microrna Therapeutics Harnessing the power of micrornas to target multiple pathways of disease

Transcription

1 microrna Therapeutics Harnessing the power of micrornas to target multiple pathways of disease January 2018

2 Safe Harbor Statement Statements contained in this presentation regarding matters that are not historical facts are "forwardlooking 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 (including with respect to development and other activities related to RG-012 or RGLS4326), the projected timeline of clinical development activities, and expectations regarding future therapeutic and commercial potential of Regulus' business plans, technologies and intellectual property related to microrna therapeutics and biomarkers being discovered and developed by Regulus. 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. These and other risks concerning Regulus are described in additional detail in Regulus' filings with the Securities and Exchange Commission. All forward-looking statements contained in this presentation 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

3 Regulus Key Investment Highlights Leading clinical-stage microrna company with several potential near-term catalysts Expertise in microrna biology and oligo chemistry with a broad IP estate Sources of new disease targets provide broad opportunity Dysregulated mirnas Host mirnas involved in pathogen infections Pathogen encoded mirnas Disciplined discovery and development approach accelerates timeline from target validation to clinic proof-of-concept Strong cash position through expected material clinical data releases in Q $71.4 million in cash and cash equivalents at September 30,

4 Our Strategy Scientific Focus & Core Competency microrna Biology Demonstrated Delivery Capability Liver, Kidney, Topical/Local Strategic Lens Development / Regulatory / Commercial Considerations Pipeline Implications Partner versus Keep 4 4

5 Our Emerging Pipeline in Kidney and Liver Diseases INDICATION (target) TARGET ORGAN COMPOUND PRECLINICAL PHASE 1 PHASE 2 PHASE 3 Alport Syndrome (mir-21) Orphan Disease Kidney RG-012 Partner: Sanofi Genzyme ADPKD (mir-17) Kidney RGLS4326 Cholestatic Diseases (undisclosed targets) HCV (mir122) Liver Liver NASH (undisclosed targets) Liver Glioblastoma Multiforme (mir-10b) CNS 5

6 What are micrornas? Short non-coding RNA sequences (~22-25 nucleotides) Highly conserved across species 550+ and counting micrornas characterized to date Broad regulators: one-hit -> multiple-target approach Dysregulated in numerous diseases 6

7 Targeting micrornas Modulation of Multiple Downstream mrnas and Proteins anti-mir mir-mimic 7 Novel class of disease-modifying drugs Chemically modified oligonucleotides Modulate pathways/networks rather than a single target

8 Sources of New Disease Targets Provides Broad Opportunity DYSREGULATED mirnas HOST mirnas INVOLVED IN PATHOGEN INFECTIONS PATHOGEN ENCODED mirnas 8

9 9 RG-012 for treatment of Alport syndrome

10 Alport Syndrome (AS) is a Hereditary Nephropathy Caused by mutations in COL4A3, A4 or A5 Mutations in either COL 4A3, A4 or A5 lead to absence of COL A3/A4/A5 trimer in GBM 80% X-linked, 15% AR, 5% AD inheritance Affects 1/5,000-10,000 of newborns (~30,000-60,000 patients in U.S.) Clinical and pathological features Defective GBM leads to hematuria, proteinuria and progressive CKD leading to ESRD Hearing loss & eye defects Significant unmet medical need Standard of care: No approved therapies ACE inhibitors used off-label (appears to slow CKD progression) Glomerular Basement Membrane Normal Alport 10

11 RG-012 is a Novel Anti-microRNA Therapy in Development for the Treatment of Alport Syndrome Robust preclinical data demonstrated reduction in kidney fibrosis, reduced renal function decline, and improvement in survival ATHENA Natural History study has provided critical information on natural progression of disease Expected near-term development milestones: Phase 1 renal biopsy initial results 1Q 2018 Phase 2 HERA blinded interim analysis 3Q 2018 Phase 2 HERA final results Q

12 mir-21 and Kidney Fibrosis microrna-21 levels are elevated in chronic kidney disease patients and animal models of kidney fibrosis including Col4A3-/- mouse mir-21 has been implicated in fibrotic disease in kidney, liver and lung Role of mir-21 in renal fibrosis has been validated through genetic knock-outs anti-mirs targeting mir-21 shown to reduce the severity of fibrosis in two distinct preclinical rodent models Chau et al., 2012, Science Translational Medicine 12

13 P e r c e n t s u r v i v a l N o r m a l P B S - H O M m p k m p k 2 5 m p k 5 0 m p k C o l 1 a 1 ( F o l d C h a n g e ) B U N ( m g / d L ) R G R G Targeting mir-21 with RG-012 Improves Kidney Histology, Renal Function, and Prolongs Survival in Preclinical Studies Kidney Fibrosis Renal Function N o r m a l P B S m g / k g / w k m g / k g / w k m g / k g / w k m g / k g / w k R G A g e ( W e e k s ) Survival P B S m g / k g / w k 2 5 m g / k g / w k 5 0 m g / k g / w k 2 5 m g / k g 2 x / w k S t a r t o f d o s in g A g e ( d a y s )

14 Change in egfr from Baseline ATHENA Natural History Study Data have Enabled the Identification of Fast Progressing Subjects for Phase II Study Change in Glomerular Filtration Rate Over Time Baseline egfr 0 Declining Renal Function (ΔeGFR) egfr (Overall Population) egfr (POC* Eligible) Weeks of Follow-up Week Since Baseline *POC = Proof-of-concept 14

15 RG-012 Development Program is Recruiting Phase II HERA Study Objective to evaluate the safety and efficacy of RG-012 Randomized, double-blind, placebo controlled study in 40 x-linked male Alport syndrome patients with rapid renal decline. 48 week of treatment with a blinded interim assessment at 24 weeks (Q3 2018) Renal Biopsy Study Measures of renal pharmacokinetics mir-21 target engagement Measure effects on downstream genomic markers of disease Anticipate data Q

16 RGLS4326 for Autosomal Dominant Polycystic Kidney Disease (ADPKD) 16

17 Disease Background and Natural History PKD1 (16p13.3) PKD2 (4q21) Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases, with ~1:1000 affected individuals in US (US >600k; Worldwide >12M) 50% patients develop ESRD by 60 years of age The 4 th leading cause of ESRD in the US Caused by mutations in PKD1 (85%) and PKD2 (15%) Renal manifestation includes bilateral renal enlargement containing multiple fluid-filled cysts, renal pain and renal insufficiency Time to ESRD Extrarenal cyst includes liver (most prevalent in female), seminal vesicles and pancreas Hypertension and cardiovascular complications are other major morbidity and mortality 17 J Hum Genet 2013 Nov;58(11):720-7

18 mir-17 is upregulated in ADPKD mouse models ns P > 0.05 * P 0.05 ** P 0.01 *** P **** P mir-17 upregulation also observed in other PKD mouse models Expression of mir-17 family of mirs are upregulated and contributed substantially (>2.7%) to the total mirna pool in kidney cysts from ADPKD mouse models 18 Patel et al. (2013) PNAS. Jun 25;110(26):10765 Hajarnis et al. (2017) Nat Commun. Feb 16;8:14395

19 Genetic Validation: Kidney-specific knockdown of mir-17~92 cluster attenuate disease in two ADPKD mouse models (Pkd1-KO & Pkd2-KO) 19 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

20 Genetic Validation: Kidney-specific knockdown of mir-17~92 cluster attenuate disease in ADPKD mouse model (Pkd1 F/RC ) MRI Imaging c: Serum Creatinine d: % Proliferation based on number of phh3+ proliferating cyst epithelial cells Hajarnis et al. (2017) Nat Commun. Feb 16;8:

21 $ (D28) (D28) # (D28) (D28) Pharmacologic Validation: Slowing of disease progression by a tool compound in Pkd2-KO mouse model in vivo Age: D1 D10 D11 D12 D19 D28 (18d treatment) WT-C57BL6 H&E (D28) H&E (D28) 21 Hajarnis et al. (2017) Nat Commun. Feb 16;8:14395 #: % Proliferation based on number of phh3+ proliferating cyst epithelial cells $: Serum BUN kidney

22 Pharmacologic Validation: Slowing of disease progression by a tool compound in Pcy mouse model in vivo Age: D0 D28 D210 WT CD1 H&E (30wks) H&E (30wks) Based on H&E: Cystic area/total kidney section surface area Hajarnis et al. (2017) Nat Commun. Feb 16;8:

23 Primary 3D-cyst Culture Assay Derived from Human ADPKD Donors ADPKD Donors from University of Kansas Medical Center PKD kidney retrieved from nephrectomy Primary PKD cyst cells isolated PKD cyst cells treated with compound and culture in Matrigel to allow 3D growth Image cyst formation Calculate total 3D cyst volume total number of cysts after treatment 3D reconstructed plot per treatment well Image processing Image 28 focal planes per treatment well 23

24 Human in vitro Proof-of-Concept: Anti-miR-17 Treatment Inhibits Cysts Growth in Primary 3D Human Cell Culture C y s t C o u n t Vehicle Anti-miR-17 (1nM) Number of PKD cysts * **** *** *** 1.0 Anti-miR-17 (5nM) Anti-miR-17 (20nM) 0.5 * P < 0.05 ** P < 0.01 *** P < **** P < V e h ic le A n ti-m ir -1 7 A n ti-m ir -1 7 A n ti-m ir -1 7 C o n tr o l# A C o n tr o l# B C o n tr o l# C (nm) Anti-miR-17 treatment reduces both the cyst count and cyst volume 24

25 RGLS Executive Summary An injectable (for subcutaneous administration) of anti-mir-17 oligonucleotide with the potential for the treatment of polycystic kidney diseases (PKD) 1 st -in-class and potential for 1 st -to-market therapy in US for ADPKD Demonstrates anti-cyst activity in human ADPKD primary cyst cultures Demonstrates efficacy in two mouse models of PKD in vivo Favorable physicochemical and pharmacological properties Exhibits acceptable safety profile in preclinical studies Phase I SAD study underway. Data anticipated Q

26 Regulus Key Investment Highlights Leading clinical-stage microrna company with several potential near-term catalysts Expertise in microrna biology and oligo chemistry with a broad IP estate Sources of new disease targets provide broad opportunity Dysregulated mirnas Host mirnas involved in pathogen infections Pathogen encoded mirnas Disciplined discovery and development approach accelerates timeline from target validation to clinic proof-of-concept Strong cash position through expected material clinical data releases in Q $71.4 million in cash and cash equivalents at September 30,

27 Key Program Events Anticipated through Early 2019 PROGRAM EVENT ESTIMATED TIMING RG-012 (Alport Syndrome) HERA study and renal biopsy Recruiting Renal biopsy study data Q HERA blinded interim study data Q ATHENA data Q HERA 48-week data Q RGLS4326 (ADPKD) File IND Phase I first-in-human study Completed Initiated Phase I safety and proof-of mechanism data in ADPKD patients 2H early 2019 Pipeline New clinical candidate nominated

28 microrna Therapeutics Harnessing the power of micrornas to target multiple pathways of disease