Corporate Overview. October 1, 2018 Cantor Douglas Fambrough, CEO

Transcription

1 Corporate Overview October 1, 2018 Cantor Douglas Fambrough, CEO

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: Phase 1 Proof of Concept Announced for Primary Hyperoxaluria In initial 6-week trial data, oxalate reduced to normal or near-normal range in majority of patients All patients, including PH2 patient, with clinically significant response Detailed data readout of the Phase 1 trial is anticipated in Q Pending regulatory feedback, registration trial initiation expected Q DCR-HBVS: regulatory filing and expected clinical entry in Q for hepatitis B virus Three programs in clinical development in 1H 2019 Strong R&D franchise with the potential to yield numerous additional target candidates and collaboration opportunities Cash >1yr beyond pivotal trial readout 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 Well tolerated in animal models and phase 1 subjects Broad applicability to any liver expressed gene Rare Diseases Liver Infectious Diseases Cardiovascular Diseases Chronic Liver Diseases 4

5 LARGE POPULATION DISEASE RARE DISEASES GalXC Development Pipeline STAGES OF DEVELOPMENT PRODUCT CANDIDATE INDICATION RESEARCH PRECLINICAL CLINICAL POC TRIALS REGISTRATION TRIALS PARTNER DCR-PHXC Primary Hyperoxalurias DCR-undisclosed Rare Disease DCR-undisclosed Rare Disease DCR-undisclosed Rare Disease DCR-HBVS DCR-PCSK9 Hepatitis B Virus Hypercholesterolemia DCR-LIV1 NASH Boehringer Ingelheim 5 DCR-undisclosed DCR-undisclosed DCR-undisclosed DCR-undisclosed Cardiometabolic Cardiometabolic Cardiometabolic Cardiometabolic

6 Selected Dicerna GalXC Programs: Primary Hyperoxalurias

7 The Primary Hyperoxalurias (PH) A family of rare, inherited, liver metabolic disorders resulting in oxalate overproduction PH Type 1: PH Type 2: PH Type 3: Most serious form of PH Median age of kidney failure mid-20s Systemic oxalosis Very serious, chronic stones with significant risk of kidney failure Chronic stones, especially in youth Primary hyperoxaluria 3 & 2 Pathway Inputs HOGA Glycolate GRHPR HEPATOCYTE Primary hyperoxaluria 1 Glycolate GO Glycine AGT Disease Progression of PH Type 1 (PH1) Abnormal liver metabolism produces excess oxalate Calcium oxalate crystals form in the kidneys Mitochondria Glyoxylate LDH Glyoxylate DCR-PHXC Peroxisome Decline in kidney function results in systemic oxalosis Median age of onset of kidney failure is mid-20s Oxalate 7 Patients require intensive daily dialysis while awaiting a liver-kidney transplant

8 PH Patient Proof of Concept for Oxalate Reduction by DCR-PHXC Single dose of DCR-PHXC can reduce urinary oxalate to normal range; duration consistent with once-quarterly dosing 8 PHYOX Single-Ascending Dose Clinical Trial of DCR-PHXC Group A: Healthy volunteers 25 healthy volunteers Randomized 3:2 DCR-PHXC:placebo 5 cohorts: 0.3, 1.5, 3.0, 6.0, 12.0 mg/kg 5 subjects per cohort Group A is complete Group B: PH Patients 16 PH1 and PH2 patients, open label PH1 cohorts: 1.5, 3.0, 6.0 mg/kg PH2 cohort: variable dosing 4 patients per cohort 11 patients dosed to date (10 PH1, 1 PH2) All dosed patients are adults Results from Interim Readout of 8 Patients Who have Reached Day 43 Post-Treatment Interim Results for Group B: All patients show a clinically significant response (>30% reduction in 24hr urinary oxalate) Cohort 1 (PH1), 1.5 mg/kg 3 of 4 patients with urinary oxalate reduced to near-normal range (<0.6 mmol/24hr) 1 additional patient with clinically significant response. Maximal response is urinary oxalate <1.0 mmol/24hr, compared to based line of 2.28 mmol/24hr, at ~3 months (latest observation) Cohort 2 (PH1), 3.0 mg/kg 2 of 4 patients with urinary oxalate reduced to normal range (<0.46 mmol/24hr) 4 of 4 patients with clinically significant response (one not yet at Day 43) Cohort 4 (PH2) 1 patient dosed at 1.5 mg/kg with clinically significant response No SAEs Three mild to moderate ISRs, transient, resolved without intervention Prior Released Results for Group A: No SAEs Two mild ISRs, transient, resolved without intervention No changes in serum lactate or pyruvate

9 DCR-PHXC is the Only RNAi Drug Candidate 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 Epidemiology, diagnostic and uptake models developed by the company predict peak sales between $500M and $1B 9 J Am Soc Nephrol Oct;26(10):supp, and applied to population sizes Pediatr Nephrol Oct;18(10): Am J Nephrol May-Jun;25(3): Am J Nephrol. 2005; 25:

10 DCR-PHXC is the Only Drug Candidate 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 DCR-PHXC Clinical Proof-of-Concept Trial Underway Detailed presentation of patient POC data anticipated in Q PHYOS: Observational Study Proof-of Concept Clinical Trial Registration Trial (Plan, pending regulatory feedback) 11 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 Healthy volunteer and patient cohorts; US, UK & EU sites NHV cohorts complete; now dosing final patients cohorts Single-ascending dose, transitioning to multiple dose safety trial Endpoints: - Urine & plasma markers (oxalate) - Safety, tolerability, PK Clinical proof-of-concept announced - All patients show clinically significant oxalate reduction (>30%) % oxalate reduction so far - 2/4 cohort 2 patients have urinary oxalate in normal range - Response seen in PH1 & PH2 - Data consistent with once quarterly dosing frequency Expected initiation Q Global 6-month trial with urinary oxalate as primary endpoint Placebo-controlled; 2:1 randomization Interim analysis when 24 patients completed All patients will be roll-over in longterm extension trial Registration trial data readout expected in 2020 Protocol under development

12 Selected Dicerna GalXC Programs: Chronic Hepatitis B Infection

13 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 regulatory filing for clinical entry expected in Q Electron micrograph of HBV showing infectious viral particles (~42 nm) and non-infectious subviral decoy particles (~22 nm) and filaments 13

14 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 14 The Promise of RNAi for HBV RNAi can simultaneously inhibit multiple viral activities due to overlapping transcripts POC for RNAi may be emerging from prior programs 1 : Evidence that some patients treated with an early generation RNAi-based treatment are achieving sustained HBsAg clearance 1. Arrowhead Pharmaceuticals corporate presentation 4/14/2018 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

15 % H B s A g r e m a in in g ( r e l a t iv e t o d a y / - S E M ) DCR-HBVS: Single Dose HBsAg Reduced to Below Lower Level of Detection in Preclinical HBV Model >3 Log reduction in HBsAg in standard mouse model Single 3 mg/kg subcutaneous injection DCR-HBVS directly targets the viral life cycle P B S G a lx C -H B V S 2.2 lo g 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 One 3mpk dose T im e (w e e k s ) These data points are below the level of detection of the assay The DCR-HBVS target sequence appears effective against >96% of all known HBV viral variants known Regulatory filing for clinical entry in New Zealand expected in Q4 2018, followed by phase 1 proof-ofconcept clinical trial 15

16 G a lx C G u id e S tr a n d ( n g /g liv e r ) % G e n o m e s C o v e r e d p g G u id e in R IS C / g L iv e r (n o rm a liz e d to m ir ) DCR-HBVS Expected to Effectively Silence 96% of HBV Variants HBVS RNAi performance confirmed in non-human primates, even in the absence of the HBV genome DCR-HBVS has confirmed activity against the sequences in 96% of HBV viral genomes worldwide While monkeys don t have HBV, we see effective liver uptake and RISC loading with GalXC-HBVS RNAi molecules Bulk liver uptake L LO Q P B S H B V S L D H A 0 A ll A B C D E F G H I RISC loaded Guide strand H B V G e n o t y p e 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 L LO Q P B S H B V S L D H A Single 4 mg/kg subcutaneous dose, day 18 LDHA mrna shows >80% knockdown

17 Selected Dicerna GalXC Programs: NASH Collaboration with Boehringer Ingelheim

18 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 18

19 GalXC Platform Improvement

20 % G - L u c if e r a s e, S e r u m (R e l to p re -d o s e a n d tim e -m a tc he d P B S ) GalXC-PCSK9: 2 nd Generation GalXC Further Improves Performance GalXC improvements yield longer duration of action in animal models, confirmed against multiple targets st Gen GalXC vs 2 nd Gen GalXC: Longer Duration One Dose, 1 mg/kg, AAV-Luc/PCSK9 model PBS Control P B S G a lx C # 1 C o n tr o l GalXC Gen 1 G a lx C # 2 G a lx C # 2 G e n 2 GalXC Gen 2 G a lx C # 3 G e n 2 G a lx C # 4 G e n 2 GalXC Gen 2 improvements driven by tetraloop optimization (unique to Dicerna) GalXC Gen 2 potency and duration improvement demonstrated for multiple genes W e e k s P o s t-d o s e 50% expression reduction three months after a single 1 mpk dose in rodents GalXC Gen 1 candidates performed equivalently (in mice and monkeys) to the PCSK9 RNAi in clinical development 20

21 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 21

22 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: 22 Rare Diseases o o Novel, differentiated MOA targeting all genetic variants of Primary Hyperoxaluria with POC Second rare disease expected to be IND-ready YE2018, seeking risk-sharing collaboration Large Population Disorders o o Hepatitis B Virus regulatory filing for clinical entry expected in Q Chronic Liver Disease BI collaboration Strong intellectual property position Capital through key pivotal data milestone Seasoned management team with extensive drug development and commercialization experience Key Milestones 2018 Milestones Report DCR-PHXC detailed clinical proof of concept data at medical meeting File to initiate clinical development of DCR-HBVS 2 nd rare disease IND-ready (clinical entry with partner) Pursue additional collaboration opportunities 2019 Milestones Initiate registration trial of DCR-PHXC Advance clinical development of additional programs, including DCR-HBVS and the second, undisclosed rare disease program 2020 Milestones DCR-PHXC pivotal data readout HBV and 2 nd rare disease human POC