1

Disclaimer

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Tim Allsopp, Hd. External Research Regenerative Medicine

Cambridge UK

Regener8 Annual Conference

Leeds, October 10th

Commercialization of Regenerative Medicines in Europe

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What does the EU pipeline look like?

Navigating across the development & regulatory landscape: a case study

Decisional features to define the clinical/commercial feasibility of cell therapy products

What is the plurality of factors hindering the transition of the regenerative cell therapy sector into a major global industry: industry conditions, market access &

prospects for collaborative development?

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Total Number of Regenerative Medicine Companies * Europe is the Second Busiest Territory

Taking Stock of Regenerative Medicine in the UK. July 2011. Office for Life Sciences, Dept. Health *Regenerative Medicines in Europe Project (REMEDiE), coordinated by the Science and Technology Studies Unit, University of York

citeline®

Pipeline drug intelligence dbase “cell therapy”, “regenerative”, “tissue”,

“transplant”, “graft”, “stem cell”, “matrix”

European Regenerative Medicine Products in Development

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www.healthcompetence.eu “cell therapy”, “clinical trial”, “stem cell”,

“matrix”, “scaffold”, “regeneration”

Pre-clinical

Clinical

EU Pipeline of

ATMPs*

*Those advanced products (except Glybera) approved since Advanced Therapy Medicinal Product classification introduced & others grand-fathered in (gene,

somatic cell (CBMP),TE products)

Policy Research and Innovation

EU support to regenerative medicine

Therapeutic Targets

Nerve tissue

Skin, eye

Wound repair

Muscle

Heart, heart valve

Artery repair

Bone and cartilage

Osteoarthritis, RA

Liver

Kidney

Pancreas

• Technologies

Serum-free media

Characterisation and identification

Cell selection

Standardisation

Expansion

Miniaturisation

Cell imaging

Bio-materials

Bio-reactors

Cell Types

All, incl tissue derived, hES, iPS

research in FP7

EU Funded Translational Regenerative Medicine Project Pipeline

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REGENER-AR

RA

Allo-ASC; Ph1a/2b

2012-2015

OSTEOGROW

Fractures/non-unions

Coagulum matrix-BMP6; Ph1

2012-2016

BAMI

AMI

Auto-BM-MNC; Ph2b

2011-2016

ADIPOA

OA

Allo-ASC; Ph1

2010-2013

The ONE Study

SOT

Reg T cells; FIH

2011-2016

ESPOIR

Pulmonary valve

Decell. hrt valves; FIH

2012-2015

VASCUBONE

Maxillary defects/FHN

Materials/MSC/EPC; Ph1

2010-2014

OPTISTEM

DMD/LSCD

Pericytes/keratinocyte

Ph1 2009-2013

www.optistem.org www.vascubone.fraunhofer.eu/index.html www.onestudy.org/index.html www.chu-montpellier.fr/fr/ADIPOA/gb/index_gb.html www.espoir-clinicaltrial.eu

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Technology Product (Company) Indication Status

allo - Endometrial ERC (Medistem) PAD /CLI-

allo -anti-viral Tc

streptamer isolated Cytovir CMV (Cell Medica)

(Stage Cell thera.)

Anti-viral, prophylaxis in BM tx Anti-viral,

prophylaxis in BM tx

allo - liver cell HHLivC (Cytonet) Liver -enzyme disorder

allo- GM-NSC CTX (ReNeuron) Cerebral ischemia

allo - NSC hCNS-SC (StemCells) Spinal cord injury, AMD

allo - BM-MSC Revascor (Mesoblast)

Prochymal (Osiris)

Heart failure, AMI

Multiple indications

allo-placenta PLX-PAD/SM (Pluristem) PAD(CLI), musculo-skeletal

allo- ADC CX621 (TiGenix) Inflammatory

Blood stem cells Cryocell-IHD (Human Stem cell Insti.) AMI

Human ES MA09-hRPE (ACT) AMD

auto -CD34 Alecmestencel-T (Apceth) PAD(CLI)

auto-myoblast

(Bioheart)

(Fina Biotech)

Heart failure, angina

Cardiomyopathy, AMI

auto-cardiac ixymyelocel-T (Aastrom) Dilated cardiomyopathy

auto- stem Cell Bandage(Azellon) Cartilage repair

auto-ADC ADC (Cytori Therapeutics) Multiple indications

auto- BM C-Cure (Cardio3) Heart failure

Phase 1 Register 2 3 Launch

Early Stage Regenerative Medicine Pipeline

Technology Product (Company) Indication Status

bone graft + GF BioMimetic-2 (BioMimetic) Fracture healing, bone fusions -

Autologous

chondrocyte implant

ProChon /BioCart-II (Histogenics)

Novocart 3D (Tetec)

MACI – Carticel

ChondroCelect (Tigenix)

Cartilage repair –

Cartilage /disc repair

Cartilage repair

Cartilage repair

autologous tissue grafts

- MicroCaps ProFibrix (The Medicines Cpy) Haemorrhage, surgery adjunct

bovine collagen &

allogeneic cells Apligraf (Organogenesis)

Ulcer – venostasis, diabetic

Wound repair

allogeneic fibroblasts

& polyglactin mesh Dermagraft (Shire) Ulcer, diabetic wound repair, EB wounds

BMP2/12-matrix

BMP7-matrix

Infuse Bone Graft (Medtronic)

Osigraft (Stryker)

Fracture healing

Fracture healing

IL-10 Prevascar (Targenics) Scar reduction/ Nerve repair

Artificial skin

Dural graft matrix

Integra (Integra Life Sciences)

DuraGen

Burns; wound healing

Spinal cord injury/surgery adjunct

Encapsulated cells ECT (NeuroTech) Ophthalmic/CNS

oral mucosa ECM sheet CellSeed (Teva) LSCD/cornea

autologous dendritic

cells - immunotherapy

Provenge (sipuleucel-T;

Dendreon)

Asymptomatic metastatic hormone

refractory prostate cancer

Phase 1 Register 2 3 Launch

Late Stage Regenerative Medicine Pipeline

• Vibrant collaborative R&D landscape with significant EU support, emphasis on SME funding and a diversity of product concepts

• Research community recognising that therapies development is more complex than initially imagined & getting into the clinic is a major bottleneck o Immature business models o Lack of skills/experience/resources

• Most advanced products are those in the med tech category o Wound/cartilage/bone repair products o Dermagraft has orphan status in UK for paediatric EB patients o Only one ‘home grown’ product launched – ChondroCelect

• Autologous only slightly more clinically advanced than allogeneic CBMP o Parenteral/direct organ delivery o BAMI study is largest Ph3 underway; patient stratification

• Majority of EU CBMP concepts in development are allogeneic o Diverse range of orphan and more common therapeutic areas o Most clinically advanced therapy is class of adoptively transferred anti-viral T cells

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EU Pipeline Summary

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Neusentis’ Regenerative Medicine Programmes

Internal partnership with clinical neurosciences to demonstrate the effective restoration of motor neural circuit function

in stroke patients

External partnership with Institute of Ophthalmology (UCL) to develop a novel cell replacement therapy using human ES

derived RPE for dry AMD

External partnership with company Athersys to demonstrate that MultiStem® cell therapy is safe & effective in patients with moderate to sever ulcerative colitis

Rationale for RPE transplantation in AMD

• RPE cells are critical for retinal function

• Trophic factor support for photoreceptors &

choriocapillaris

• Phagocytosis of shed photoreceptor outer segments

• Nutrient supply to & from subretinal space & blood

• Re-isomerisation of all-trans retinal (visual cycle)

• Maintenance of immune privilege of anterior chamber

• Transplantation of RPE cells show efficacy in

preclinical models of retinal degeneration

• Sub-retinal delivery maintains visual function

(optokinesis) in RCS dystrophic rat

• Transplantation of RPE layer, or macular

translocation shows clinical efficacy

• Macular translocation: 10 / 40 patients maintain 3 line

gain in acuity after 3 years

Photoreceptors

“viable RPE functional photoreceptors maintenance of vision”

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RPE

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The Cell Based Medicinal Product

En face view of polyester membrane seeded with 100,000 RPE cells

• Human embryonic stem cell derived RPE cells phenotypically & functionally

equivalent to native RPE

• RPE cells seeded as a monolayer on vitronectin coated polyester membrane

• Monolayer of RPE cells mimics normal morphology enabling optimal function in-

situ

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PAX6+PMEL17

Choice of patient population for initial clinical study

• Subjects (n=10) with wet AMD with significant recent decline in vision

related to an RPE tear, sub-macular haemorrhage

o Risk: benefit to patient considered appropriate

o Some clinical precedent shows that macular translocation is effective

• Objectives

o Safety and anatomical success of surgery and delivery technique

o Safety of cells and membrane

o Anatomical and functional survival of transplanted RPE cells

o Visual improvement / stability

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• Risk-benefit ratio to patients is critical

• Safety is the key objective; however other outputs are desirable

• overview of the development &

regulation of cell therapy (CBMP,

cell based medicinal product) in the

EU/USA

• a process map of key steps from

„bench to bedside to market‟

• identify legal requirements &

guidelines applicable to each stage

of the process map

• Does not cover: • solid organ transplantation or blood transfusions,

blood products

• xenogeneic products and xenogeneic feeder cells,

• combination products,

• tissue and cell products regulated in the US as

devices,

• genetically modified cell or tissues products

Preparing a CBMP for a Clinical Trial A ‘top down’ Approach

RPE-CBMP Development The ‘Bottom Up’ Approach

Manufacture of

Reg tox hESC &

RPE cells

Human

Fibroblast

feeder cell bank

hESC Master

Cell Bank

GMP Engineering run

Development &

validation of

surgical delivery

device

GLP Pig

Toxicology

GLP Mouse

teratoma

Toxicology

Development,

validation of QC

process /release/

comparability assays

Safety/proof of

mechanism

clinical study

Clinical

manufacture

Development &

validation of

manufacturing process

Phenotypic

validation of

hESC derived

RPE

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Regulatory

approval

(MHRA)

Ethics

approval

(GTAC-

NRES)

Development

& validation of

patch cutter

Development

& validation

transporter

Manufacture of

Reg tox hESC &

RPE cells

Human

Fibroblast

feeder cell bank

hESC Master

Cell Bank

GMP Engineering run

Development &

validation of

surgical delivery

device (UCL)

Pig

Toxicology

Mouse teratoma

Toxicology

Development,

validation of QC

process /release/

comparability assays

Regulatory & Ethical

approval

(MHRA & GTAC)

Safety/proof of

mechanism

clinical study

Clinical

manufacture

Development &

validation of

manufacturing process

Phenotypic

validation of

hESC derived

RPE Demonstrating phenotypic and functional

equivalence of hESC derived RPE cells

Developing and validating Quality Control

assays

Demonstrating hESC derived RPE are safe:

toxicology

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RPE-CBMP Development The ‘Bottom Up’ Approach

Phenotypic/functional properties of hESC derived RPE is indistinguishable from native RPE

Property hESC derived

RPE

Native fetal /

adult human

RPE

“Cobblestone” appearance

Pigmentation

Expression of RPE phenotypic

markers (whole genome

transcript, and protein)

Expression of and formation

of tight junction proteins

Apical and basolateral

polarisation

Secrete immunomodulatory

cytokines

Inhibit T cell activation

Vectoral secretion of trophic

factors such as VEGF and

PEDF

Phagocytosis of rod outer

segments

Maintain vision in the RCS rat

Phenotype

Ultra-structure

Immune- activity

In-vitro function

In-vivo function

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Choices of analytical test

methods Method

Selection

CRO & GMP

feasibility

Development &

Standardisation

System &

Sample

suitability

Performance

Characterisation

Sensitivity

Accuracy

Flow Cytometry

staining Quantification of

100,000 cells staining Quantification

of 2,000 cells

fixation Staining

&

fixation

Manufacturing

Facility

Manufacturing

Facility GMP CRO GMP CRO

Upper 95% TI

LOD +hESC @ 1% RPE

Selected population (double gated) Total population

300,000

cells 5,000 cells

Sample use: 50 fold more cells required Increased efficiency enabling retains for re-testing

Single test opportunity Images of individual cells preserved

Quality Control Assay: testing for impurity

Image Cytometry

Tech’ transfer &

validation at

CRO- GMP 19

0

5

10

15

20

25

0%

(0/20) 0%

(0/20)

0%

(0/38) 0%

(0/38)

3%

(1/34)

24%

(9/38)

hESC derived RPE does not form teratomas in immuno-deficient mice

Intra-ocular administration

- RPE cells

- hESC (+ive control)

6 months Pathology %

an

ima

ls d

eve

lop

ing

tera

tom

a

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A detailed understanding of the specific disease dynamics, key processes, and product profile

are necessary to assess the opportunity for any cellular therapeutic

Disease

Dynamics

Cell Therapy

Product Profile

Cell Therapy

Key Processes

Indicative Framework for CBMP Evaluation

• remaining unmet need & white space opportunities • size & make up of addressable population • pricing benchmarks • clinical requirements

• attributes of the TPP • efficacy, safety • administration route • differentiation vs. other medicines

• price, penetration • commercial viability

• technical feasibility • developmental challenges • capital expense • COGs • transport & storage

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Paucity of demonstrable clinical data sets from many patients

How does cell therapy compare with general attrition rate for NMEs?

•PTRS rates generally declining

•End points linked to significant disease modification

•Regulatory paths are navigable but can be complex

Developers are predominantly biotech

•Diverse pipelines lacking focus – too many Ph-I/II indications pursued

•Lacking Investment – large companies keeping investments modest; public sector squeeze

•No target product profiles & what is owned, process (autologous) or product (allogeneic)?

Clinical Strategy – lack of focus

•Understand the disease space & know when a good margin of benefit is likely compared with SoC

•Logistics of multi-centre, multinational trials

•Time to reach and failure to meet end point

Manufacturing

•lack of scalability

•Unrealistic COGs for clinic & market

•Understanding how the medicine will be paid for sufficiently early

Lack of Positive, Randomized, Placebo Controlled Data

Is there corrective potential emerging?

Provenge® Xalkori®

Medicine cellular immunotherapy; personalized

Anaplastic lymphoma kinase inhibitor ; Precision medicine

Patient Category

Asymptomatic or minimally symptomatic metastatic hormone refractory prostate cancer in whom chemo is not yet clinically indicated

ALK positive, non-small cell lung cancer

Key P3 Result

IMPACTstudy; median survival 4.1mths longer vs control. no effect on

disease progression

Median PFS 7.7mths vs 3 for chemo grp

Disease Incidence (England)*

~60,000* ~29,000*

UK launch date# Approved (pending launch)

Nov 2012

Cost £57,000 (3 injections)

£14,000 per mth survival £4689 (60 capsules)

NICE to be determined

Sept 2013 – does not recommend Not cost

effective of NHS resources even with a patient access scheme offered by Pfizer

23 *based on new diagnosis per annum; age standardised proportion, 2008; National Cancer Intelligence Network

# UK Medicines Information

Will pipeline products emerge into a reimbursement nirvana?

Healthcare providers - Stand and Deliver?

• CMS proposed rule entitled "Medicare

and Medicaid Programs: Hospital

Outpatient Prospective Payment and

Ambulatory Surgical Center Payment

Systems and Quality Reporting

Programs",

• published in the Federal Register on July

19, 2013

• Improperly classifies skin substitute

products

• Bundles all categories of wound

repair/care products together

• Considers all wound repair/care products

as surgical supplies

• By extension considers that all

regenerative cell or tissue product used

as part of a surgical procedure ,as a

surgical supply

• Negatively impacts innovation

Policy Research and Innovation

Multiple opportunities for regenerative medicine

• Successor of current health program

• Legal papers currently in decision taking process in Brussels o Expect to sail through o Regenerative Medicine identified as a support priority

• Societal Challenge: "Health, demographic change and well being" o Collaborative R&D with industrial partners (not basic) o Regenerative medicine, clinical research o Tools and technologies for advanced therapies o Broad topics on chronic and rare diseases (rather than e.g. diabetes) o Inno-2 category – fast track to Innovation o Unfortunately , as yet no strategic programme on ATMP manufacture/supply chain

• Industrial research o Nanotechnology, materials and SMEs

• European Research Council grants (basic science) o Expect budget allocation x2 for H2020

• Marie Curie actions on training

• Calls expected to be published early 2014

research in Horizon 2020

Summary

• Product Concepts per million people over age of 65* o EU = 0.4, USA = 0.2

• Sector continues to share strong EU public sector support for innovation up to & through the clinic

• Adoptive T cell immuno-therapies represents the fastest recent growth sector o 13 late stage trials (11 in P3), 70% autologous, 30% gene modification o All oncology o early stage - 80% autologous

• Opportunism aside, commercialization will remain the domain of biotech until such time as efficacy is demonstrated across TA from large RCT

• Only at such time will a broad range of strategies & the experience gained by pharma for market access become apparent

25 *Product concepts EU~220, USA~240 (Werner et al Drug Disc. World 2011); 2012 Age 65 or over EU ~84x106, USA~41x106

Thank You

Acknowledgements: Neusentis colleagues Paul Whiting & Devyn Smith Charles Kessler & Torbjoern Ingemansson – EU Research Directorate, FP7 & Horizon2020

Timothy.allsopp@pfizer.com (t) 01304 643483 (c) 07803584066

hESC do not survive the production process

RPE cells spiked with hESC

produce RPE cultures free of hESC RPE culture conditions do

not support hESC survival

Dissociated RPE cells spiked with

0 →100% hESC

Culture for 6 weeks

Quantify hESC & RPE by image analysis &

flow cytometry

No hESC (Tra-1- 60 events) detected

hESC dissociated using RPE conditions

hESC maintained under RPE

culture conditions for 0, 2 & 4 days

96% of cells dead by day 4

Remaining live cells were Tra-1-60 negative

27 20% 50% 100%

20% 50% 100%

0

20

40

60

80

100

0d 2d 4d

% P

I (d

ead

cel

ls)

Days post seeding

Quantify hESC by image analysis

& flow cytometry

pmel17 (RPE)

Dapi/tra-1-60 (hESC)

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Therapeutic Cells/tissues Therapeutic Antibody2

Industry initiation (representative product or service launch)

44 years ago (public service)* 26 years ago**

PRE-COMMERCIAL

Regulations Development Complex product characteristics

needing further definition lacking adequate standards

Simpler product characteristics definable

comparable with standards

Landmark Science Leading to Technical Step Change

Reprogramming enabling therapeutics Humanization of mouse antibodies

Founding Manufacturing Base Diversified production

(in house & CMOs) Unified production

(in house)

Raw material ->DS->DP Protracted with

no generic platform(s) applicable

Rapid with capitol efficient platform use

Current Industry Focus Demonstrating product efficacy Up- and downstream manufacturing

process optimization

COMMERCIAL

Industry profile small biotech spin outs based on

university IP predominate

Extensive consolidation from many university spin outs, bio-pharma

predominate

Aggregate sales of the top 10 approved products (2010)

$0.5B1 $43B

Limiting factor for high value Transactions

Slow pace of technology development e.g. ↓COGs

Size of therapeutic target space

Literature & primary research interview (1. Buckler, 2011 2. John G. Elvin, pers comm.). *features of the cell/tissue therapy sector emergent subsequent to blood cell transplantation and service provision, product based industry not materialize until much later. **Muronomab-OKT3®

Learning the Lesson: what has supported transformed the rAntibody sector?