthalmic gene therapy program.
It is administered as a subretinal injection of an RPE65-expressing vector for the
treatment RPE65-deficiency. The company plans to discuss registrational criteria
with the FDA for AAV-RPE65 in RPE65 deficiency by YE19, following the positive
Phase I/II readouts we saw earlier this year. In the Phase I/II trial of AAV-RPE-65,
a total of 15 patients were treated: 9 adults in 3 dose escalation cohorts and
6 pediatric patients in an expansion cohort. The study met its primary endpoint of
safety and tolerability at 6 months and met statistical significance across multiple
secondary endpoints including improvements in retinal sensitivity (p<0.01 for both
adult and pediatric cohorts). Visual acuity was also improved following AAV-RPE65
treatment (p=0.02 for adults, and p=0.03 for children).
The company’s achromatopsia program consists of two therapeutics.
AAV-CNGB3 is designed to restore cone function in achromatopsia patients with
mutations in CNGB3 and is administered by subretinal injection. The FDA and
EMA have granted orphan drug designation, rare pediatric disease designation,
Fast Track designation, and PRIME designation for this therapy. This program is
being developed under a co-development agreement with Janssen. Data from the
Phase I/II trial of AAV-CNGB3 for achromatopsia, which is currently ongoing, are
expected in 2019/20. A total of 23 patients have been enrolled, including
11 adults in dose escalation cohorts and 12 children in a pediatric expansion
cohort. Additionally, data from the Phase I/II trial for the second candidate,
AAV-CNGA3, are expected in 2022. A total of 18 pediatric patients are expected to
enroll in this trial. This product utilizes a synthetic promoter to yield robust gene
expression, which accounts for the larger amount of protein production needed to
restore cone function in patients with a CNGA3 mutation. It is also being developed
under the Janssen agreement.
MeiraGTx (MGTX): Van Buren, OW (Page 1 of 2)
Source: Company Reports. Piper Jaffray Research.
MeiraGTx Pipeline
EXHIBIT 115
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 111
Meira’s is also developing AAV-RPGR for the treatment of the subset of XLRP
caused by mutations in RPGR. The FDA and EMA have granted orphan drug
designation and Fast Track designation. This program is being developed under
agreement with Janssen. Data from the ongoing Phase I/II trial of AAV-RPGR in
XLRP are expected in 2021. A total of 36 adult and pediatric patients are expected
to enroll.
In neurological disorders, the company’s main focus is Parkinson’s disease.
Nearly 1 million people in the US alone (and 10M people worldwide) are affected
by PD, making it the second-most common neurodegenerative disease after
Alzheimer’s disease. There are currently no approved gene therapies for PD.
However, Duodopda has been approved as a first line therapy for PD, and is a gel
for continuous intestinal administration of a mixture of levodopa and carbidopa.
MeiraGTx aims to replace this continuously administered drug with a one-time
gene therapy, AAV-GAD. AAV-GAD delivers the glutamic acid decarboxylase
(GAD) gene directly to subthalamic nucleus (STN) neurons and is designed to
rebalance excitation and inhibition by bypassing the circuitry disrupted by
dopamine loss. Expression of GAD should increase production of inhibitory GABA,
thereby normalizing the hyperactive motor circuits as a way to improve symptoms
in PD patients without affecting other brain regions. The company recently
completed a Phase II clinical study of AAV-GAD in 45 PD patients. The study met
its primary endpoint at 6 months of a change from baseline in off-medication
Unified Parkinson Disease Rating Scale (UPDRS) motor score (8.1 point
improvement for AAV-GAD vs 4.7 point improvement for sham, p<0.03).
The number of responders with clinically meaningful improvements of 9 points or
greater in UPDRS motor score was 50% in AAV-GAD treated patients and 14% in
the sham cohort at 6 months (p<0.03), which increased to 62% and 24% at
12 months, respectively (p<0.02). Moreover, there was a correlation between levels
of a biomarker for the formation of new polysynaptic pathways that link the STN to
motor cortical regions (GADRP, p<0.009). The company plans to discuss
registrational criteria with the FDA for AAV-GAD in PD by YE19.
In addition to a robust clinical pipeline, the company has developed in-house
manufacturing capabilities provided by a wholly-owned cGMP manufacturing
facility located in London. The facility allows for faster start up time, capabilities for
scaling to multiple programs and vector types, and acceleration of processing times
due to its modular design. The company is looking to expand its manufacturing
capacity in the near-term and is planning to produce plasmids in-house as well.
MeiraGTx (MGTX): Van Buren, OW (Page 2 of 2)
Source: Company Reports. Piper Jaffray Research.
Upcoming Catalysts
EXHIBIT 116
Indication Drug Upcoming Catalyst
Parkinson’s Disease AAV-GADMeet with FDA to discuss
registrational criteria by YE:2019
REP65 Deficiency AAV-RPE65Meet with FDA to discuss
registrational criteria by YE:2019
Achromatopsia AAV-CNGB3Data from the Phase I/II trial by
late 2019/early 2020
X-Linked Retinitis
PigmentosaAAV-RPGR Phase I/II data in 2021
Achromatopsia AAV-CNGA3 Phase I/II data in 2022
Radiation-Induced
XerostomiaAAV-AQP1 Phase I/II data in 2022
112 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Company Overview. Orchard Therapeutics is a commercial-stage
biopharmaceutical company utilizing ex vivo autologous hematopoietic stem cell
(HSC) gene therapy to transform the lives of patients with rare diseases, with
current franchises spanning neurometabolic disorders, primary immune
deficiencies, and hemoglobinopathies (see below). To produce long-lasting effects,
the company uses a lentiviral vector to introduce functional exogenous copies of a
non- or dysfunctional gene into a patient’s own HSCs, which are isolated and
treated in an ex vivo process and then re-administered to the patient.
Deep portfolio of product candidates. Strimvelis is an EU marketed
gammaretroviral-based product for the treatment of adenosine deaminase severe
combined immunodeficiency (ADA-SCID), and ORTX has six lentiviral product
candidates in clinical-stage development, with several additional candidates in
preclinical development. ORTX anticipates near-term regulatory submissions for
approval of three advanced clinical-stage product candidates: OTL-101 for the
treatment of ADA-SCID, OTL-200 for metachromatic leukodystrophy (MLD), and
OTL-103 for the treatment of Wiskott-Aldrich syndrome (WAS).
Orchard Therapeutics (ORTX): Not Covered
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 117
Orchard’s Gene Therapy Pipeline
EXHIBIT 119
Upcoming Catalysts
Indication Drug Upcoming Catalyst
ADA-SCID OTL-101 Regulatory filings expected 1H20
MLD OTL-200 EMA filing expected 1H20
WAS OTL-103 FDA/EMA regulatory filings expected in 2021
EXHIBIT 118
Ex Vivo Gene Delivery to HSCs Can Correct Multiple Diseases
Applicability across multiple diseases. Genetically modified HSCs have
wide-ranging uses for a number of indications (see above) given their ability to
differentiate into multiple cell types, which facilitates targeting of diverse
physiological systems, including the CNS, immune system, and red blood cell
lineage. By leveraging the innate self-renewing capability of HSCs as well as the
ability of lentiviral vectors to achieve stable integration of a modified gene into the
HSC genome, these therapies have the potential to provide a durable effect
following a single administration of product.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 113
Company Overview. Passage Bio is harnessing decades of gene therapy
expertise to streamline the development of novel therapies for genetic neurological
diseases. Their co-founder and Chief Scientific Advisor, Jim Wilson, MD, PhD is a
world-renowned authority on gene therapy. Passage has a formal research,
collaboration, and license agreement with the Gene Therapy Program (GTP) and
Orphan Disease Center at the University of Pennsylvania, and currently has a
portfolio that includes treatments for GM1 gangliosidosis, frontotemporal dementia
(FTD) and Krabbe disease, which are primed to enter the clinic throughout 2020.
UPenn and Passage Bio Partnership Model. Under the unique partnership
model, UPenn’s GTP is responsible for all pre-clinical and IND-enabling studies,
after which Passage Bio takes responsibility for all clinical development. Passage
Bio’s partnership with UPenn gives them access to the initial 5 programs
(2 undisclosed) and the option to license 7 additional programs using next-gen
capsids. In return, UPenn receives an upfront payment, sponsored research
agreement funding, along with royalties and milestones from development and
potential sales. During clinical development, UPenn’s Orphan Disease Center is
responsible for the ongoing GM1 natural history study.
Preclinical biomarker data for AAV-GLB1 in GM1 and AAV-PGRN in FTD are
early indicators of efficacy. Initial studies of AAV-GLB1 in mice have shown
improvements in HEX activity upon administration. Additionally, preclinical work in
non-human primates (NHP) using AAV-PGRN has demonstrated 5–10x increases
of PGRN levels in the cerebral spinal fluid (CSF), compared with PGRN levels in
healthy human subjects (Exhibit 121). Both programs are expected to initiate
clinical development in 2020.
Passage Bio (Private)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 120
Passage’s Gene Therapy Pipeline
EXHIBIT 122
Upcoming Catalysts
Indication Drug Upcoming Catalyst
GM1 AAV-GLB1 Enter Phase I clinical development 1H20
FTD AAV-PGRN Enter Phase I clinical development 1H20
Krabbe
DiseaseAAV-GALC Enter Phase I clinical development 2H20
EXHIBIT 121
CSF Levels of PGRN After AAV-PGRN Treatment of NHPs vs Healthy Humans
Stage of Development
Indication Program Preclinical Phase I Phase II Phase III
GM1 AAV-GLB1
FTD AAV-PGRN
Krabbe
DiseaseAAV-GALC
114 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Rocket Pharmaceuticals, founded in 2015, is a clinical stage biotechnology
company with a robust pipeline of AAV- and LVV-based gene therapy programs
with potential to be first-in-class for rare and devastating pediatric diseases.
The company has generated a group of promising proprietary therapies, including:
• RP-A501: AAV9 vector containing the lysosome-associated membrane protein
2 B (LAMP2B) gene for the treatment of Danon Disease (DD)
• RP-L102: LVV containing Fanconi anemia complementation group A (FANCA)
gene for the treatment of Fanconi Anemia (FA)
• RP-L301: LVV containing the pyruvate kinase L/R (PKLR) gene for the
treatment of Pyruvate Kinase Deficiency (PKD)
• RP-L201: LVV containing the integrin subunit beta-2 gene (ITGB2) for the
treatment of Leukocyte Adhesion Deficiency-1 (LAD-1)
• RP-L401: LVV carrying the TCIRG1 gene, which encodes the a3 subunit of
vacuolar H+-ATPases, to treat infantile malignant osteopetrosis (IMO)
RP-A501 is Rocket’s lead AAV-based candidate for the treatment of
Danon Disease. Currently, there are no targeted therapies in development for DD.
DD is caused by mutations in the LAMP2B gene, which plays an important role in
autophagy. This mutation prevents clearance of cell debris which causes
pathological accumulation and often leads to profound cardiomyopathy. There are
approximately 40,000 patients with DD in the US and EU that could be treated by
Rocket’s RP-A501. RP-A501 is an AAV-delivery vector containing the LAMP2B
gene and has distinct tropism for the heart and skeletal muscle, which are target
tissues for the disease. Backed by strong preclinical proof-of-concept, Rocket
began recruiting for the Phase I clinical trial for RP-A501 in 1Q19 and dosed the
first patient in 2Q19. The company intends to enter registrational studies next year.
If successful, approval of RP-A501 may be supported by 2024, which puts it on
track to be the first targeted therapy approved for DD. We believe RP-A501 could
be a very significant sales opportunity for Rocket as it has the potential to reach
$10B+ in US and EU sales by 2035.
RP-L102 is Rocket’s lead LVV-based candidate for the treatment of
Fanconi Anemia. FA is caused by mutations in the FA core protein complex
(FANCA/B/C/E/F/G/L/M). In particular, mutations in the FANCA protein account for
over 70% of cases. It is characterized by bone marrow failure often before the age
of 10 and is commonly comorbid with blood malignancies and developmental
disabilities. The current SoC is allogeneic hematologic stem cell transplant (HSCT),
but is not suitable for all patients due to the intrinsic DNA repair defects in FA
patients. HLA-matches may also be unavailable for some patients. Another
complication of HSCT is that about 30% of patients display increased sensitivity to
graft-versus-host-disease (GvHD). As an alternative to HSCT, Rocket is developing
RP-L102 which delivers the functional FANCA gene via a lentivirus vector to
potentially provide a cure for this devastating disease.
Rocket Pharma (RCKT): Not Covered (Page 1 of 2)
Source: Company Reports. Piper Jaffray Research.
Rocket’s Pipeline
EXHIBIT 123
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 115
If successful, RP-L102 could be a first-in-class, curative therapy for Fanconi
Anemia. Importantly, RP-L102 may be superior to SoC HSCT because it could be
given prior to the development of a potentially fatal bone marrow failure, whereas
HSCT is given to patients whose bone marrow has already dangerously failed.
Rocket is currently evaluating two methodologies for RP-L102 in FA: Process A
and Process B. Process B differs from Process A in that it administers higher
doses of virus, utilizes transduction enhancers, and employs a commercial-grade
vector. Long-term data (30+ months follow-up) in patients treated by Process A and
initial data for Process B are expected by YE19. A registrational Phase II trial is
expected to begin by YE19 as well. If successful, RP-L102 may represent a
~$200MM peak sales opportunity for the company.
RP-L301 is a preclinical stage drug candidate for the treatment of PKD that is
entering the clinic in 2019. Patients with Pyruvate Kinase Deficiency (PKD) have a
mutation in the pyruvate kinase L/R (PKLR) gene, which is critical for ATP
production in red blood cells. As a result, these patients develop splenomegaly,
pallor, jaundice, and excess iron in the blood. Rocket’s RP-L301 is an LVV-based
therapy in which expression of PKLR cDNA is driven by the constitutive human
PGK promoter. The LVV is expected to enter the clinic this year based on strong
preclinical evidence of safety and efficacy. We believe RP-L301 may be a
$100MM+ opportunity that could reach $250MM+ by 2028. We note that Agios
Pharmaceuticals (AGIO; covered by Van Buren) is currently evaluating mitapivat,
an oral, small molecule PKR activator for PKD and thalassemia, which has
demonstrated a durable increase in hemoglobin in ~50% of PKD patients. While
successful development of mitapivat could limit Rocket’s market opportunity, we
believe the opportunity is still meaningful given that half of patients may not derive
benefit from mitapivat. Additionally, management believes that patients may prefer
a singular gene therapy treatment as opposed to a twice-daily oral treatment, which
may allow RP-L301 to penetrate further into the PKD market.
RP-L201 is an LVV-based gene therapy for the treatment of LAD-1. Leukocyte
Adhesion Deficiency-1 (LAD-1) is a devastating immune disorder that can range in
severity with a majority of the most-severe patients facing mortality before the age
of 3 years. The disease is caused by mutations in the ITGB2 gene that encodes
CD18, a component of the Beta-2 integrin that is critical for the adherence of
leukocytes to blood vessels and surrounding tissues. This defect results in the
patient’s leukocytes being unable to exhibit cytotoxic activities, which significantly
increases susceptibility to bacterial and fungal infections. Infections lead to death in
about half of patients before the age of 2. Rocket is developing RP-L201, which is
an LVV vector encoding the ITGB2 gene, to treat LAD-1. The company estimates
RP-L201 may treat 25–50 LAD-1 patients per year. Rocket began recruiting for the
Phase I/II clinical trial for RP-L201 in 1Q19 and expects to dose its first patient
soon. We expect data for the Phase I portion of the trial by the end of 2019.
If successful, we estimate a launch by 2023, resulting in a ~$30MM opportunity
by 2028.
Rocket Pharma (RCKT): Not Covered (Page 2 of 2)
Source: Company Reports. Piper Jaffray Research.
Upcoming Catalysts
EXHIBIT 124
Indication Drug Upcoming Catalyst
Danon Disease RP-A501 IND ready for Phase I by early 2020
Fanconi Anemia RP-L102 Initial data from Process B in 2H19
Pyruvate Kinase
Deficiency (PKD)RP-L301 Initiation of Phase I in 2H19
Leukocyte Adhesion
Deficiency (LAD)RP-L201 Initial data from Phase I in 2H19
116 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Sarepta Therapeutics is a biopharmaceutical company that develops
therapies for rare neurodegenerative disorders. The company’s research and
development efforts span several therapeutic modalities including RNA, gene
therapy, and gene editing. Sarepta has one exon skipping product on the market to
treat DMD with mutations in exon 51, EXONDYS51. Gene therapy has become a
primary focus for Sarepta, with 14 different programs in the pipeline (see below).
Lead gene therapy program delivers truncated dystrophin
(“microdystrophin”) protein via AAV for DMD. Sarepta’s SRP-9001, houses the
microdystrophin (MD) protein in their proprietary AAVrh74 vector and implements a
MHC7 promotor. The vector has been optimized to reduce immunogenicity and the
promoter shows enhanced expression in skeletal and cardiac muscles. SRP-9001
is currently being tested in a randomized controlled trial of 40 DMD patients (dosed
at 2x1014 vg/kg). Dosing is expected to be completed by YE19, with 12-month
expression and functional data anticipated by YE20. A trial using commercial
supply of SRP-9001 is expected to launch in 1H20.
Data from a previous open-label trial (n=4) showed improvements in biomarkers
(such as CK-levels, which are inversely correlated with muscle degradation) and
functional metrics, summarized in Exhibit 127, below.
Other companies are also developing truncated-dystrophin gene therapies, namely
Pfizer and Solid Biosciences (PFE, SLDB, not covered). However, both suffered
setbacks following serious safety events related to complement-activation (both
use AAV9 vector). As a result, Sarepta has a comfortable lead in time-to-market.
Sarepta Therapeutics (SRPT): Brill, OW (Page 1 of 2)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 125
Sarepta’s Current Gene Therapy Pipeline
EXHIBIT 127
Key Metrics from OL Microdystrophin Gene Therapy Study (n=4)
SRP-9001 Construct
EXHIBIT 126
Wild-type Dystrophin gene = 14 kb
Microdystrophin gene = 3.6 kb
1. Clinical update from March 25, 2019. *** NorthStar Ambulatory Test.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 117
Sarepta’s second gene therapy in Limb-Girdle Dystrophy Type 2E (LGMD-2E),
has shown promising results thus far. SRP-9003 employs the same vector and
promoter (AAVrh74 and MHCK7) as the company’s DMD gene therapy but
delivers the full-length β-sarcoglycan gene. It is currently being investigated in an
open-label trial. Early biomarker data in 3 LGMD2E patients who were dosed at
5x1013 vg/kg showed an average of 51% of muscle fibers showing β-sarcoglycan
expression (primary endpoint ≥20%) and significant CK reductions of >90%.
Average expression by Western Blot was 36% of normal. One patient exhibited
high liver transaminase levels, which was controlled using steroids. A longer
steroid taper was implemented to prevent LFT elevations moving forward.
Accelerated approval based on β-sarcoglycan expression is possible.
Unlike SRP-9001, which delivers a truncated dystrophin protein, SRP-9003
packages the whole, naturally-occurring (β-sarcoglycan) gene – meaning
accelerated approval based on biomarker expression should be possible.
One KOL suggested that β-sarcoglycan levels akin to asymptomatic carriers
(~30%–50%) may be sufficient for approval. Initial mean expression levels (36%),
are within this range. We await future updates on durability of effect and safety.
LGMD-2E opportunity is modest but de-risk other LGMD programs (2A, B, C,
D, L). By our estimates, the LGMD-2E gene therapy could generate $400M for
Sarepta. However, Sarepta also has earlier stage programs in LGMD subtypes 2A,
B, C, D and L. Successful development of the LGMD2E program should have
positive read through to the broader LGMD gene therapy pipeline (which have the
same vector, similar promoter and treat a similar disease pathology) – see middle
right. Our conservative estimates put the overall LGMD opportunity at ~$3B.
Manufacturing capabilities. Sarepta plans to use an adherent cell-based
manufacturing method that should allow for an easier transition to commercial
product. They have agreements with Brammer Bio (now Thermo Fisher) that gives
them preferred access and reserved space for commercial production of their
microdystrophin gene therapy. The iCellis adherent cell unit bioreactors will be
utilized for manufacturing. Additionally, Sarepta also has an agreement with
Paragon Biosciences (now Catalent), who will manufacture their LGMD gene
therapies and provide overflow production space.
Sarepta Therapeutics (SRPT): Brill, OW (Page 2 of 2)
Source: Sarepta Therapeutics. Piper Jaffray Research.
EXHIBIT 129
Upcoming Catalysts
Indication Gene/Drug Upcoming Catalyst
Duchenne
Muscular
Dystrophy
Casimersen NDA Filing – 2H19
SRP-9001DMD RCT study data readout – YE20;
Commercial product RCT initial data – YE20
LGMD-2E SRP-9003 Updated OL data from trial at WMS – Oct. 2019
EXHIBIT 128
Sarepta’s LGMD Gene Therapy Programs: Genes, Vectors, and Promoters
118 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Once a wild card, RARE’s gene therapy platform continues to deliver...
RARE announced the acquisition of Dimension Therapeutics in September 2017,
adding the company’s AAV gene therapy platform to RARE’s treatment modality
base of small molecules, proteins, and mRNA programs, and providing an optimal
set up to treat a number of rare monogenic, metabolic diseases by selecting the
best treatment strategy for each indication. Since this time, clinical programs
DTX301 (AAV8-OTC) for ornithine transcarbamylase deficiency and DTX401
(AAV8-G6Pase) for glycogen storage disease type Ia have demonstrated initial
proof-of-concept results with treatment generally well tolerated in patients.
…and has further expanded with a now budding pipeline of preclinical
candidates. The gene therapy pipeline continues to grow, with UX701 (AAV8-
ATP7B or AAV9-ATP7B) for Wilson disease expected to enter the clinic in 2020.
Initial excitement was highlighted at the R&D day in April 2019 for up and coming
program UX055 (AAV9-CDKL5), a rare genetic neurological disorder, and a
potential pivot from the normal liver-based metabolic indications.
Ultragenyx Pharmaceutical (RARE): Raymond, OW (Page 1 of 2)
Source: RARE. Piper Jaffray Research.
EXHIBIT 131
Upcoming Catalysts
Indication Drug Upcoming Catalyst
OTC
DeficiencyDTX301 Initial Cohort 3 data (1E13 GC/kg) expected 3Q19
GSDIa DTX401 Initial Cohort 2 data (6E12 GC/kg) expected 3Q19
Wilson
DiseaseUX701 IND filing expected in 2020
EXHIBIT 130
RARE’s Gene Therapy Pipeline
Both mammalian transient transfection and producer cell line platforms
provide a nice setup for scalable manufacturing. RARE has established an
internal non-GMP process to develop gene therapy manufacturing processes for
each indication at full scale in house, and then transfer the process to a contract
manufacturing organization for full clinical and/or commercial development.
However, management has noted that they plan to build their own in-house GMP
manufacturing facility to support future gene therapy manufacturing needs.
Additional details are still TBD.
For platforms, RARE utilizes both a mammalian transient transfection system with
HEK293 cells for smaller indications (eg, OTC deficiency, GSDIa) and HeLa
producer cell lines for larger indications (eg, Hemophilia A - partnered with Bayer,
Wilson disease). RARE believes the HeLa system is the future for gene therapy
manufacturing, and has made a substantial investment to maximize the potential of
the HeLa platform, developing a production system that they’ve branded HeLa 2.0.
This system significantly shortens the time to producer cell generation, boosts
titers, increases product quality and scale, and contributes to an accelerated
product development timeline.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 119
Highlighting positive Phase I/II updates for DTX301 in the treatment of OTC
deficiency. At the last major update for the program last September, RARE
toplined results for the second dose cohort treated at 6E12 GC/kg from the ongoing
Phase I/II study of DTX301 for the treatment of ornithine transcarbamylase (OTC)
deficiency. The update was similar to results from Cohort 1 (treated at
2E12 GC/kg), with one of three patients achieving a clinically meaningful change in
the rate of ureagenesis. The study moved to dosing Cohort 3 patients last year at
the highest dose (1E13 GC/kg), with topline results expected in 3Q19.
• Like Cohort 1, Cohort 2 was one for three in responses. Six patients in total
have been treated with DTX301 (Cohort 1, n=3; Cohort 2, n=3), with two
responders reported, one from each dosing cohort. The two responders
(Exhibit 132) continue to demonstrate sustained normalization of ureagenesis at
weeks 78 (patient 1) and 52 (patient 4), and have been able to discontinue both
alternate pathway medications and protein-restricted diets
• Safety continues to look benign. DTX301’s safety profile continues to look
favorable, with no infusion-related AEs or SAEs reported. Similar to Cohort 1,
patient 4 in Cohort 2 has had mild ALT elevations that have successfully been
controlled with two courses of tapering steroids, which is par for the course with
gene therapies
• Still looking for a dose. After completing a review of Week 12 data, the DMC
recommended RARE begin dosing of Cohort 3 patients (1E13 GC/kg), with
management indicating success would be 2 of 3 patients achieving a clinically
meaningful increase in the rate of ureagenesis at that dose. If this mark is hit,
RARE would add another three patients at that dose, and then use the data to
plan a potentially registrational Phase III study. We expect an initial update on
Cohort 3 patients in 3Q19
Ultragenyx Pharmaceutical (RARE): Raymond, OW (Page 2 of 2)
Source: RARE. Piper Jaffray Research.
EXHIBIT 132
Durable Normalization in Ureagenesis in Patients with OTC Deficiency
Cohort 1, Patient 1 (2E12 GC/kg)
Cohort 2, Patient 4 (6E12 GC/kg)
120 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
uniQure is a biotechnology company that focuses on developing liver-
directed and CNS-targeted gene therapies. They currently have one gene
therapy in a pivotal trial for Hemophilia B with a second program for Huntington’s
disease entering the clinic this year. uniQure also has preclinical assets in
development for Fabry disease and spinocerebral ataxia type 3 (SCA Type 3).
Pivotal data from lead program, AMT-061, for Hemophilia B expected in 2020.
AMT-061 utilizes the AAV5 vector and an engineered variant of the Factor IX (FIX)
called the Padua variant as the functional gene. FIX is implicated in the blood
clotting pathway and enables proper clotting function. uniQure is currently running
a Phase III pivotal trial of ~55 hemophilia B patients that are serving as their own
controls following a 6-month lead-in phase to treatment. This trial design is very
similar to that of the ongoing Phase Iib trial, which has shown strong efficacy and
durability of response out to 36 weeks.
.
Phase IIb OL data in 3 patients indicate strong efficacy and durability of
response. Data from the Phase IIb trial in (n=3) Hemophilia B patients looks better
than its Hemophilia-B gene therapy competitor, Spark Therapeutics (ONCE, not
covered) across all times points (see below). Specifically, FIX activity levels, which
correlate with number of bleeding events, have been consistently higher for
uniQure’s therapy over ~36 weeks of follow-up. AMT-061 also appears to be
durable as FIX activity does not fluctuate significantly over time.
The hemophilia B market may be modest, but QURE is poised to dominate it.
Another differentiating factor for AMT-061 beyond better efficacy and durability of
response is that immunogenicity is very low and patients are not screened out
based on presence of neutralizing antibodies. In the Phase Iib trial, 2 out of 3
patients safely received treatment despite the presence of neutralizing antibodies.
Current Piper Jaffray estimates indicate the Hemophilia B gene therapy market
could be ~$1B – and uniQure could capture the lion’s-share with superior efficacy,
safety, and a first movers advantage.
uniQure (QURE): Brill, OW (Page 1 of 2)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 133
uniQure’s Current Pipeline
EXHIBIT 134
Phase II Trial Comparison of Hemophilia B Gene Therapies
12 wks 26 wks 36 wks 52 wks
Sparks Therapeutics ~24% ~30% ~30% 35.5%
uniQure 38% 47% 45% NA
Sparks Therapeutics ~38% ~43% ~42% ~60%
uniQure 51% 57% 54% NA
Sparks Therapeutics* ~12% ~18% ~15% <10%
uniQure 25% 33% 30% NA
*Includes patients before SPK-9001 protocol adjustment
FIX Activity to Normal
Average
Highest
Lowest
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 121
AMT-130, is a gene therapy for Huntington’s disease (HD) that aims to reduce
mHTT aggregation. AMT-130 utilizes an AAV5 vector housing a CAG promoter
that drives expression of a novel miRNA (“miQURE”) that targets mutated
huntington gene (mHTT) aggregates and exon 1 protein fragments. Exon 1 is
implicated in the production of the most toxic inclusion body generating fragments.
The miQURE oligomer is designed in such a way that it produces negligible
“passenger strands” in order to prevent off-target effects. Upon expression,
miQURE is incorporated in the cytoplasmic RNA-induced silencing complex (RISC)
and helps degrade the mHTT mRNA; a similar RNAi effect also occurs in the
nucleus to cause cell-wide lowering of mHTT aggregates.
A Phase I/II trial of AMT-130 in HD will commence in 2H19. The RCT will
include ~25 patients with early manifestations (Stage 1) of HD that are at risk for a
rapidly progressive disease (≥44 HTT CAG repeats). Safety and efficacy – in the
form of motor function, CSF mHTT protein levels and other biomarkers – will be
monitored over 9–18 months. AMT-130 has received orphan drug designation by
the FDA and EMA, and Fast Track Designation in the US.
Robust preclinical suggestive of durable mHTT knock down with AMT-130.
AMT-130 showed transduction throughout the brains of mini-pigs which translated
to strong mHTT lowering that was durable from 6- to 12-months (Exhibit 135).
Cortical neurons are affected in mid-to-late stage HD, meaning AMT-130 may be
effective in this population. Minipig brains are ~5x larger than NHP brains and
provide a more realistic model of human brains.
Earlier stage assets also look promising. Preclinical data presented on
AMT-150, their gene therapy for SCA3, at AAN 2019 showed that an intrathecal
AMT-150 injection resulted in strong transduction, and reductions of mutant ataxin-
3 levels in the cerebellum and the brainstem, of 53% and 65%, respectively.
uniQure possesses in-house manufacturing capabilities. QURE’s large-scale
manufacturing capability allows them to produce commercial grade product
throughout development and to scale-up to commercial supply quickly.
uniQure (QURE): Brill, OW (Page 2 of 2)
Source: Company Reports. Piper Jaffray Research.
EXHIBIT 136
Upcoming Catalysts
Indication Gene/Drug Upcoming Catalyst
Hemophilia B AMT-061 Top-line data from Ph3 – YE20
Huntington’s
DiseaseAMT-130
Initial Phase I/II biomarker and safety data –
YE19 or early 2020
EXHIBIT 135
AMT-130 Shows mHTT Lowering Across Various Regions of the Brain
Company Model Region %∆ mHTT from naïve Time Period
uniQure
(AMT-130)Mini-pigs
putamen ~68%
12-mosthalamus >50%
caudate >70%
cortical neurons 47% (6-mos) ~28%-47%
122 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Appendix
06.
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 123
Ongoing Gene Therapy Trials
by Indication
06.1
124 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Dermatology
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Abeona Therapeutics ABEO Recessive Dystrophic EB EB-101 Retrovirus Phase III
Abeona Therapeutics ABEO Recessive Dystrophic EB EB-102 AAV Preclinical
Amryt Pharma AMYT Recessive Dystrophic EB AP103 Non-viral GT Preclinical
BioVec Pharma Private Epidermolysis Bullosa - Retrovirus Preclinical
Fibrocell Science FCSC Recessive Dystrophic EB FCX-007 Lentivirus Phase I/II
GlaxoSmithKline GSK Epidermolysis Bullosa - - Preclinical
Holostem Terapie Avanzate Srl Private Recessive Dystrophic EB Hologene 7 Retrovirus Phase II
Immusoft Corp. Private Epidermolysis Bullosa - - Preclinical
Krystal Biotech KRYS Dystrophic EB KB103 HSV-1 Phase I/II
Krystal Biotech KRYS Junctional EB KB-107 Hsv-1 Preclinical
Temprian Therapeutics Private Vitiligo - Non-viral GT Preclinical
ViroMed Co KOSDAQ 084990 Wounds pIKO AAV Preclinical
Canton Biotechnologies Private WoundsCA5 HIF
(DNA electroporation)Non-viral GT Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 125
Gene Therapies Landscape: Hematology (Page 1 of 2)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Aruvant Sciences Private
Beta-thalassemia
ARU-1801 Lentivirus Preclinical
bluebird bio BLUE LentiGlobin Lentivirus Phase III Van Buren
CSL Behring CSLLY CAL-H - Preclinical
Errant Gene Therapeutic Private Thalagen - Preclinical
Orchard Therapeutics plc ORTX OTL-300 Lentivirus Phase I/II
Audentes Therapeutics BOLD
Crigler-Najjar Syndrome
AT342 AAV8 Phase I/II Raymond
Genethon SA Private - AAV Preclinical
Logicbio Therapeutics LOGC LB-301 AAV Discovery/Preclinical
BioMarin Pharmaceutical BMRN
Hemophilia A
valoctocogene
roxaparvovec
(Valrox, BMN 270)
AAV5 Phase III Raymond
Expression Therapeutics PrivateEx vivo stem cell-LV-
FVIII gene therapyLentivirus Preclinical
Expression Therapeutics Private AAV-FVIII AAV Preclinical
Sangamo Therapeutics SGMO SB-525 - Phase I/II
Spark Therapeutics ONCE SPK-8011 AAV5 Phase III
Spark Therapeutics ONCE SPK-8016 AAV5 Phase II
Takeda Pharmaceutical Co TAK TAK-754 (SHP654) - Phase I
Ultragenyx Pharmaceutical RARE DTX201 AAV Phase II Raymond
UniQure QURE AMT-180 AAV5 Preclinical Brill
126 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Hematology (Page 1 of 2)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Spark Therapeutics ONCE
Hemophilia B
Fidanacogene
elaparvovec
(SPK-9001)
AAV Phase III
UniQure QURE AMT-061 AAV5 Phase III Brill
Freeline Therapeutics Private FLT-180a AAV Phase I/II
Expression Therapeutics Private AAV-FIX AAV Preclinical
Takeda Pharmaceutical Co TAK SHP648 - Preclinical
Logicbio Therapeutics LOGC LB-101 AAV Discovery/Preclinical
Catalyst Biosciences CBIO CB 2679d-GT AAV8 Preclinical
Adverum Biotechnologies ADVM Hereditary angioedema ADVM-053 - Preclinical Van Buren
Rocket Pharmaceuticals RCKT
Fanconi Anemia
RPL-102 Lentivirus Phase I
Genethon SA Private - - Phase II
Abeona Therapeutics ABEO ABO-301 AAV Preclinical
bluebird bio BLUE
Sickle Cell Disease
LentiGlobin Lentivirus Phase II Van Buren
bluebird bio BLUE Bcl11a shmiR Lentivirus Phase I Van Buren
Aruvant Sciences Private ARU-1801 Lentivirus Phase I/II
Généthon SA Private
Wiskott-Aldrich
- Lentivirus Phase II
Orchard Therapeutics ORTXOTL-103
(GSK2696275)Lentivirus Phase III
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 127
Gene Therapies Landscape: Inborn Errors of Metabolism – Lysosomal Storage Disorders (Page 1 of 2)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Rocket Pharma RCKT Danon disease (GSDIIb) RP-A501 AAV9 Phase I
Abeona Therapeutics ABEO
Fabry disease
- AAV Preclinical
Amicus Therapeutics FOLD- - Preclinical
AVROBIO AVROAVR-RD-01 Lentivirus Phase I/II
Freeline Therapeutics Private FLT190 AAV Preclinical
Sangamo Therapeutics SGMO ST-920 AAV6 Preclinical
UniQure QURE AMT-190 AAV5 Preclinical Brill
Axovant Sciences Private
GM1
AXO-AAV-GM1 AAV Ph 1/2
Lysogene LYS LYS-GM101 AAVrh10 Preclinical
Passage Bio Private AAV-GM1 AAV Preclinical
Axovant Sciences AXVT GM2 AXO-AAV-GM2 AAV Ph 1/2
Abeona Therapeutics ABEO
MPS IIIA
(Sanfilippo type A)
ABO-102 AAV9 Phase I/II
Esteve Pharmaceuticals SA Private EGT-101 AAV9 Phase II
Lysogene SAS/Sarepta
TherapeuticsSRPT LYS-SAF302 AAVrh10 Phase III Brill
Orchard Therapeutics ORTX OTL-201 Lentivirus Preclinical
128 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Inborn Errors of Metabolism – Lysosomal Storage Disorders (Page 2 of 2)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Abeona Therapeutics ABEO
MPS IIIB
(Sanfilippo type B)
ABO-101 AAV9 Phase I/II
Esteve Pharmaceuticals SA Private EGT-201 AAV9 Preclinical
Orchard Therapeutics ORTX OTL-202 Lentivirus Preclinical
bluebird bio BLUE
MPS I
(Hurler Syndrome)
LVV-IDUA HSC LVV Preclinical Van Buren
Immusoft Corp Private ISP-001 - Preclinical
Regenxbio RGNX RGX-111 AAV9 Phase I/II
Sangamo Therapeutics SGMO SB-318 AAV6 Phase I/II
Tamid Bio Private Tamid-001 AAV Preclinical
Esteve Pharmaceuticals SA Private
MPS II
(Hunter Syndrome)
EGT-301 AAV9 Preclinical
Regenxbio RGNX RGX-121 AAV9 Phase II
Sangamo Therapeutics SGMO SB-913 AAV6 Phase II
Abeona Therapeutics ABEO
Pompe disease
- AAV Preclinical
Actus Therapeutics Private ACTUS-101 AAV2/8 Phase II
Amicus Therapeutics FOLD - AAV Preclinical
Audentes Therapeutics BOLD AT845 AAV8 Preclinical Raymond
AVROBIO AVRO AVR-RD-03 Lentivirus Preclinical
Sarepta Therapeutics (Lacerta) SRPT - AAV Discovery Brill
Spark Therapeutics ONCE SPK-3006 AAV Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 129
Gene Therapies Landscape: Inborn Errors of Metabolism – Neurology
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Abeona Therapeutics ABEOBatten Disease (CLN1)
Infantile
ABO-202 AAV9 Phase I/II
Amicus Therapeutics FOLD AAV-CLN1 AAV9 Discovery/Preclinial
Regenxbio RGNXBatten Disease (CLN2)
Late Infantile
RGX-181 AAV9 Preclinical
Spark Therapeutics ONCE SPKTPP-1 rAAV Preclinical
Abeona Therapeutics ABEOBatten Disease (CLN3)
Juvenile
ABO-201 AAV9 Phase I/II
Amicus Therapeutics FOLD AAV9-CLN3 AAV9 Phase I/II
Amicus Therapeutics FOLD Batten Disease (CLN6) scAAV9-CB-CLN6 AAV9 Phase I/II
Amicus Therapeutics FOLD Batten Disease (CLN8) - - Preclinical
bluebird bio BLUE CALD Lenti-D Lentivirus Phase III/Pivotal Van Buren
Ultragenyx Pharmaceutical RARE GSD1a DTX401 AAV Phase I/II Raymond
130 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Inborn Errors of Metabolism – Other
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
ApicBio Private A1AT Deficiency Apb-101 - Preclinical
Adrenas PrivateCongenital Adrenal
HyperplasiaBBP-631 AAV Preclinical
Selecta Biosciences SELBOTC Deficiency
SEL-313 AAV Preclinical
Ultragenyx Pharmaceutical RARE DTX301 AAV Phase I/II Raymond
American Gene Technologies
InternationalPrivate
PKU
- Lentivirus Preclinical
BioMarin Pharmaceutical BMRN BMN 307 AAV5 Preclinical Raymond
Generation Bio Corp. Private - ceDNA Preclinical
Homology Medicines FIXX HMI-102 AAVHSC Preclinical
Homology Medicines FIXX HMI-103 AAVHSC Preclinical
Rubius Therapeutics RUBY RTX-134 Lentivirus Preclinical
Ultragenyx Pharmaceutical RARE UX-501 AAV8 Preclinical Raymond
Aligen Therapeutics SL Private
Wilson disease
CM-1186 AAV Preclinical
Ultragenyx RARE UX701 AAV Preclinical Raymond
Vivet Therapeutics SAS Private VTX-801 AAV Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 131
Gene Therapies Landscape: Infectious Disease
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Benitec Biopharma Ltd Private Hepatitis B BB-103 AAV Preclinical
Excision BioTherapeutics Private Hepatitis B EBT106 AAV Preclinical
American Gene Technologies
InternationalPrivate HIV AG-103-T Lentivirus Preclinical
Enzo Biochem, Inc ENZ HIV HGTV-43 Stealth Vector Phase I/II
Excision BioTherapeutics Private HIV EBT-101 AAV Preclinical
NIAID Private HIV AAV8-VRC07 AAV8 Phase I
Excision BioTherapeutics PrivateSimplexvirus (HSV)
infectionsEBT-104 AAV Preclinical
Excision BioTherapeutics PrivateSimplexvirus (HSV)
infectionsEBT-105 AAV Preclinical
Inovio Pharmaceuticals INO Zika Virus Infections INO-002 non-viral GT Phase I Raymond
132 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Immunodeficiency
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Orchard Therapeutics ORTXADA-SCID
Strimvelis LentivirusApproved/Marketed
(EU)
Orchard Therapeutics ORTX OTL-101 Lentivirus Phase III/Pivotal
Orchard Therapeutics ORTX X-CGD
(chronic granulomatous
disease)
OTL-102 Lentivirus Phase I/II
Genethon SA Private OTL-102 Lentivirus Phase I/II
Mustang Bio MBIO X-SCID MB-017 Lentivirus Phase I/II
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 133
Gene Therapies Landscape: Musculoskeletal (Page 1 of 2)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Milo Biotechnology PrivateBecker Muscular
DystrophyAAV1-Follistatin AAV Phase I/II
Audentes Therapeutics BOLD
DMD
AT702, AT751, AT753 AAV9 and 8 Preclinical Raymond
Exonics Therapeutics Private - AAV Preclinical
Genethon SA Private - AAV Preclinical
Milo Biotechnology Private AAV1-Follistatin AAV Phase I/II
Pfizer PFE PF-06939926 AAV Phase I/II
Sarepta Therapeutics SRPTSRP-9001
(AAVrh74-MHCK7)AAV Phase I/II Brill
Sarepta Therapeutics SRPT AAV-GALTG2 AAV Phase I/II Brill
Solid Biosciences SLDB SGT-001 AAV Phase I/II
Tolerion Private - - Preclinical
Milo Biotechnology Private Inclusion body myositis AAV1-Follistatin AAV Phase I/II
Sarepta Therapeutics SRPT LGMD2B MYO-201 AAV Phase I/II Brill
Sarepta Therapeutics SRPT LGMD2C MYO-103 AAV Preclinical Brill
Sarepta Therapeutics SRPT LGMD2D MYO-102 AAV Phase I/II Brill
Sarepta Therapeutics SRPT LGMD2E MYO-101 AAV Phase I/II Brill
Sarepta Therapeutics SRPT LGMD2L MYO-301 AAV Preclinical Brill
134 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Musculoskeletal (Page 2 of 2)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Audentes Therapeutics BOLD Myotonic Dystrophy type 1 AT-466 AAV Preclinical Raymond
Axovant Sciences AXVTOPMD
AXO-AAV-OPMD AAV Preclinical
Benitec Biopharma Private BB-301 AAV Preclinical
Biogen BIIB SMA BIIB-089 - Preclinical Raymond
Novartis/Avexis NVS SMA Type 1AVXS-101
(Zolgensma)AAV9 Filed
Novartis/Avexis NVS SMA Type 2AVXS-101
(Zolgensma)AAV9 Phase I/II
Audentes Therapeutics BOLD XLMTM AT132 AAV8 Phase I/II Raymond
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 135
Gene Therapies Landscape: Neurology (Page 1 of 3)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Apic Bio Private ALS APB-102 - Preclinical
Axovant Sciences AXVT ALS - C9ORF72AXO-AAV-ALS/
AXO-AAV-FTDAAV Discovery/Preclinical
CavoGene Lifesciences Private ALS SYNCAV-1 - Preclinical
MeiraGTx MGTX ALS AAV-UPF1 AAV Preclinical Van Buren
NeuExcell Therapeutics Private ALS NXLAAV-002 AAV Preclinical
Novartis/Avexis NVS ALS - SOD1 AVXS-301 AAV Preclinical
Oxford Biomedica OXBDF ALS - - Preclinical
ViroMed Co Ltd 084990.KQ ALS VM-301 AAV Preclinical
Voyager Therapeutics VYGR ALS - SOD1 VY-SOD102 AAV Preclinical
Brainvectis SAS Private
Alzheimer's disease
BVCYP-01 AAV Preclinical
CavoGene Lifesciences Private SynCav-2 - Preclinical
NeuExcell Therapeutics Private NXLAAV-001 AAV Preclinical
Sangamo Therapeutics SGMO - - Preclinical
Telocyte Private TEL-01 AAV Preclinical
Voyager Therapeutics VYGR - AAV Preclinical
Aspa Therapeutics Private
Canavan Disease
BP-812 - Preclinical
Pfizer PFE - - Phase I/II
Pfizer PFE - - Preclinical
136 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Neurology (Page 2 of 3)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Pfizer PFE
Friedreich's Ataxia
- - Preclinical
PTC Therapeutics PTCT PTC-FA - Phase I/II
Voyager Therapeutics VYGR VY-FXN01 AAV Preclinical
Axovant Sciences AXVTFrontotemporal Dementia
AXO-AAV-FTD AAV Preclinical
Passage Bio Private AAV Preclinical
AskBio Private
Huntington's Disease
- AV Preclinical
Brainvectis SAS Private BVCYP-01 AAV Preclinical
NeuExcell Therapeutics Private NXLAAV-003 AAV Preclinical
Spark Therapeutics ONCE - AAV Preclinical
Takeda Pharmaceutical Co TAK - - Preclinical
uniQure QURE AMT-130 AAV Preclinical Brill
Voyager Therapeutics VYGR VY-HTT01 AAV Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 137
Gene Therapies Landscape: Neurology (Page 3 of 3)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Apollo Therapeutics Private
Parkinson's Disease
- - Preclinical
AskBio Private - AAV Phase I/II
Axovant Sciences AXVTAXO-LENTI-AADC-
TH-CH1Lentivirus Phase I/II
Copernicus Therapeutics Private AAV-GDNF - Preclinical
Gene Therapy Research Inst Co Private AAV-AADC-TH-CH1 AAV Preclinical
MeiraGTx MGTX AAV-GAD AAV Phase I/II Van Buren
Prevail Therapeutics PRVL PR001 AAV9 Preclinical/IND Active
SanBio Co SNBIF SB-623 - Preclinical
Takara Bio TYO: 4974 - - Phase I/II
Takeda Pharmaceutical Co TAK - - Preclinical
Voyager Therapeutics VYGR VY-AADC AAV Phase I/II
uniQure QURE SCA-Type 3 - AAV Preclinical Brill
138 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Ophthalmology (Page 1 of 2)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
agtc AGTC Achromatopsia
(ACHM-A3)
AAV-CNGA3 AAV Phase I/II
MeiraGTx MGTX AAV-CNGA3 AAV Preclinical Van Buren
agtc AGTC Achromatopsia
ACHM-B3
AAV-CNGB3 AAV Phase I/II
MeiraGTx MGTX AAV-CNGB3 AAV Phase I/II Van Buren
Aevitas Therapeutics PrivateAMD
AVTS-001 AAV Preclinical
Gemini Therapeutics Private GR-1008 AAV Preclinical
Gemini Therapeutics Private
Dry AMD
GR-1017 AAV Preclinical
Gyroscope Therapeutics Private GT-005 - Phase I/II
NanoScope Technologies Private VMCO-1 - Preclinical
Nightstar Therapeutics/Biogen NITE/BIIB NSRBEST-1 AAV Preclinical Raymond
SanBio Co SNBIF SB-623 - Preclinical
Adverum Biotechnologies ADVM
Wet AMD
ADVM-022 AAV Phase I/II Van Buren
Amarna Therapeutics Private AMA003 - Preclinical
Benitec Biopharma BNTC BB-201 AAV Preclinical
Hemera Biosciences Private HMR-59 - Phase I/II
iTherapeutics Corp. Private - - Preclinical
Oxford Biomedica OXBDF OXB-201 - Phase I/II
Regenxbio TGNX RGX-314 - Phase I/II
4D Molecular Therapeutics 4DMT
Choroideremia
4D-110 AAV Preclinical
Nightstar/Biogen NITE/BIIB NSR-REP1 AAV2 Phase III Raymond
Spark Therapeutics ONCE SPK-7001 - Phase I/II
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 139
Gene Therapies Landscape: Ophthalmology (Page 2 of 2)
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
GenSight Biologics GSGTF Leber's Hereditary Optic
Neuropathy
GS010 AAV Phase III
Spark Therapeutics ONCE SPK-LHON AAV Preclinical
Horama SA PrivatePDE6B Retinitis
pigmentosaHORA-PDE6B AAV Phase I/II
Horama SA Private RLBP1 Retinal Dystrophy HORA-RLBP1 AAV Preclinical
MeiraGTx MGTX RPE65-deficiency AAV-RPE65 AAV Phase I/II Van Buren
Horama SA PrivateRPE65-mediated IRD
HORA-RPE65 AAV Phase I/II
Spark/Novartis ONCE/NVS Luxterna AAV Approved/Marketed
Copernicus Therapeutics Private
Stargardt disease
- - Preclinical
Generation Bio Corp. Private - - Preclinical
Nightstar/Biogen NITE/BIIB NSR-ABCA4 AAV Preclinical
Sanofi/Oxford Biomedica OXBDF SAR422459 (StarGen) - Phase I/II
Sanofi SA SNY Usher Syndrome Type 1B SAR421689 - Phase I/II
agtc AGTC
XLRP
AAV-RPGR AAV Phase I/II
Biogen BIIB BIIB112 AAV8 Phase I/II Raymond
IVERIC bio Private - - Preclinical
MeiraGTx MGTX AAV-RPGR AAV Phase I/II Van Buren
agtc AGTCX-linked retinoschisis
(XLRS)AAV-RS1 AAV Phase I/II
140 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Additional Indications
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Cardiovascular Disease
Audentes BOLD CASQ2-CPVT AT307 - Phase I/II Raymond
Renova Therapeutics Private HFrEF RT-100 - Phase I/II
Oncology
Tocagen TOCA Glioma Toca 511 and Toca FC Retrovirus Phase III/Pivotal
Tocagen TOCA Metastatic solid tumor Toca 511 and Toca FC Retrovirus Phase I/II
Otology
Akouos Private Hearing loss Anc80AAV AAV Preclinical
Novartis NVS Hearing loss CGF166 - Phase I/II
Miscellaneous
Intellia Therapeutics NTLAAmyloid transthyretin
amyloidosis- - Preclinical
MeiraGTx MGTX Xerostomia (dry mouth) A00X - Phase I/II Van Buren
Rocket RCKTInfantile Malignant
OsteopetrosisRP-L401 - Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 141
Ongoing Gene Therapy Trials
by Company
06.2
142 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
4D Molecular Therapeutics PrivateChoroideremia 4D-110 AAV Preclinical
Cystic Fibrosis 4D-710 AAV Preclinical
Abeona Therapeutics ABEO
Batten Disease (CLN1), Infantile ABO-202 AAV9 Phase I/II
Batten Disease (CLN3), Juvenile ABO-201 AAV9 Phase I/II
Cystic Fibrosis ABO-401 AAV Preclinical
Fabry disease - AAV Preclinical
Fanconi Anemia ABO-301 AAV Preclinical
MPS IIIA (Sanfilippo type A) ABO-102 AAV9 Phase I/II
MPS IIIB (Sanfilippo type B) ABO-101 AAV9 Phase I/II
Pompe disease - AAV Preclinical
Recessive Dystrophic EB EB-101 Retrovirus Phase III
Recessive Dystrophic EB EB-102 AAV Preclinical
Actus Therapeutics Private Pompe disease ACTUS-101 AAV2/8 Phase II
Adrenas BBIO Congenital Adrenal Hyperplasia BBP-631 AAV Preclinical
Adverum Biotechnologies ADVMHereditary angioedema ADVM-053 - Preclinical
Van BurenWet AMD ADVM-022 AAV Phase I/II
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 143
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Aevitas Therapeutics Private AMD AVTS-001 AAV Preclinical
Akouos PrivateHearing loss Anc80AAV AAV Preclinical
Balance disorders Anc80AAV AAV Preclinical
Aligen Therapeutics SL Private Wilson disease CM-1186 AAV Preclinical
Amarna Therapeutics Private Wet AMB AMA003 - Preclinical
American Gene Technologies
InternationalPrivate
HIV AG-103-T Lentiviral Preclinical
PKU - Lentiviral Preclinical
Amicus Therapeutics FOLD
Batten Disease (CLN1), Infantile - - Discovery/Preclinical
Raymond
Batten Disease (CLN3), Juvenile AAV9-CLN3 AAV9 Phase I/II
Batten Disease (CLN6) scAAV9-CB-CLN6 AAV9 Phase I/II
Batten Disease (CLN8) - - Preclinical
CDKL5 Deficiency - - Preclinical
Fabry disease - Preclinical
Pompe disease - AAV Preclinical
Amryt Pharma AMYT Recessive Dystrophic EB AP103 non-viral GT Preclinical
Apic Bio PrivateALS APB-102 - Preclinical
A1AT Deficiency Apb-101 - Preclinical
Apollo Therapeutics Parkinson's disease - Preclinical
Applied Genetic Technologies
Corp.AGTC
Achromatopsia (ACHM-A3) AAV-CNGA3 AAV Phase I/II
Achromatopsia (ACHM-B3) AAV-CNGB3 AAV Phase I/II
XLRP AAV-RPGR AAV Phase I/II
X-linked retinoschisis (XLRS) AAV-RS1 AAV Phase I/II
144 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Aruvant Sciences PrivateSickle Cell Disease ARU-1801 Lentivirus Phase I/II
Beta-thalassemia ARU-1801 Lentivirus Preclinical
AskBio PrivateHuntington's - AV Preclinical
Parkinson's disease - AAV Phase I/II
Aspa Therapeutics Private Canavan Disease BP-812 - Preclinical
Audentes BOLD
CASQ2-CPVT AT307 - Phase I/II
Raymond
Crigler-Najjar Syndrome AT342 AAV8 Phase I/II
DMDAT702, AT751,
AT753AAV9 and 8 Preclinical
Myotonic Dystrophy type 1 AT-466 AAV Preclinical
Pompe disease AT845 AAV8 Preclinical
XLMTM AT132 AAV8 Phase I/II
AVROBIOAVRO
Cystinosis AVR-RD-04 Lentivirus Preclinical
Fabry disease AVR-RD-01 Lentivirus Phase I/II
Gaucher AVR-RD-02 Lentivirus Preclinical
Pompe disease AVR-RD-03 Lentivirus Preclinical
Axovant Sciences Ltd AXVT
ALS - C9ORF72AXO-AAV-ALS/
AXO-AAV-FTDAAV Discovery/Preclinical
Frontotemporal dementia AXO-AAV-FTD AAV Preclinical
GM1 AXO-AAV-GM1 AAV Ph 1/2
GM2 AXO-AAV-GM2 AAV Ph 1/2
OPMD AXO-AAV-OPMD AAV Preclinical
Parkinson's diseaseAXO-LENTI-AADC-
TH-CH1Lentivirus Phase I/II
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 145
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Benitec Biopharma Ltd Private
Hepatitis B BB-103 AAV Preclinical
Oculopharyngeal muscular
dystrophyBB-301 AAV Preclinical
Wet AMD BB-201 AAV Preclinical
Biogen BIIBX-Linked Retinitis Pigmentosa
(XLRP)BIIB112 AAV8 Phase II/III Raymond
BioMarin Pharmaceutical BMRNHemophilia A
Valoctocogene
roxaparvovec
(Valrox, BMN 270)
AAV5 Phase IIIRaymond
PKU BMN 307 AAV5 Preclinical
BioVec Pharma Private Epidermolysis Bullosa - Retrovirus Preclinical
bluebird bio BLUE
Beta-thalassemia LentiGlobin Lentivirus Phase III
Van Buren
CALD Lenti-D Lentivirus Phase III/Pivotal
MPS I (Hurler Syndrome) LVV-IDUA HSC LVV Preclinical
Sickle Cell Disease LentiGlobin Lentivirus Phase II
Sickle Cell Disease Bcl11a shmiR Lentivirus Phase I
Brainvectis SAS PrivateAlzheimer's disease BVCYP-01 AAV Preclinical
Huntington's BVCYP-01 AAV Preclinical
Catalyst Biosciences CBIO Hemophilia B CB 2679d-GT AAV8 Preclinical
146 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
CavoGene Lifesciences PrivateAlzheimer's disease SynCav-2 - Preclinical
ALS SYNCAV-1 - Preclinical
Copernicus TherapeuticsPrivate Stargardt disease - - Preclinical
Parkinson's disease AAV-GDNF - Preclinical
CRISPR Therapeutics AG CRSPBeta-thalassemia, SCD CTX001 - Preclinical
Cystic Fibrosis - - Preclinical
CSL Behring CSLLY Beta-thalassemia, SCD CAL-H - Preclinical
Editas Medicine EDIT Cystic Fibrosis - AAV or LNP Preclinical
Enzo Biochem ENZ HIV HGTV-43 Stealth Vector Phase I/II
Errant Gene Therapeutics Private Beta-thalassemia Thalagen - Preclinical
Esteve Pharmaceuticals SA Private
MPS II (Hunter Syndrome) EGT-301 AAV9 Preclinical
MPS IIIA (Sanfilippo type A) EGT-101 AAV9 Phase II
MPS IIIB (Sanfilippo type B) EGT-201 AAV9 Preclinical
Excision BioTherapeutics Private
Hepatitis B EBT106 AAV Preclinical
HIV EBT-101 AAV Preclinical
Simplexvirus (HSV) infections EBT-104 AAV Preclinical
Simplexvirus (HSV) infections EBT-105 AAV Preclinical
Exonics Therapeutics Private DMD - AAV Preclinical
Expression Therapeutics Private
Hemophilia AEx vivo stem cell-LV-
FVIII gene therapyLentivirus Preclinical
Hemophilia A AAV-FVIII AAV Preclinical
Hemophilia B AAV-FIX AAV Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 147
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Fibrocell Science FCSC Recessive Dystrophic EB FCX-007 lentivirus Phase I/II
Freeline Therapeutics PrivateFabry disease FLT190 AAV Preclinical
Hemophilia B FLT-180a AAV Phase I/II
Gemini Therapeutics PrivateDry AMD GR-1017 AAV Preclinical
AMD GR-1008 AAV Preclinical
Gene Therapy Research
Inst CoPrivate Parkinson's disease AAV-AADC-TH-CH1 AAV Preclinical
Generation Bio Corp. PrivatePKU - ceDNA Preclinical
Stargardt disease - - Preclinical
Genethon SA Private
Crigler-Najjar Syndrome - AAV Preclinical
DMD - AAV Preclinical
Fanconi Anemia - - Phase II
Wiskott-Aldrich - Lentivirus Phase II
X-CGD OTL-102 lentivirus Phase I/II
GenSight Biologics SA GSGTF LHON GS010 AAV Phase III
GlaxoSmithKline GSK Epidermolysis Bullosa - - Preclinical
Gyroscope Therapeutics Private Dry AMD GT-005 - Phase I/II
Hemera Biosciences Private Wet AMD HMR-59 - Phase I/II
Holostem Terapie Avanzate Srl Private Recessive Dystrophic EB Hologene 7 retrovirus Phase II
Homology Medicines FIXXPKU HMI-102 AAVHSC Preclinical
PKU HMI-103 AAVHSC Preclinical
148 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Horama SA Private
PDE6B Retinitis pigmentosa HORA-PDE6B AAV Phase I/II
RPE65-mediated IRD HORA-RPE65 AAV Phase I/II
RLBP1 Retinal Dystrophy HORA-RLBP1 AAV Preclinical
Immusoft Corp. PrivateEpidermolysis Bullosa - Preclinical
MPS I (Hurler Syndrome) ISP-001 * Preclinical
iTherapeutics Corp. Private Wet AMD - - Preclinical
IVERIC bio ISEEBEST1 Related Retinal Diseases IC-200 - Preclinical
RHO-adRP IC-100 AAV Preclinical
Krystal Biotech KRYSDystrophic EB KB103 HSV-1 Phase I/II
Junctional EB KB-107 HSV-1 Preclinical
Lamellar Biomedical Private Cystic Fibrosis CF-NA non-viral GT Preclinical
Logicbio Therapeutics LOGC
Crigler-Najjar Syndrome LB-301 AAV Discovery/Preclinical
Hemophilia B LB-101 AAV Discovery/Preclinical
Methylmalonic acidemia (MMA) LB-001 AAV Preclinical
Lysogene LYS GM1 LYS-GM101 AAVrh10 Preclinical
Lysogene SAS/
Sarepta TherapeuticsSRPT MPS IIIA (Sanfilippo type A) LYS-SAF302 AAVrh10 Phase III
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 149
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
MeiraGTx MGTX
Achromatopsia (ACHM-A3) AAV-CNGA3 AAV Preclinical
Van Buren
Achromatopsia (ACHM-B3) AAV-CNGB3 AAV Phase I/II
ALS AAV-UPF1 AAV Preclinical
Parkinson's disease NLX-P101 AAV Phase I/II
RPE65-deficiency AAV-RPE65 AAV Phase I/II
Wet AMD A-006 Preclinical
XLRP (RPGR) AAV-RPGR AAV Phase I/II
Milo Biotechnology Private
Becker Muscular Dystrophy AAV1-Follistatin AAV Phase I/II
DMD AAV1-Follistatin AAV Phase I/II
Inclusion body myositis AAV1-Follistatin AAV Phase I/II
Mustang Bio MBIO X-SCID MB-017 lentivirus Phase I/II
NanoScope Technologies Private Dry AMD VMCO-1 - Preclinical
NeuExcell Therapeutics Private
ALS NXLAAV-002 AAV Preclinical
Alzheimer's disease NXLAAV-001 AAV Preclinical
Huntington's NXLAAV-003 AAV Preclinical
Nightstar Therapeutics/
BiogenNITE/BIIB
Dry AMD NSRBEST-1 AAV Preclinical
Choroideremia NSR-REP1 AAV2 Phase III
Stargardt disease NSR-ABCA4 AAV Preclinical
XLRP NSR-XLRP AAV8 Phase I/II
150 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Novartis NVS Hearing loss CGF166 Phase I/II
Novartis/Avexis NVS/AVXS
ALS - SOD1 AVXS-301 AAV Preclinical
SMA Type 1AVXS-101
(Zolgensma)AAV9 Filed
SMA Type 2AVXS-101
(Zolgensma)AAV9 Phase I/II
Orchard Therapeutics ORTX
ADA-SCID Strimvelis lentivirusApproved/Marketed
(EU)
ADA-SCID OTL-101 lentivirus Phase III/Pivotal
Beta-thalassemia OTL-300 Lentivirus Phase I/II
Metachromatic leukodystrophy OTL-200 Lentivirus Phase III/Pivotal
MPS IIIA (Sanfilippo type A) OTL-201 Lentivirus Preclinical
MPS IIIB (Sanfilippo type B) OTL-202 Lentivirus Preclinical
Wiskott-AldrichOTL-103
(GSK2696275)Lentivirus Phase III
X-CGD OTL-102 lentivirus Phase I/II
Oxford Biomedica OXBDFALS - - Preclinical
Wet AMD OXB-201 Phase I/II
Passage Bio PrivateFrontotemporal dementia AAV Preclinical
GM1 AAV-GM1 AAV Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 151
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Pfizer PFE
Canavan Disease - - Phase I/II
Canavan Disease - - Preclinical
DMD PF-06939926 AAV Phase I/II
Friedreich's Ataxia - - Preclinical
Prevail Therapeutics PRVL
Parkinson's disease PR001 AAV9 Preclinical/IND Active
Neuronopathic Gaucher Disease PR001 AAV9 Preclinical
FTD-GRN PR006 AAV9 Preclinical
Synucleinopathies PR004 AAV9 Preclinical
PTC Therapeutics PTCT
AADC Deficiency AGIL-AADC AAV Phase III/Pivotal
Friedreich's Ataxia PTC-FA - Phase I/II
Friedreich's Ataxia GIL-FA AAV Phase I/II
Regenxbio RGNX
Batten Disease (CLN2),
Late InfantileRGX-181 AAV9 Preclinical
HoFH RGX-501 AAV Phase I/II
Wet AMD RGX-314 - Phase I/II
MPS I (Hurler Syndrome) RGX-111 AAV9 Phase I/II
MPS II (Hunter Syndrome) RGX-121 AAV9 Phase II
Renova Therapeutics Private HFrEF RT-100 - Phase I/II
Rocket Pharmaceuticals RCKT
Danon disease (GSDIIb) RP-A501 AAV9 Phase I
Fanconi Anemia RPL-102 Lentivirus Phase I
Infantile Malignant Osteopetrosis RP-L401 - Preclinical
LAD-1 Program RP-L201 LVV Phase I
Pyruvate Kinase Deficiency RP-L301 LVV Preclinical
152 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Rubius Therapeutics RUBY PKU RTX-134 Lentivirus Preclinical
SanBio Co SNBIFDry AMD SB-623 - Preclinical
Parkinson's disease SB-623 - Preclinical
Sangamo Therapeutics SGMO
Alzheimer's disease - - Preclinical
Beta-thalassemia
Sickle Cell DiseaseST-400
- Phase II
Fabry disease ST-920 AAV6 Preclinical
Hemophilia A SB-525 - Phase I/II
Hemophilia B SB-FIX - Phase I/II
MPS I (Hurler Syndrome) SB-318 AAV6 Phase I/II
MPS II (Hunter Syndrome) SB-913 AAV6 Phase II
Sanofi SA SNY Usher Syndrome Type 1B SAR421689 - Phase I/II Raymond
Sanofi SA/Oxford BiomedicaSNY/
OXBDFStargardt disease SAR422459 - Phase I/II
Sarepta Therapeutics SRPT
DMDSRP-9001
(AAVrh74-MHCK7)AAV Phase I/II
BrillDMD AAV-GALTG2 AAV Phase I/II
LGMD2B MYO-201 AAV Phase I/II
LGMD2C MYO-103 AAV Preclinical
LGMD2D MYO-102 AAV Phase I/II
LGMD2E MYO-101 AAV Phase I/II
LGMD2L MYO-301 AAV Preclinical
Sarepta Therapeutics (Lacerta) SRPT Pompe disease - AAV Discovery Brill
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 153
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Selecta Biosciences SELBMethylmalonic acidemia (MMA) SEL-302 - Preclinical
OTC Deficiency SEL-313 AAV Preclinical
Solid Biosciences SLDB DMD SGT-001 AAV Phase I/II
Spark Therapeutics ONCE
Batten Disease (CLN2), Late
InfantileSPKTPP-1 rAAV Preclinical
Choroideremia SPK-7001 - Phase I/II
Hemophilia A SPK-8011 AAV5 Phase III
Hemophilia A with inhibitors SPK-8016 AAV5 Phase II
Hemophilia B
Fidanacogene
elaparvovec
(SPK-9001)
AAV Phase III
Huntington's - AAV Preclinical
Leber's Hereditary Optic
NeuropathySPK-LHON AAV Preclinical
Pompe diseaseSPK-3006
(AAV-sec-GAA)AAV Preclinical
Spark Therapeutics/Novartis ONCE/NVS RPE65-mediated IRD Luxterna AAV Approved/Marketed
Takara Bio Parkinson's disease - - Phase I/II
TakedaTAK
Hemophilia A TAK-754 (SHP654) - Phase I
Hemophilia B SHP648 - Preclinical
Huntington's - - Preclinical
Parkinson's disease - - Preclinical
Talee Bio PrivateCystic Fibrosis TL-101 AAV Preclinical
Cystic Fibrosis TL-102 Lentivirus Preclinical
154 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Tamid Bio Private MPS I (Hurler Syndrome) Tamid-001 AAV Preclinical
Telocyte Private Alzheimer's disease TEL-01 AAV Preclinical
Temprian Therapeutics Private Vitiligo - non-viral GT Preclinical
The National Institute of
Allergy and Infectious
Diseases
Private HIV AAV8-VRC07 AAV8 Phase I
Tocagen TOCA
GliomaToca 511 and
Toca FCretrovirus Phase III/Pivotal
Metastatic solid tumorToca 511 and
Toca FCretrovirus Phase I/II
Tolerion Private DMD - - Preclincal
Ultragenyx Pharmaceutical RARE
GSD1a DTX401 AAV Phase I/II
Raymond
Hemophilia A DTX201 AAV Phase II
OTC Deficiency DTX301 AAV Phase I/II
PKU UX-501 AAV8 Preclinical
Wilson disease UX701 AAV Preclinical
UniQure QURE
Fabry disease AMT-190 AAV5 Preclinical
Brill
Hemophilia A AMT-180 AAV5 Preclinical
Hemophilia BAMT-061 (Padua
variant of Factor IX)AAV5 Phase III
Huntington's AMT-130 AAV Preclinical
SCA-Type 3 xxx AAV Preclinical
ViroMed Co Ltd 084990.KQALS VM-301 AAV Preclinical
Wounds pIKO AAV Preclinical
Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 155
Gene Therapies Landscape: Companies
Source: Company Reports. GlobalData. Piper Jaffray Research.
Company Ticker Indication Drug Vector Development Stage Analyst
Vivet Therapeutics SAS Private Wilson disease VTX-801 AAV Preclinical
Voyager Therapeutics VYGR
Alzheimer's disease (Tauopathy program) AAV Preclinical
ALS - SOD1 VY-SOD102 AAV Preclinical
Friedreich's Ataxia VY-FXN01 AAV Preclinical
Huntington's VY-HTT01 AAV Preclinical
Parkinson's disease (advanced) VY-AADC AAV Phase I/II
156 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
Risks associated with all companies described in this report are common to other biotech companies.
Clinical risk. Success in clinical trials will be essential for companies to market their products, but success in the clinic is not guaranteed.
Regulatory risk. The FDA, EMA or other regulatory bodies may have a different view on the benefit-risk balance demonstrated in clinical testing than the company
seeking approval. Companies may be required to do additional trials, which may make the development of the candidates more time- and cost-prohibitive.
Commercial risk. The cell therapy space that companies operate in is very specific and challenging as there are multiple competitors and significant pricing pressure.
Additionally, if cell therapies are successfully developed, they will be entering a market that has have several other modalities available and/or close by in development.
Clinical and/or regulatory success does not guarantee commercial success.
Financing risk. Pipeline development and commercial plans will require capital and time. In addition to cash flow from marketed products and funding from partners,
companies may need to raise more money through an equity offering, which may negatively impact the stock price.
Intellectual property risk. Protection of a company’s drugs and processes is dependent on issued or pending patents and in-house knowledge. One or more parties
often challenge the intellectual property estate of a successful product, claiming priority for other patents or that the patents are invalid or infringe. Significant expense on
legal protection could be required in the future, with no guarantee of success.
Risks
Source: Piper Jaffray Research.
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BioInsights Report Library
Source: Piper Jaffray Research.
Date Title Topic
10/31/18 Oncology Series: Assessing Heme-Oncs’ Early CAR-T Experience & Potential Competition CAR-T Cells
11/26/18 BioInsights: A Deep Dive on Anti-VEGFs and Next-Gen Therapies for Wet AMD & DME Ophthalmology - Retinal Diseases
12/27/18Hematology Series – Sickle Cell Disease (SCD): A Deep Dive on the Current Management of Sickle
Cell Disease and Therapies in Clinical TrialsHematology - Sickle Cell Disease
01/31/19 Oncology Series: Bispecific Antibodies – Long “Emerging,” Now Ready for Prime Time Bispecific Antibodies
03/04/19 Investing in Gene Editing – Early Days, but Huge Therapeutic Potential Gene Editing
03/29/19 Rare Disease Series: Disease Modifying Therapies in Cystic Fibrosis Cystic Fibrosis
04/29/19Oncology Series – Cell Therapy Compendium: Cell Type Considerations For The Next Generation Of
Cellular TherapyCell Therapies
05/30/19 Oncology Series – Targeting DNA Damage Response (DDR) Pathways Through Precision Oncology DNA Damage Response
06/25/19 Targeting FcRn – A Deep Dive Into a Rapidly Advancing Therapeutic ApproachFcRn and IgG-mediated
Autoimmune Disorders
07/31/19 Medical Dermatology From “A to V”: A Rapidly Evolving Landscape Medical Dermatology
158 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research
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Important Research Disclosures
Distribution of Ratings/IB ServicesPiper Jaffray
IB Serv./Past 12 Mos.
Rating Count Percent Count Percent
BUY [OW] 407 63.40 100 24.57
HOLD [N] 227 35.36 18 7.93
SELL [UW] 8 1.25 0 0.00
Note: Distribution of Ratings/IB Services shows the number of companies currently covered by fundamental equity research in each rating categoryfrom which Piper Jaffray and its affiliates received compensation for investment banking services within the past 12 months. FINRA rules requiredisclosure of which ratings most closely correspond with "buy," "hold," and "sell" recommendations. Piper Jaffray ratings are not the equivalent ofbuy, hold or sell, but instead represent recommended relative weightings. Nevertheless, Overweight corresponds most closely with buy, Neutralwith hold and Underweight with sell. See Stock Rating definitions below.
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Time of dissemination: 3 September 2019 03:33EDT.
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September 2019
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