2015 Jefferies Healthcare Conference

Transcription

1 2015 Jefferies Healthcare Conference Douglas Fambrough, CEO James Dentzer, CFO November Dicerna Pharmaceuticals 87 Cambridgepark Drive Cambridge, MA USA

2 2 Forward-looking statements This information may contain projections and other forward looking statements regarding future events, including regarding Dicerna s technology platform, product candidates, preclinical and clinical pipeline and milestones, regulatory objectives, market opportunities, and intellectual property. Such statements are predictions only and are subject to risks and uncertainties that could cause actual events or results to differ materially. These risks and uncertainties include, among others, the cost, timing and results of preclinical studies and clinical trials and other development activities; the unpredictability of the duration and results of regulatory review of New Drug Applications and Investigational NDAs; market acceptance for approved products and innovative therapeutic treatments; competition; the possible impairment of, inability to obtain and costs of obtaining intellectual property rights; and possible safety or efficacy concerns, general business, financial and accounting risks and litigation. More information concerning Dicerna and such risks and uncertainties is available on its website and in its press releases, and in its public filings with the U.S. Securities and Exchange Commission. Dicerna is providing this information as of its date and does not undertake any obligation to update or revise it, whether as a result of new information, future events or circumstances or otherwise. Additional information concerning Dicerna and its business may be available in press releases or other public announcements and public filings made after the date of this information.

3 3 About Dicerna Developing and commercializing new pharmaceuticals using RNAi Human proof-of-concept established for RNAi drugs Natural mechanism for potent gene-specific silencing Dicerna RNAi drug delivery technology for liver and for solid tumors Broad pharmaceutical pipeline engine for liver & tumors Rare inherited diseases involving the liver DCR-PH1 & beyond Tumors with genetically-defined drivers DCR-MYC & beyond Potential to expand to other diseases of the liver fibrosis/nash, lipid/cv, viral disease, etc. Founded in 2007 based on proprietary RNAi technology Based in Cambridge, MA, with approximately 50 employees Dicerna is resourced to drive clinical proof-of-concept for our announced programs. Dicerna ended Q with $108 million.

4 4 LIVER TARGETED ONCOLOGY Development Pipeline RESEARCH PRECLINICAL PHASE 1 DCR-PH1 HOA1 Primary Hyperoxaluria Type 1 DsiRNA-EX payload, Arbutus LNP (IV) Rare Disease undisclosed target DsiRNA-EX Conjugate (subcutaneous) Fibrosis undisclosed target DsiRNA-EX Conjugate (subcutaneous) Rare Disease undisclosed target DsiRNA-EX Conjugate (subcutaneous) Multiple additional research stage programs underway DsiRNA-EX Conjugate (subcutaneous) DCR-MYC Hepatocellular Carcinoma Solid Tumors DsiRNA payload, EnCore LNP (IV) DCR-BCAT DsiRNA-EX payload, EnCore LNP (IV) KHK-KRAS DsiRNA payload, KHK LNP (IV) KHK-XXX DsiRNA payload, KHK LNP (IV)

5 Liver Target Pipeline Engine DsiRNA-EX Conjugates for Subcutaneous Administration

6 6 DsiRNA-EX Conjugate Delivery System

7 DsiRNA-EX Conjugate Development Timeline 2013 development of structural strategies Q begin staffing up chemistry effort 12/31/2013 S-1 filing discloses that we will use conjugation in future product candidates 1 with a working system expected within the next twelve months 2 Q initial subcutaneous knockdown results of >10 mg/kg Q announcement of SC knockdown of ~2mg/kg All future liver disease programs to be DsiRNA-EX Conjugates instead of lipid nanoparticles. EC50 >10 mg/kg EC50 ~2 mg/kg Q translation of activity from rodents to non-human primates Q announcement of SC knockdown of ~0.6 mg/kg EC50 ~0.6 mg/kg 7 1 Dicerna Form S-1 pg. 70; 2 pg. 75 EC50 = 50% knockdown of mrna levels in mice

8 8 H A O 1 m R N A (R e la tiv e to P B S ) DsiRNA-EX Conjugate Development Results & Process HAO1 Gene Silencing Results Single Dose SC, 72 h Post-Dose Single dose EC50 ~0.6 mg/kg DsiRNA-EX Conjugate Development Process 1. Sequence optimization in DsiRNA format Add GalNAc ligands and a standard stabilization pattern day 3 sac 3. Customization of stabilization pattern to maximize stability. Validate activity in mice and monkeys. Iterate P B S US Patents No. 8,349,809; 8,513,207; 8,927,705 and pending applications

9 EC50 (mg/kg) Single Dose in Mice M o u s e S in g le -d o s e E C 5 0 (m g /k g ) Potency Improvements in Dicerna Conjugates Continuous improvement in potency Continuous improvement in conjugate potency DsiRNA-EX Conjugates comparison to existing conjugate programs Long duration of action Proprietary format simplifies discovery, optimization, and manufacturing 1 0 DsiRNA-EX Conjugates Alnylam Conjugates HAO1 HAO1 Other T T R Currently being broadly applied across multiple liver targets Apr 14 Oct 14 Nov 14 Sep 15 EC50 mrna A A T A T 3 P C S A N G C C 5 EC50 Serum Protein Sources: 9 ALNY Various Conjugate Data, serum protein EC50: AAT: ALN-AAT Roundtable TTR, AT3, PCS: Conjugate Delivery Roundtable ANG: R&D Day CC5: ALN-CC5 Roundtable ALNY HAO1 Conjugate Data, mrna EC50: Poster, 10 th Annual OTS Meeting ALN-GO1 Roundtable

10 10 The Liver Opportunity Space --- First-in-class programs currently being prosecuted by Dicerna --- HAO1 PH1 XXXXXXXX XXXXXXXX Redacted XXXXXXXX XXXXXXXX XXXXXXXX Multiple Fibrosis/NASH LNP formulation IND Q3/15 in Phase 1 Q4/15 ODD in US/EU DsiRNA-EX Conjugate in NHP studies Q3/15 Potent leads and conjugates identified Animal efficacy model data in ABC & XYZ PD studies in NHPs Q3/15 Potent leads identified Animal efficacy testing underway PD studies in mouse models Q3/15 Potent leads identified PD studies in mouse models Q3/15 Screening initiated Leads expected Q4/2015 Multiple indication target Screening initiated In vivo data Q4/15 Screening initiated PD studies in mouse models Q3/ Fast follower targets being explored by Dicerna researchers --- SERPINA1 A1AT liver disease SERPINC1 Hemophilia A & B CC5 PNH, ahus TTR Amyloidosis APOC3 Dyslipidemia ALAS-1 AIP (Porphyria) Multiple HBV Potent leads and conjugates identified PD studies in mouse models Q2/15 PD studies in NHPs Q3/15 Potent leads and conjugates identified PD studies in mouse models Q3/15 Potent leads and conjugates identified PD studies in mouse models Q4/15 Potent leads and conjugates identified PD studies in mouse models Q4/15 Screening initiated Leads expected Q4/15 Screening initiated Leads expected Q4/15 Potent leads and conjugates identified PD studies in mouse models Q3/15

11 DCR-PH1 for Primary Hyperoxaluria Type 1 HAO1-targeted DsiRNA-EX formulated in a lipid nanoparticle

12 Actual PH1 Patient Journey Normal/ Healthy ER/PCP Jun Jul Aug Sept Oct Nov Dec-May Jun Jul-Aug Sept 5 th BD Starts pre-k AM nausea 6 th BD Starts K (lifelong immunosuppression) Hem Concerning blood work AMC Airlifted (alone) for dialysis Dx PH1 will need 2 Tx to survive Dialysis Tx List Patient and parent move from Southeast to Midwest, dialysis q6d/wk Matching difficulties parents devastated LTx Surgery #1 12 KTx Complications Surgery #2 Surgery #3

13 13 Primary Hyperoxaluria Type 1 (PH1): From genetic mutation to outcomes Abnormal liver metabolism produces excess oxalate which is concentrated in the renal filtrate (Cochat, 2013) Bone Systemic oxalosis in PH1 Bone & Kidney Calcium oxalate crystals form, inducing nephrolithiasis & nephrocalcinosis (Cochat, 2013) Subsequent decline in kidney function results in systemic oxalosis (Cochat 2013) Over 50% have already experienced kidney failure; median onset at 23 yrs (van der Hoeven, 2012) Skin Kidney Patients then require intensive daily dialysis while awaiting a dual liver-kidney transplant (Hoppe, 2012) Eye Children have poorer transplant outcomes vs. non-ph patients (Harambat, 2012) Photographs reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Nephrology 8 (2012) pg. 467

14 Early Child 0-4 Late Child 5-9 Juvenile Adult 20+ Primary Hyperoxaluria Type 1 (PH1) Epidemiology Addressable market of ~5,000 PH1 patients in the US & EU PH1 is an ultra rare disease Median age of diagnosis is 12 years Estimated prevalence: 1-3 cases per million pop. (diagnosed today in EU countries) Estimated genotypic incidence: 1 case per ~150,000 births (based on disease allele frequency) PH-1 30% 18% 18% 34% P. Cochat et al NEJM 369;7; Hopp et al, 2015 JASN epub >1,000 PH1 patients identified in registries ~5,000 Patients in US & EU based on Genotypic Incidence 328 PH1 patients Rare Kidney Stone Consortium, Jul PH1 patients OxalEurope, Jul 2015 ~2,000 patients ~3,000 patients personal communication Hopp K et al, J Am Soc Nephrol. 2015; EU28 population = 506.9M (Source: Eurostat)

15 DCR-PH1 Strategy: Target oxalate formation by re-directing pathway to produce glycolate The DCR-PH1 strategy is to target the metabolic pathway at glycolate production, by silencing the HAO1 gene which encodes for the GO protein Hydroxyproline Urinary oxalate excretion rate of >2 mmol/1.73m 2 /24hr associated with a significantly lower rate of end stage renal disease (ESRD) Hydroxyproline, derived from collagen breakdown, is converted in several steps into Glycolate stable Glycolate RNAi Therapy targets the pathway before glyoxylate production (one step before the disease) is converted by the GO protein into Glycolate excretion in urine is harmless PH1 Disease blocks the pathway after glyoxylate production (due to loss of AGT protein function) Glyoxylate is converted by the AGT protein into converts to Oxalate Oxalate excretion in urine causes kidney damage 15 Glycine Glycine produced in this pathway is re-used in cell metabolism Analysis of Urinary Risk Factors for ESRD among Patients with Primary Hyperoxaluria, Zhao, F. et al., J. Am. Soc. Neph, vol 25 Abstract suppl. (TH-PO310)

16 Oxalate/Creatinine Ratio vs PBS Groups Cumulative Effects of DCR-PH1 on Urinary Oxalate in PH1 Disease Model Mice PBS treated P B S (N = 5 ) DCR-PH1 H A O 1 E x treated (N = 4 ) normal oxalate range dosed Day Mouse PH1 model (AGXT -/- ) dosed 0.3 mg/kg Repeat dosing of DCR- PH1 leads to near normal levels of urinary oxalate in the mouse genetic model of PH1 16 A corresponding rise in urinary glycolate is observed

17 17 DCR-PH1 Preclinical Studies in PH1 Model Mice: Oxalate crystal deposition AGXT -/- PH1 mouse model challenged with ethylene glycol Studies in PH1 model mice AGXT-/- fed 0.7% ethylene glycol to induce crystal deposition in the kidneys showed that DCR-1171X can prevent the formation of calcium oxalate crystals in the kidneys of hyperoxaluric mice A Week 1 Week 2 Week 3 No treatment ethylene glycol PBS PBS PBS A B C B ethylene glycol Late treatment PBS PBS DCR-1171X 0.3 mg/kg C ethylene glycol DCR-1171X 0.3 mg/kg DCR-1171X 0.3 mg/kg Early treatment DCR-1171X 0.3 mg/kg No treatment Late treatment Early treatment

18 18 PHYOS: Primary Hyperoxaluria Observational Study Observational study will facilitate enrollment and execution of phase 1 clinical trial of DCR-PH1 Primary Objective: - To collect data regarding changes in oxalate, glycolate and other biochemical parameters over time in subjects with PH1 who may be candidates for clinical trials of DCR-PH1 Eligibility: - Genetically confirmed diagnosis of PH1 - Urine oxalate excretion 0.8 mmol/1.73m 2 in 24 hours - Age 12 years (Cohort A) or Age 6 years (Cohort B) - Estimated glomerular filtration rate (egfr) 40mL/min/1.73m 2 No. of patients: - Up to 50 Countries: - US, EU (Germany, France, UK, The Netherlands), Israel

19 19 DCR-PH1: Initial Clinical Trial IND filed in Q Objectives: To determine the safety profile, maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) effects of DCR-PH1 Single Ascending Dose Patients with confirmed PH1 diagnosis Cohorts of 1-3 patients Endpoints: - Safety & Tolerability - PK - PD (oxalate, glycolate) Multiple Ascending Dose Patients with confirmed PH1 diagnosis Cohorts of 3-6 patients Endpoints: - Safety & Tolerability - PK - PD (oxalate, glycolate) Dosing Regimen: IV infusion over minutes Timeline: IND filed in Q3 2015, Seek to enroll 1 st patient in Q or Q1 2016

20 DCR-MYC: Solid tumor therapy targeting the MYC oncogene All-comers phase 1 trial for RNAi oncology proof-of-concept Pancreatic neuroendocrine tumor (PNET) patient cohort Hepatocellular carcinoma (HCC) phase 1b/2a trial

21 21 Dicerna DsiRNA-EnCore Tumor Delivery System MOA

22 MYC: One of the First Discovered and Broadly Implicated Oncogenes MYC has historically been considered an undruggable target Deregulation of MYC has been described in numerous cancers MYC Genomic Duplication or Higher Order Amplification Rate: Hepatocellular 50% Breast 80% Colorectal 70% Gastric 51-77% Gynecological 90% Prostate 80-90% SCLC 18-30% Human translocations and cancerassociated SNPs also occur for MYC Apoptosis Proliferation MYC is a central regulator of several oncogenic processes: Universal Amplifier STAT Division, Cell Size Wnt MYC MAPK Target Processes PI3K Differentiation Angiogenesis, Tumor stroma mirnas, lncrnas Genetic models show the powerful antitumor effects of MYC inhibition Glycolysis, Lipids, Amino Acids Genomic instability Transformation 22 Genes and Cancer 1 (2010), pg. 532 Cell 151 (2012), pg. 68 Science 338 (2012), pg Genes Dev. 27 (2013), pg. 504 Genes Dev. 25 (2011) pg. 907

23 23 [D s ir N A ] n g /g DCR-MYC Preclinical Data Drug accumulation, gene knockdown, and efficacy correlate with dosing in tumor model Accumulation of Drug (DsiRNA accumulation in Hep3B xenograft model) Gene Knockdown (reduction of MYC mrna transcript) Efficacy (Tumor volume reduction) T u m o r D s ir N A e x p o s u re 4 8 h p o s t s in g le iv d o s e L L O Q P B S M Y C D s ir N A [m g /k g ]

24 24 DCR-MYC: Ongoing Clinical Trials Two clinical studies ongoing in solid tumors Study initiated: 2Q2014 Eligibility: Patients with solid tumors, myeloma or lymphoma Pancreatic neuroendocrine tumor (PNET) cohort at MTD Endpoints: - Safety & tolerability, PK - Evidence of RNAi Activity (by biopsy at MTD) - Metabolic Response (by FDG-PET) - Efficacy Response (by RECIST) Sites: US only - START San Antonio - Univ. of Chicago DCR-MYC Study 101 Phase 1 study in advanced solid tumors - Additional sites for PNET cohort Three Checked Boxes will establish human proof-of-concept DCR-MYC Study 102 Phase 1b/2 study in hepatocellular cancer (HCC) Study Initiated: 4Q2014 Eligibility: Patients with advanced HCC who have failed sorafenib, are intolerant to sorafenib or lack access to therapies Endpoints: - Safety & tolerability - Pharmacokinetics - RNAi activity (biopsies in MTD cohort) - Response by mrecist Sites: US, Asia - US: MGH Cancer Center, START San Antonio - Asia: NCCS Singapore, ASAN Medical Center Korea Data from these trials may support a rapid path to approval in PNET and HCC

25 25 DCR-MYC: Phase 1 Study Preliminary Results 2 of 3 Pancreatic Neuroendocrine (PNET) patients in study show preliminary response to treatment 1 st PNET Patient (Metabolic Response by FDG-PET) 2 nd PNET Patient (Efficacy Response by RECIST) (baseline) 4/14/14 (post-treatment) 6/4/14 Initial Treatment (re-treatment baseline) 5/11/15 (post-treatment) 5/22/15 Re-Treatment After 12 Month Drug Holiday Initial Treatment: One Cycle (3 doses) Break in Therapy: Patient discontinued after DLT (but re-entered the study when tumor relapsed) Re-Treatment: Metabolic response shown after two doses Diagnosis: Pancreatic neuroendocrine tumor (PNET), lymph node and renal metastasis Prior therapies: Everolimus, OPB (STAT/metabolic inhibitor), trametinib + GSK (MEK + Akt inhibitors) Tumor response: 34% shrinkage after Cycle 4, confirmed after Cycle 6 Partial Response (PR) by RECIST 1.1 criteria

26 DCR-MYC: Additional Cohort to be Enrolled after MTD Seek to expand early success by enrolling a new cohort of 20 patients with PNET Plan: After the DCR-MYC-101 Study hits MTD, enroll a new cohort of up to 20 patients with PNET Rationale: 2 of 3 patients in low dose cohorts have responded MYC is expressed in 100% of PNET tumors assayed by IHC 1 PNET genetically-engineered model (RIP1-Tag2) is MYC responsive 2 Both approved treatments are poorly effective Sutent: Approval trial 171 pts, 9.3% OR rate in treatment group 3 Afinitor: Approval trial 411 pts, 5.0% OR rate in treatment group 4 PNET is an uncommon cancer originating in the endocrine tissue of the pancreas Estimated incidence: 3K patients per year in the US Median age at presentation 60 years Median survival is 24 months 5-year survival < 43% Wang D-G et al, Cancer 1997;80: Sodir NM et al, Genes & Dev 2011;25: Raymond E et al, NEJM 2011;364: Yao JC et al, NEJM 2011;364:514-23

27 DCR-BCAT: b-catenin targeted DsiRNA-EX in improved EnCore LNP The next oncology product in the pipeline also targets multiple tumor types Delivery Activity in Diverse Tumor Types Tumor type Description Tumor location in model Acute lymphoblastic leukemia ALL697 disseminated/spleen Acute lymphoblastic leukemia NALM-6 disseminated/spleen Acute myelogenous leukemia KG1 disseminated/spleen, liver Colorectal LS411N CLDX subcutaneous/flank Colorectal SW403 CLDX subcutaneous/flank Colorectal LS174T CLDX subcutaneous/flank Colorectal PDX subcutaneous/flank Hepatoblastoma liver-specific GEMM/CTNNB1-YAP spontaneous/liver Hepatoblastoma HepG2 CLDX subcutaneous/flank Hepatoblastoma HepG2 CLDX orthotopic/liver Hepatocellular Carcinoma Hep3B CLDX subcutaneous/flank Hepatocellular Carcinoma Hep3B CLDX orthotopic/liver Hepatocellular Carcinoma PDX orthotopic/liver Hepatocellular Carcinoma GEMM/Mst1 spontaneous/liver Hepatocellular Carcinoma liver-specific GEMM/CTNNB1-KRAS spontaneous/liver Hepatocellular Carcinoma liver-specific GEMM/Myc spontaneous/liver Lung Lewis Lung Carcinoma subcutaneous/flank Melanoma B16F10 CLDX subcutaneous/flank Melanoma B16F10 CLDX disseminated/lung, liver Multiple Myeloma KMS11 subcutaneous/flank NSCLC PDX subcutaneous/flank Osteosarcoma PDX subcutaneous/flank Ovarian PDX subcutaneous/flank Pancreatic MiaPaca2 subcutaneous/flank Pancreatic PDX subcutaneous/flank Renal Cell Carcinoma 786/0 subcutaneous/flank Anti-Tumor Activity in Colorectal Cancer Model 1 mg/kg, qdx3 2 cycles N=6/group 0 (LS411N) S t u d y d a y b-catenin protein immunohistochemistry P B S P la c e b o BEFORE TREATMENT (brown = b-catenin protein) D C R -B C A T 8 2 % S t u d y d a y P B S P la c e b o D C R -B C A T AFTER TREATMENT (3 mg/kg; 2 cycles; qdx3) 8 2 %

28 28 LIVER TARGETED ONCOLOGY Development Pipeline RESEARCH PRECLINICAL PHASE 1 DCR-PH1 HOA1 Primary Hyperoxaluria Type 1 DsiRNA-EX payload, Arbutus LNP (IV) Rare Disease undisclosed target DsiRNA-EX Conjugate (subcutaneous) Fibrosis undisclosed target DsiRNA-EX Conjugate (subcutaneous) Rare Disease undisclosed target DsiRNA-EX Conjugate (subcutaneous) Multiple additional research stage programs underway DsiRNA-EX Conjugate (subcutaneous) DCR-MYC Hepatocellular Carcinoma Solid Tumors DsiRNA payload, EnCore LNP (IV) DCR-BCAT DsiRNA-EX payload, EnCore LNP (IV) KHK-KRAS DsiRNA payload, KHK LNP (IV) KHK-XXX DsiRNA payload, KHK LNP (IV)

29 29 Key Milestones Company expectations for the next months DCR-PH1 for Primary Hyperoxaluria Type 1 IND filed in Q3 2015; accepted in Q Phase 1 initiation late Q or early Q Human POC 2016 Initiation of multi-dose approximately mid-year 2016 DCR-MYC for hepatocellular carcinoma and other solid tumors Additional Phase 1 data update ~YE 2015 Pancreatic neuroendocrine cohort data in 2016 Hepatocellular carcinoma trial data by YE 2016 Additional clinical candidates DsiRNA-EX Conjugate candidate declaration by YE 2015 (IND 2017) Add l DsiRNA-EX Conjugate candidate declaration by mid-2016, IND ~YE 2017 DCR-BCAT launch decision upon achieving DCR-MYC proof-of-concept