Corporate Overview. January 2019 Douglas Fambrough, CEO

Transcription

1 Corporate Overview January 2019 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 Vision and Strategy Vision To build a fully-integrated rare disease company by providing innovative RNAi-based therapies for high unmet medical needs To broadly realize the potential value of RNAi-based therapeutics across diverse disease areas Strategy Build Value in rare diseases by independently developing and commercializing programs with high value and high probability of success Capture Value in common diseases by developing high probability of success programs through clinical proof of concept before seeking development and commercialization partners Enhance Value by partnering with therapeutic field leaders on discovery stage programs that are non-strategic for Dicerna 3

4 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 Oxalate reduced to normal or near-normal range in majority of patients All patients, including PH2 patient, with clinically significant response Pending regulatory feedback, registration trial initiation expected Q DCR-HBVS: CTA filed for phase 1 proof-of-concept trial targeting Hepatitis B virus Three programs in clinical development in 1H 2019 Strong R&D franchise with the potential to yield numerous additional program opportunities Collaborations with Lilly, Alexion, and Boehringer Ingelheim for non-strategic programs Seasoned management team with extensive drug development experience Strong balance sheet to drive growth: starting year with ~$397 million cash & net receivables 4

5 The Foundation of Our Value Dicer substrate (DsiRNA) RNAi trigger GalNAc targeting ligands Proprietary, patented RNA interference technology Objectively excellent pharmaceutical properties Subcutaneously delivered convenient administration Long duration of action convenient regimens High target specificity predictable activity High therapeutic index broad applicability Potential to extend the GalXC platform to diverse tissues beyond the liver 5

6 ORPHAN COMMON COMMON ORPHAN GalXC Development Pipeline Dicerna Strategic Programs CANDIDATE INDICATION RESEARCH PRECLINICAL CLINICAL POC TRIALS REGISTRATION TRIALS DCR-PHXC DCR-undisclosed DCR-HBVS DCR-undisclosed Primary Hyperoxalurias Rare Disease Hepatitis B Virus undisclosed Partner Programs CANDIDATE INDICATION RESEARCH PRECLINICAL CLINICAL POC TRIALS REGISTRATION TRIALS PARTNER DCR-LIV1 NASH Boehringer Ingelheim DCR-LIV2 NASH Boehringer Ingelheim DCR-CM1 Cardiometabolic Lilly DCR-CM2 Cardiometabolic Lilly DCR-CM3 Cardiometabolic Lilly DCR-COMP1 Complement-mediated Alexion 6 DCR-COMP2 Complement-mediated Alexion

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: 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 Disease Progression of PH Type 1 (PH1) Abnormal liver metabolism produces excess oxalate Calcium oxalate crystals form in the kidneys Decline in kidney function results in systemic oxalosis Primary hyperoxaluria 1 Peroxisome Glycine AGT Glycolate Glyoxylate LDH GO HEPATOCYTE Oxalate Primary hyperoxaluria 2 & 3 Glycolate GRHPR Glyoxylate DCR-PHXC Pathway Inputs HOGA Mitochondria Median age of onset of kidney failure is mid-20s 8 Patients require intensive daily dialysis while awaiting a liver-kidney transplant DCR-PHXC silences LDHA, the final common pathway of oxalate production, for the treatment of all forms of PH

9 PHYOX: An Ongoing Phase 1 Study of DCR-PHXC in PH1 and PH2 A two-part, single-ascending dose study (ClinicalTrials.gov: NCT ) PHYOX: A Placebo-Controlled, Single-Blind, Single-Center Phase 1 Study in Normal Healthy Volunteers and Open-Label Multi-Center Study in Patients With Primary Hyperoxaluria (PH) to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Doses of DCR-PHXC Solution for Injection (Subcutaneous Use) 9 Group A: Healthy volunteers 25 healthy volunteers Randomized 3:2 DCR-PHXC to 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 Genetically confirmed diagnosis Uox 0.7mmol/24hr egfr 30mL/min/1.73m 2 PH1 cohorts: 1.5, 3.0, 6.0 mg/kg PH2 cohort: variable dosing 4 patients per cohort 12 patients dosed as of today (11 PH1, 1 PH2) Cohort 1 (1.5 mg/kg): - 3/4 participants 24Hr Uox values reached near-normalization (<0.6 and >0.46 mmol/24hr) at one or more post-dose time points - Mean maximal 24Hr Uox reduction = 50% (range: 39%-59%) - Per protocol, 2 participants are still in follow-up as of postdose Day 85, as their 24Hr Uox has not yet returned to within 80% of the lowest baseline 24Hr Uox measurement Cohort 2 (3.0 mg/kg): - 3/4 participants 24Hr Uox values have reached normalization (<0.46 mmol/24hr) at one or more postdose time points - Mean maximal 24Hr Uox reduction = 65% (range: 56%-80%) - 3 participants are still in follow-up and may not yet have reached maximal 24Hr Uox reductions Cohort 3 (6.0 mg/kg): - As of October 1, 2018 data cut, only 1 participant has 24Hr Uox results - Maximum reduction for that 1 participant = 64% as of postdose Day 43

10 Mean [± SEM] Uox Content (mmol/24hr) Mean [± SEM] Uox:Cre (umol/mmol) 10 PHYOX: Uox Reduction in Patients After a Single Dose PD and safety/tolerability results lay groundwork for planned Phase 2/3 registration trial Mean 24Hr Oxalate Over Time, Following Single Administration of DCR-PHXC Single Dose DCR-PHXC Days After Single Dose * * * * 1.5 mg/kg 3.0 mg/kg Mean Oxalate-to-Creatinine Ratio Over Time, Following Single Administration of DCR-PHXC Single Dose DCR-PHXC Days After Single Dose At 1.5 mg/kg, n=5 at all time points, except where 057* denotes data point where only 3 participants are included. At 3.0 mg/kg, n=4 at all time points, except where * denotes data point where only 3 participants are included. Results based on availability of data as of October 1, * * * *

11 Uox mmol/l % Change Screening to Maximum Observed Reduction in 24hr Urinary Oxalate 6/10 patients achieve normalization or near-normalization; 8/10 patients with >50% Uox reduction 2500 Observed Uox Values (mmol/l) Screening to Maximal Reduction 100 % Reduction in Uox Maximal Reduction vs. Screening and <600 near-normal <460 normal Screening Maximal Reduction 0 Screening Maximal Reduction 11

12 DCR-PHXC: Moving into Approval Campaign in Q Coordinated program of Phase 2/3 registration trial and additional supportive trials REGISTRATION TRIAL: Double-blind, randomized, placebo-controlled trial (2:1 randomization) in approx. 36 patients with PH1 and PH2 (Q initiation). Convenient, monthly fixed-dose regimen, enabling pre-filled syringes or autoinjectors at product launch. PHASE 1 ROLL-OVER STUDY: Patients from PHYOX may be re-enrolled into a long-term, multi-dose open label extension trial, allowing continuous readout of multi-dose data (Q initiation) PH3 Patient Trial: Open-label study in 10 patients with PH3 ESRD Patient Trial: Single dose trial in adults with end stage renal disease (ESRD) to determine PK Pediatric Trial: Open-label study in children (2-5 years) following data from 5 patients aged 6-11 years Additional trials exploring dosing paradigms are also anticipated These plans may be adjusted pending outcome of regulatory meetings in Q

13 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 Current Diagnosis Rates Genetic prevalence (per million) PH1 PH2 PH US 2,681 1,655 4,098 EU 2,607 1,609 3,986 Total Potential Patients 5,288 3,264 8,084 PH1 PH2 PH3 Hoppe et al 2003 (US) 20.5% 3.8% Unknown Hoppe et al 2005 (Germany) 20.3% 2.0% Unknown OxalEUROPE 23.2% 4.0% Unknown We anticipate that diagnostic rates will increase with an available effective treatment, especially for PH2 Epidemiology, diagnostic and uptake models developed by the company predict peak sales between $500M and $1B 13 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:

14 Selected Dicerna GalXC Programs: Chronic Hepatitis B Infection

15 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 Electron micrograph of HBV showing infectious viral particles (~42 nm) and non-infectious subviral decoy particles (~22 nm) and filaments 15

16 GalXC RNAi May Play a Key Role in Establishing a Functional HBV Cure Organization of the HBV genome enables effective RNAi targeting of multiple viral functions Current HBV Therapies Are Insufficient Functional Cure of chronic HBV is the best treatment outcome currently Overlapping RNAs, mrnas and ORFs enable targeting multiple HBV genes and proteins with a single RNAi trigger GalXC-HBVS 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 P: Viral genome production 2,856 3,221 pres1, pres2 and S S: HBsAg, hepatocyte entry and immune decoy The Promise of RNAi for HBV RNAi can simultaneously inhibit multiple viral activities due to overlapping transcripts Polymerase 2,458 2,309 EcoRI 834 RNAi can target viral transcripts and pgrna from cccdna and integrated genomes DCR-HBVS Poised to Enter to Clinic CTA Filed in New Zealand, other geographies to follow First human dosing expected early Q C: Capsid assembly; E antigen secretion precore, Core 1,873 1,622 1,816 X gene 1,376 X: Epigenetic maintenance of viral genome 16

17 GalXC-HBVS %HBsAg +/- SEM (Normalized to d0) X targeted Vehicle Ctl. Single Dose HBsAg Reduced to Below Lower Level of Detection Driven by striking pharmacodynamic differences between targeting in the S versus X ORFs mg/kg qwx3 HDI-HBV Plasmid Model (cccdna-dependent) 0 1 2/3 BLOQ 2 3 Vehicle Control 4 3/3 BLOQ Time (weeks) (days) GalXC-HBVS: 3.9 log reduction, long duration of activity 5 X gene targeted: 3.0 log reduction, shorter duration of activity X Gene targeted treatment GalXC-HBVS HDI-HBV Immunohistochemical staining of mouse liver sections for HBV Core Protein (HBc) reveals extreme differences in subcellular localization of HBc in the HDI-HBV plasmid model These results have been reproduced using alternative guide strand sequences (i.e., different mrna binding sites) for both GalXC-HBVS and GalXC-HBVX 17

18 DCR-HBVS Clinical Program for Proof of Concept Includes placebo-controlled studies in both NUC-naïve and NUC-experienced patients Three Part Study in Healthy Volunteers and Chronic HBV Patients Group A: Single dose ascending dose study, placebo controlled, in 30 normal healthy volunteers - 5 dose cohorts: 0.1, 1.5, 3.0, 6.0, 12.0 mg/kg Group B: Single-dose study, placebo controlled, in 8 NUC-naïve chronic hepatitis B patients - 1 dose cohort at 3 mg/kg - Introduction of NUCs after 12 weeks Group C: Multiple dose-ascending dose study, placebo-controlled, in 18 NUC-experienced chronic hepatitis B patients - 3 dose cohorts: 1.5, 3.0, and 6.0 mg/kg, 4 monthly doses, in parallel to Group A after 2nd cohort complete - Patients with HBsAg seroclearance will be followed up for seroconversion (anti-hbsag) Study it Poised to Launch in Early 2019 Filed Clinical Trial Application (CTA) with the New Zealand Medicines and Medical Devices Safety Authority (MedSafe) and the Health and Disability Ethics Committee (HDEC). Further CTA submissions in Asia-Pacific planned Expect first NHV dosing January 2019 and first patient dosing approximately end of Q First interim data 2H 2019

19 Selected Dicerna GalXC Programs: Collaborations with Lilly, Alexion, and Boehringer Ingelheim

20 Enhancing Value Through Corporate Collaborations Lilly, Alexion and Boehringer Ingelheim Developing GalXC candidates against non-strategic targets This monetizes our GalXC technology without diluting the value of our strategic programs. If not for these collaborations, we would not be pursuing these targets. Lilly: cardiometabolic targets Alexion: complement pathway targets Boehringer Ingelheim: NASH targets Expanding the range of the GalXC technology platform This draws on partner resources to extend the power of our technology to non-liver tissues. With our Lilly collaboration, we are more likely to be succeed, and to achieve higher performance. Neural tissues: exclusive collaboration with Lilly to develop RNAi neural delivery technology Non-liver Cardiometabolic tissue: non-exclusive collaboration with Lilly Providing resources to drive our strategic programs $262 million in upfront payments and equity at a premium between the three collaborations >$200 million is allocated to our strategic programs 20

21 Elements of Portfolio Strategy We seek to generate value across the full spectrum of GalXC clinical applications Highest Resource Investment Strategic Programs Partnered Programs Lower Resource Investment ORPHAN DISEASE COMMON DISEASE COMMON DISEASE ORPHAN DISEASE Dicerna drives to market Dicerna drives to clinical POC Dicerna discovers Partner develops Dicerna discovers Partner develops Primary Hyperoxalurias Undisclosed indication Hepatitis B Virus Undisclosed indication Lilly & Boehringer Collaborations DCR-LIV1 DCR-LIV2 DCR-CM1 DCR-CM2 DCR-CM3 Alexion Collaboration DCR-COMP1 DCR-COMP2 Key Value Drivers Additive Value 21

22 Investment Highlights and Upcoming Milestones GalXC platform applicable to a broad range of diseases Internal pipeline aimed at: Orphan Diseases o Novel, differentiated MOA targeting all genetic variants of Primary Hyperoxaluria with POC. Registration trial initiating in Q o Second rare disease IND or CTA filing in 1H 2019 Common Diseases o HBV CTA filed, clinical entry early Q Partnered pipeline with Lilly, Alexion & Boehringer Ingelheim Strong intellectual property position Capital through key pivotal data milestone Seasoned management team with extensive drug development and commercialization experience Key Upcoming Milestones 2019 Milestones Initiate registration trial of DCR-PHXC IND or CTA filing for second rare disease Clinical entry for DCR-HBVS POC data for DCR-HBVS 22