Corporate Overview H.C. Wainwright & Co. Global Life Sciences Conference April 10, 2018 Douglas M. Fambrough, CEO Jack Green, CFO

Transcription

1 NASDAQ: DRNA Corporate Overview H.C. Wainwright & Co. Global Life Sciences Conference April 10, 2018 Douglas M. Fambrough, CEO Jack Green, CFO

2 Forward looking statements This information may contain projections and other forward looking statements regarding future events, including statements 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 this 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. 2

3 Dicerna Pharmaceuticals Developing innovative therapeutics targeting both rare and large population diseases GalXC RNAi technology platform DCR PHXC, currently in Phase 1 for all forms of Primary Hyperoxaluria Including PH2 and PH3, not targeted by peers Patient proof of concept data expected in 2H 2018 DCR HBVS for HBV scheduled for IND or CTA filing in Q Three programs in clinical development by early 2019 Strong R&D franchise with the potential to yield numerous additional target candidates and collaboration opportunities Well financed with cash runway through 2019 Seasoned management team with extensive drug development experience 3

4 Dicerna Gene Silencing Technology for the Liver Proprietary, patented RNA interference technology Subcutaneous administration Long duration enables infrequent dosing regimen Very well tolerated in animal models Broad applicability to any liver expressed gene Rare Diseases Liver Infectious Diseases Cardiovascular Diseases Chronic Liver Diseases 4

5 GalXC Development Pipeline STAGES OF DEVELOPMENT PRODUCT CANDIDATE INDICATION RESEARCH PRECLINICAL CLINICAL POC STUDIES PARTNERING STATUS DCR PHXC Primary Hyperoxalurias Proprietary program RARE DISEASES DCR undisclosed DCR undisclosed Rare Disease Rare Disease DCR undisclosed Rare Disease DCR HBVS Hepatitis B Virus LARGE POPULATION DISEASE DCR PCSK9 DCR LIV1 DCR undisclosed DCR undisclosed DCR undisclosed Hypercholesterolemia NASH Cardiometabolic Cardiometabolic Cardiometabolic Partnered with Boehringer Ingelheim 5 DCR undisclosed Cardiometabolic

6 Portfolio Development Strategy for GalXC Dicerna development programs: to be retained as wholly owned or with risk sharing collaborations Genetically and molecularly defined rare diseases with high unmet need and efficient development paths Rare Diseases Partner focused development programs Large population size disorders where subcutaneous RNAi presents a compelling commercial profile All Forms of Primary Hyperoxaluria Liver Infectious Diseases Cardiovascular Diseases Chronic Liver Diseases Chronic hepatitis B infection Hypercholesterolemia (PCSK9) Fibrotic liver diseases such as NASH 6

7 Selected Dicerna GalXC Programs: Primary Hyperoxalurias

8 The Primary Hyperoxalurias (PH) A family of rare, inherited, liver metabolic disorders resulting in oxalate overproduction PH Type 1: Most serious form of PH Median age of kidney failure mid 20s Systemic oxalosis Bone Systemic Oxalosis Bone & Kidney PH Type 2: Less common, very serious, chronic stones with some patients progressing to kidney failure PH Type 3: Chronic stones, especially in youth Disease Progression of PH Type 1 (PH1) Abnormal liver metabolism produces excess oxalate Skin Kidney Calcium oxalate crystals form in the kidneys Decline in kidney function results in systemic oxalosis Eye 8 Median age of onset of kidney failure is 23 yrs Patients require intensive daily dialysis while awaiting a liver kidney transplant Photographs reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Nephrology 8 (2012) pg. 467

9 DCR PHXC is the Only Treatment in Development for All PH Types DCR PHXC significantly expands to the patient pool compared to PH1 specific therapy The Genetics of PH An Effective Therapy Will Drive Up Diagnosis Rates Genetic prevalence (per million) PH1 PH2 PH PH1 PH2 PH3 Hoppe et al 2003 (US) 20.5% 3.8% Unknown US 2,681 1,655 4,098 EU 2,607 1,609 3,986 Total Potential Patients 5,288 3,264 8,084 Hoppe et al 2005 (Germany) 20.3% 2.0% Unknown OxalEUROPE 23.2% 4.0% Unknown Comparison of diagnosis rates in literature Genome sequencing projects predict up to as many as ~16K patients in the US and EU who might benefit from DCR PHXC Conservative diagnostic and uptake models predict peak sales between $500M and $1B 9

10 DCR PHXC is the Only Treatment in Development for All PH Types High unmet medical need with potential for accelerated approval Disease severity suggests a high reimbursement rate: Adult 41% 59% ~60% of cases diagnosed as children Ped Symptoms at diagnosis: PH1 PH2 PH3 Renal Stones (%) Renal Failure (%) Williams et al 2012: Oxalate levels correlate with severity, making oxalate reduction the likely clinical approval endpoint Urinary oxalate excretion rate of >2 mmol/1.73m 2 /24hr associated with a significantly higher rate of progression to end stage renal disease (ESRD) 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) Quality of Life and Pharmacoeconomic Impact of PH1: If left untreated, PH1 can lead to kidney failure and require patients to undergo a sequential liver kidney transplant. Significant medical risk Limited availability of donor organs, resulting in long wait times In 2014, the average wait for a kidney was 679 days, while the average wait for a liver was 239 days 1 Expensive over $1.2 million 1 Highly invasive procedures requiring lengthy hospital stays and rigorous outpatient followup Requires ~2,000 life long use of immunosuppressants that carry significant side effects 1 Milliman Research, 2017 U.S. Organ and Tissue Transplant Cost Estimates and Discussion 10

11 GalXC Blocks the Production of the Oxalate Producing Enzyme LDHA GalXC LDHA yields potent, long duration silencing in monkeys and efficacy in multiple mouse models of PH 11 % LDHA Protein Remaining mg per kg monthly doses Enzyme Reduction in Non Human Primates Months Enzyme reduction was proportional with excess oxalate reduction in PH1 animal models LDHA reduction caused oxalate reduction in mouse models of PH1, PH2 and idiopathic PH, to approximately baseline levels Humans naturally deficient in LDHA are healthy with no liver symptoms Untreated Mice Treated Mice Visualization of Oxalate Crystals in Kidney of Mice with PH1

12 DCR PHXC Clinical Proof of Concept Study Underway Patient POC data expected in 2H 2018 PHYOS: Observational Study DCR PHXC Clinical Development Natural history and clinical course of patients with Primary Hyperoxalurias Collected urine & plasma biomarkers Collected quality of life and economic burden of disease information 20 patients enrolled Many PHYOS patients are eligible to enroll in DCR PHXC clinical trials First human dosed on December 6, 2017 Multiple study sites in UK, EU and US Healthy volunteer and patient cohorts, including both PH1 and PH2 patients Single ascending dose, transitioning to multiple dose Clinical proof of concept 2H 2018 Endpoints: - Urine & plasma biomarkers (oxalate) - Safety, tolerability, pharmacokinetics Dosing Regimen: Single 1ml subcutaneous injection 12 Expect to initiate multi dose Phase 2/3 study of DCR PHXC in 1Q 2019

13 Selected Dicerna GalXC Programs: Chronic Hepatitis B Infection

14 Hepatitis B: A Severe, Global Unmet Medical Need Massive worldwide economic burden: ~257 million chronically infected (WHO) >10th leading cause of death worldwide: 887,000 in 2015 (WHO) Asymptomatic during the acute infection phase: just 9% of all HBV infections were diagnosed in 2015, and just 8% of those diagnosed were on treatment (WHO) Responsible for 80% of primary liver cancers Current treatments are rarely effective in achieving functional cures Dicerna s DCR HBVS program should have an IND or CTA filing in Q Electron micrograph of HBV showing infectious viral particles (~42 nm) and non infectious subviral decoy particles (~22 nm) and filaments 14

15 RNAi May Play a Key Role in Establishing a Functional HBV Cure Viral genome organization enables targeting of multiple genes with a single RNAi trigger Current HBV Therapies Are Insufficient Functional Cure of chronic HBV is the best treatment outcome currently Defined by the lack of detectable HBsAg in serum (often associated with seroconversion to anti HBsAg+) Interferons and NUCs are the only approved therapies, but offer very low functional cure rates Organization of the HBV Genome Overlapping, Polycistronic mrna Targets P Polymerase 2,458 2,856 3,221 EcoRI S pres1, pres2 and S DCR HBVS target region 15 The Promise of RNAi for HBV RNAi can simultaneously inhibit multiple viral activities due to overlapping transcripts POC for RNAi functional cures may be emerging: Evidence that 4 of 8 individuals treated with an early generation RNAi based treatment are achieving sustained HBsAg clearance E precore, Core 2,309 HBeAg 1,873 1,622 1,816 X gene 1,376 One RNAi trigger silences multiple mrna transcripts and the pre genomic RNA template required for new viral genomes X 834 HBsAg

16 DCR HBVS: Highest Reported Preclinical Potency of Any Subcutaneous RNAi HBV Therapeutic >3 Log reduction in HBsAg in standard mouse model Single 3 mg/kg subcutaneous injection DCR HBVS directly targets the viral life cycle %HBsAg remaining (relative to day -1 +/- SEM) PBS GalXC-HBVS 2.2 log One 3mpk dose Time (weeks) These data points are below the level of detection of the assay There are early indications in the HBV field that RNAi may be able to induce a functional cure for HBV We believe RNAi is an ideal approach due to ability to silence multiple viral genes simultaneously The DCR HBVS target sequence appears effective against >96% of all HBV viral variants known IND filing in Q4 2018, followed by phase 1 proof of concept clinical trial 16

17 DCR HBVS Should Effectively Silence 96% of HBV Variants HBVS RNAi performance confirmed in non human primates, even in the absence of the HBV genome 17 DCR HBVS has confirmed activity against the sequences in 96% of HBV viral genomes worldwide % Genomes Covered Most Common Genotypes A: North America (NA), Europe, Africa (better outcomes) B: Highest in Asia (better outcomes) C: Highest in Asia (most aggressive, greater risk of HCC) D: Mediterranean / Worldwide (worse outcomes) A, C, B and D are the most common genotypes in the US While monkeys don t have HBV, we see effective liver uptake and RISC loading with GalXC HBVS RNAi molecules pg Guide in RISC / g Liver (normalized to mir-16) GalXC Guide Strand (ng/g liver) Single 4 mg/kg subcutaneous dose, day 18 LDHA mrna shows >80% knockdown Bulk liver uptake RISC loaded Guide strand

18 Selected Dicerna GalXC Programs: NASH Collaboration with Boehringer Ingelheim

19 Boehringer Ingelheim Collaboration in Chronic Liver Disease Overview Collaboration focuses on chronic liver diseases, with an initial focus on NASH Agreement is for development of a product candidate targeting one undisclosed gene BI is responsible for formal development activities after clinical candidate selection Key Features Total Potential Value: $201 million Upfront: $10 million R&D reimbursement to agreed limit High single digit to low double digit royalties Option to add a 2nd target gene for additional payments 19

20 GalXC Platform Improvement

21 GalXC PCSK9: 2 nd Generation GalXC Further Improves Performance GalXC improvements yield longer duration of action in animal models, confirmed against multiple targets % G-Luciferase, Serum (Rel to pre-dose and time-matched PBS) 1 st Gen GalXC vs 2 nd Gen GalXC: Longer Duration One Dose, 1 mg/kg, AAV Luc/PCSK9 model PBS Control GalXC Gen 1 GalXC Gen 2 50% expression reduction three months after a single 1 mpk dose in rodents GalXC Gen 2 improvements driven by tetraloop optimization (unique to Dicerna) GalXC Gen 2 potency and duration improvement demonstrated for multiple genes GalXC Gen 1 candidates performed equivalently (in mice and monkeys) to the PCSK9 RNAi in clinical development 21

22 Our Vision for GalXC Powerful Capability designed to provide durable, specific liver gene silencing Expansive Opportunity multiple gene targets across four disease areas Rare Diseases Liver Infectious Diseases Cardiovascular Diseases Chronic Liver Diseases All Forms of Primary Hyperoxaluria Chronic hepatitis B infection Hypercholesterolemia (PCSK9) Fibrotic liver diseases such as NASH 22

23 Investment Highlights and Upcoming Milestones GalXC technology platform applicable to a broad range of diseases, providing multiple value creating inflection points Full pipeline aimed at: Rare Diseases o o Novel, differentiated MOA targeting all forms of Primary Hyperoxaluria in Phase 1 Second rare disease IND ready 2H 2018, seeking risk sharing collaboration Large Population Disorders o Hepatitis B Virus IND late 2018 o Chronic Liver Disease BI Collaboration Strong intellectual property position Well financed, with cash runway through 2019 Seasoned management team with extensive drug development and commercialization experience Key Milestones 2018 Milestones Initiated DCR PHXC clinical dosing Report DCR PHXC clinical proof of concept data File 2 nd rare disease IND with a partner File GalXC IND for HBV drug candidate Advance additional GalXC clinical candidates Pursue additional collaboration opportunities 2019 Milestones Initiate Phase 2/3 trial of DCR PHXC Advance clinical development of additional programs, including DCR HBVS and the second, undisclosed rare disease program 23

24 For more information: 24