PowerPoint PresentationCorporate Presentation
August 2021
Statements contained in this presentation regarding matters that
are not historical facts are "forward-looking statements" within
the meaning of the Private Securities Litigation Reform Act of
1995, including statements associated with the expected ability of
Regulus to undertake certain activities and accomplish certain
goals with respect to development, regulatory and other activities
related to the RGLS4326 program in ADPKD, including the projected
timeline of clinical development activities, the sufficiency of the
data resulting from the ongoing clinical or completed preclinical
studies required to recommence clinical studies for extended
duration dosing, expectations regarding future therapeutic and
commercial potential of Regulus’ programs including its ADPKD and
other preclinical programs, Regulus’ business plans, technologies
and intellectual property related to its programs, biomarkers being
discovered and developed by Regulus or the timing of potential
milestones from RG-012. Because such statements are subject to
risks and uncertainties, actual results may differ materially from
those expressed or implied by such forward-looking statements.
Words such as "believes," "anticipates," "plans," "expects,"
"intends," "will," "goal," "potential" and similar expressions are
intended to identify forward-looking statements. These
forward-looking statements are based upon Regulus' current
expectations and involve assumptions that may never materialize or
may prove to be incorrect. Actual results and the timing of events
could differ materially from those anticipated in such
forward-looking statements as a result of various risks and
uncertainties, which include, without limitation, risks associated
with the process of discovering, developing and commercializing
drugs that are safe and effective for use as human therapeutics,
and in the endeavor of building a business around such drugs. In
addition, while Regulus expects the COVID-19 pandemic to adversely
affect its business operations and financial results, the extent of
the impact on Regulus’ ability to achieve its preclinical and
clinical development objectives and the value of and market for its
common stock, will depend on future developments that are highly
uncertain and cannot be predicted with confidence at this time,
such as the ultimate duration of the pandemic, travel restrictions,
quarantines, social distancing and business closure requirements in
the U.S. and in other countries, and the effectiveness of actions
taken globally to contain and treat the disease. These and other
risks concerning Regulus' financial position and programs are
described in additional detail in Regulus filings with the
Securities and Exchange Commission, including under the “Risk
Factors” heading of Regulus’ quarterly report on Form 10-Q for the
quarter ended June 30, 2021, filed with the SEC on August 10, 2021.
All forward-looking statements contained in this press release
speak only as of the date on which they were made. Regulus
undertakes no obligation to update such statements to reflect
events that occur or circumstances that exist after the date on
which they were made
2
Leading microRNA Co leveraging novel technology into first-in-class
therapeutics
Expertise in microRNA biology and oligo chemistry based on company
foundation through joint venture between Ionis and Alnylam with
access to IP/technology
Platform optimized to deliver oligonucleotide anti-miR therapies to
the kidney
Clinical pipeline of microRNA therapeutics for unmet needs in
genetic kidney disease
RGLS4326 for Autosomal Dominant Polycystic Kidney Disease (ADPKD):
Phase 1b ongoing
Demonstrated target engagement with significant increase in key
biomarkers in first cohort of patients
Granted Orphan Drug Designation by FDA
Lademirsen (RG-012) for Alport Syndrome: Phase 2 enrolling
Data demonstrate desired exposure with target engagement and
attractive safety profile to date
Multiple Near-Term Milestones
RGLS4326:
Completed preparations and request for FDA Meeting to obtain
feedback on approach to addressing remaining hold requirements:
expected late Q3 2021
Phase 1b cohort 2 top-line data expected Q4 2021
Next generation ADPKD compound: IND submission expected by Q1
2022
Lademirsen (RG-012):
balance sheet
Target Validation
Lead Optimization
Nephrology
4
Clinical demonstration of desired kidney exposure & binding of
target, miR-21
5
Achieved $10m milestone in 2020
Regulus eligible to receive $25M milestone upon completion of Phase
2
Attractive safety profile to date: Chronic treatment with
lademirsen is well tolerated (Q2W for one year) with no SAEs
reported
Promising trend in key disease markers
Sanofi currently enrolling global, randomized, placebo- controlled
Phase 2 study in patients with Alport Syndrome
Autosomal Dominant Polycystic Kidney Disease (ADPKD) Orphan disease
and high unmet medical need
6
Kidney Function Decline by Age
The Underlying Pathology Mutation of either PKD1 or PKD2 genes
causes fluid-filled cysts to proliferate in the kidneys
leading to loss of kidney function over time
K id
n ey
F u
n ct
io n
7
Autosomal Dominant Polycystic Kidney Disease (ADPKD) Orphan disease
and high unmet medical need
85% 160K patients with PKD1 mutation
diagnosed individuals in U.S.
Health Burden
$3.8B+ estimated annual cost of renal replacement therapy in
U.S.1
1. Cloutier et al. (2020) BMC Health Serv. Res. 20:126
The Unmet Medical Need 50% of patients develop ESRD by
age 60 and require dialysis or transplantation
Kidney failure average age: 55 years for PKD1 patients 74 years for
PKD2 patients
Only FDA approved therapy has boxed warning and potentially fatal
liver toxicity
Jynarque® (tolvaptan, vasopressin V2 antagonist) – FDA approved
April 2018
Boxed warning due to potentially fatal liver injury & failure
requiring transplant
REMS program with restricted distribution & ongoing liver
monitoring in patients
Despite limitations, 2020 sales were $694M in US (2021 est.
$837M)*
8
Limitations of Standard of Care Creates opportunity for innovative
and safe new therapies
Only FDA approved therapy has Boxed warning
*GlobalData
Decreases PC1 and PC2 protein levels
Mutations in PKD1 and PKD2 genes
ADPKD Pathology
Treatment with RGLS4326
Pathway to Target Validation
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
miR-17 is Upregulated in ADPKD models Mouse kidney cysts &
human ADPKD cyst cells
12
Hajarnis et al. (2017) Nat Commun. Feb 16;8:14395
N o
rm al
H u
m an
K id
n e
y A
D P
K D
K id
n e
Normal Kidney ADPKD Kidney
miR-17 Directly Binds PKD1 & PKD2 Genes Mediating ADPKD
3’UTRs of PKD1 and PKD2 contain conserved miR-17 binding
sequences
miR-17 mimic represses PKD1 and PKD2 in mouse collecting duct
(IMCD3) cells
13 PNAS 2013 June;110(26): 10765-10770
WT: wildtype 3’UTR MT: mutated 3’UTR
PKD1: 3’UTR conserved binding site for miR-17 PKD2: 3’UTR conserved
binding site for miR-17
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
Kidney-specific Knockdown of miR-17~92 Cluster Attenuates disease
in ADPKD mouse model (PKD1F/RC)
14 Hajarnis et al. (2017) Nat Commun. Feb 16;8:14395
MRI Imaging
c: Serum Creatinine d: % Proliferation based on number of pHH3+
proliferating cyst epithelial cells
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
Kidney-specific Knockdown of miR-17~92 Cluster Attenuates Disease
in Two ADPKD Mouse Models
15 Hajarnis et al. (2017) Nat Commun. Feb 16;8:14395
b, f: Serum Creatinine c, g: % Proliferation based on number of
pHH3+ proliferating cyst epithelial cells
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
Age: D1 D10 D11 D12 D19 D28 (18d treatment)
Targeting miR17 with RGLS4326 Causes de-repression of PKD1 &
PKD2 Gene Expression in PKD2-KO Mice
16
Inject
Lee et al., (2019)10:4148 Nat. Comm.KW = kidney weight BW = Body
weight
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
mouse model of ADPKD
KW = kidney weight; BW = Body weight
PKD1F/RC mice were dosed s.c. with RGLS4326 or Control Oligo at 20
mg/kg on post-natal day (P)8, 10, 12 and 15 and sacrificed at
P18.
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
15w (sacrifice)
RGLS4326 Compares Favorably to Standard of Care Efficacy in the
Pcy/DBA Mouse Model
18 Lee et al. (2018) ASN-Kidney Week; Poster Presentation
Age: 6w 14w
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
RGLS4326 Slows Cystic Expansion Efficacy in the Pcy/DBA mouse
model
19
Changes in body-weight adjusted total kidney volume (bwTKV) from
baseline at week 8, 11 and 14 was significantly reduced after
RGLS4326 treatment by 25%, 37% and 50%, respectively (p<0.05 for
all).
Stabilization
Reduction
Reduction
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
Urinary Biomarker Assay Can Detect PC1 and PC2 in Humans Protein
levels correlated with disease severity
20
a ti
a ti
N=8 N=8
Lower levels of PC1 and PC2 are associated with disease severity
based on increased kidney size
Preliminary analysis support sample size (n=9) sufficient to detect
~45% and ~70% increase in PC1 and PC2
respectively (Power=80%)
*ExosomeDx developer
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
RGLS4326 treatment de-represses PKD1 and PKD2 Leads to increased
PC1 and PC2 in PKD1RC/- mouse cells
21
F o
l d
F o
l d
n -
B
Treatment of Human ADPKD Cyst Cells with RGLS4326 Causes increases
in polycystin levels
22
PC1 Expression PC2 Expression * **
Disease Association
Genetic Validation
Pharmacologic Validation
Biomarker Validation
24
0 2 0 0 0 0 4 0 0 0 0 6 0 0 0 0
Ad r e n a l g la n d
B o n e M a r r o w ( fe m u r )
B o n e ( fe m u r )
B r a in
K id n e y (c o r te x )
K id n e y (m e d u lla )
L a r g e in te s t in e (w a ll)
L iv e r
L u n g
L ym p h n o d e (c e r v ic a l)
M u s c le ( fe m o r a l)
P a n c r e a s
P itu ita r y g la n d
S k in (n o n -p ig m e n te d )
S m a ll in te s t in e (w a ll)
S p le e n
S to m a c h (w a ll)
T e s te s
T h ym u s
T h yr o id g la n d 2 d a y s a fte r s in g le d o se
1 4 d a y s a fte r s in g le d o se
R G L S 4 3 2 6 E q u iv a le n ts (n g /g )
Tissue distribution profile of RGLS4326 based on quantitative
whole-body autoradiography in male CD1 mice after a single SC dose
of 30mg/kg
Representative immunofluorescence image of kidney samples of
PKD2-KO mice after four SC doses of 20mg/kg
Lee et al. (2018) ERA-EDTA; Oral Presentation
RGLS4326: Favorable PK/PD Profiles After a single subcutaneous (SC)
dose of 30 mg/kg
25 Lee et al. (2018) ASN-Kidney Week; Poster Presentation
RGLS4326 rapidly absorbed into and cleared from plasma. RGLS4326
distributes primarily to kidney, with kidney-to-liver ratio of
>10-fold RGLS4326 potently engages miR-17 peaking on Day 7
post-dose
0 10 20 30
x p
RGLS4326: Estimated Human Kidney Exposures
26
Predicted Kidney Exposure in Phase 1b Study After First and Last
Doses
0.01 0.1 1 10 100 0
25
50
75
100
EC90 ~ 11g/g
PK/PD Analysis in C57BL Mice At 7 Days Past Single Dose
PK/PD analysis in mice demonstrated that EC90 is associated with
kidney concentration of ~11 μg/g The model predicts that kidney
exposures from 0.3mg/kg dose in Phase 1b trial will exceed levels
that are
associated with effective target inhibition The minimal Human
Effective Dose (mHED) is estimated to be 0.05 mg/kg - 0.17
mg/kg
0 7 14
dose ~ 11g/g
dose ~ 11g/g
Modified from: Lee et al., (2019)10:4148 Nat. Comm.
7-week IND enabling tox completed with NOAELs established at top
dose tested
450 mg/kg QW – mouse ; 150 mg/ kg QW– monkey
27
NOAEL = no observed adverse-effect level; DLT = dose limiting
toxicity; ADME = absorption, distribution, metabolism,
excretion
Chronic tox studies completed with NOAELs established at
mid-dose
100mg/kg Q2W for 27 weeks – mouse; 60 mg/kg Q2W for 39 weeks-
monkey
DLT level identified at top doses tested (300mg/kg- mouse ;
150mg/kg – monkey)
Long-term dosing requires resolution of remaining partial clinical
hold requirements
Need to develop robust ADME model to predict exposure of longer
durations and ensure acceptable safety margins to move forward in
clinical development
RGLS4326 Clinical Program
29
PD biomarkers developed to measure changes in both PC1 & PC2 in
urinary exosomes
Utilizing 13 clinical sites in the US with 12 sites currently
actively recruiting
Cohort 1- 1 mg/kg SC, Q2W for 4 doses (n≤9) Completed
Cohort 2- 0.3 mg/kg SC, Q2W for 4 doses (n≤9) Enrollment complete
and treatment ongoing
Cohort 3- 0.1 mg/kg or 0.5 mg/kg SC, Q2W for 4 doses (n≤9)
SAD completed up to top dose of 6 mg/kg in healthy volunteers MAD
completed up to top dose of 1 mg/kg (Q2W x 4) Administration of
RGLS4326 well-tolerated with no SAEs reported and dose proportional
PK
Phase 1 SAD/MAD completed - in Healthy Volunteers to evaluate
safety, tolerability, and PK
Phase 1b MOA study ongoing - Evaluating safety, tolerability, PK
and PD in ADPKD patients
Phase 1b First Cohort: Significant Increase in Key Biomarkers
30
Significant increase in urinary PC1 and PC2 were observed at the
end of the study (D71) compared to baseline (p=0.004 and p=0.026,
respectively, based on paired t-test)
Lee et al. (2021) PKD-Connect; Poster Presentation
Safety
RGLS4326 at 1mg/kg was well tolerated by all nine patients with no
serious adverse events reported
All reported adverse events were mild and generally transient in
nature
Pharmacokinetics
Overall, the PK profile of RGLS4326 in patients with ADPKD was
similar to the PK profile observed in the prior healthy volunteer
study:
The half-life of RGLS4326 in plasma was longer in patients (~ 9
hours) than in healthy volunteers (~6 hours) and did not exhibit
any signs of accumulation in plasma
The Cmax was also higher in patients (~3 micrograms/ml) than in
healthy volunteers (~2 micrograms/ml)
Higher plasma exposure is anticipated to lead to higher exposure in
target organ, kidney
31
RGLS4326 Summary
2019): company resumes MAD study
Completion of chronic toxicity studies and satisfactory safety
margins enabled re- initiation of Phase 1 studies in healthy
volunteers and patients with ADPKD
SAD/MAD study dosing completed in
July 2020 in healthy volunteers
First cohort of Phase 1b study in
ADPKD completed
Significant increases in excreted PC1 and PC2 validate target
engagement of miR-17 as designed
32
study in ADPKD completed
Requested a Type A meeting with FDA to
discuss our approach to addressing the
remaining partial clinical hold requirements
Addressing remaining partial hold requires development of a robust
PK model to simulate dosing of extended durations with acceptable
safety to proposed clinical dose and frequency
Goal to optimize new compound
with improved product profile
33
Next Step: IND-enabling activities
While maintaining beneficial
miR-17 inhibition potency and duration of action in kidney
In vitro and in vivo efficacy
Favorable physicochemical properties
Good safety profile
Completed: non-GLP toxicity studies at significantly higher dose
levels with no similar dose-limiting toxicity signs
Anticipated Milestones
FDA engagement for feedback on approach to addressing remaining
hold requirements
Late Q3 2021
Topline data for remaining RGLS4326 Phase 1b cohorts • Cohort 2
data (0.3 mg/kg) • Initiation of Cohort 3 (dose TBD)
Q4 2021 Q4 2021
2H 2021
Corporate Presentation