corporate presentation august 2021
TRANSCRIPT
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
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