Corporate Overview - Jefferies · This presentation includes forward-looking statements....
Transcript of Corporate Overview - Jefferies · This presentation includes forward-looking statements....
©2019 DICERNA
June 4, 2019
Corporate OverviewJefferies Global Healthcare Conference
©2019 DICERNA
This presentation includes forward-looking statements. Forward-looking statements are subject to risks and uncertainties that could cause actual resultsto differ materially from those expressed or implied in such statements. Examples of forward-looking statements include, among others, statements wemake regarding: (i) the therapeutic and commercial potential of DCR-PHXC, DCR-HBVS and the GalXC™ platform; (ii) research and development plans andtimelines related to DCR-PHXC, DCR-HBVS and GalXC; and (iii) the potential of Dicerna’s technology and drug candidates in the Company’s research anddevelopment pipeline. The process by which an early stage investigational therapy such as DCR-PHXC and an early stage platform such as GalXC couldpotentially lead to an approved product is long and subject to highly significant risks. Applicable risks and uncertainties include those relating to Dicerna’sclinical research and other risks identified under the heading "Risk Factors" included in the Company’s most recent Form 10-K filing and in other futurefilings with the Securities and Exchange Commission. These risks and uncertainties include, among others, the cost, timing and results of preclinicalstudies and clinical trials and other development activities; the likelihood of Dicerna’s clinical programs being executed within timelines provided andreliance on the Company’s contract research organizations and predictability of timely enrollment of subjects and patients to advance Dicerna’s clinicaltrials; the potential for future data to alter initial and preliminary results of early stage clinical trials; the unpredictability of the duration and results ofthe regulatory review of Investigational New Drug Applications (NDAs) and Clinical Trial Applications that are necessary to continue to advance andprogress the Company’s clinical programs and the regulatory review of NDAs; market acceptance for approved products and innovative therapeutictreatments; competition; the possible impairment of, inability to obtain and costs of obtaining intellectual property rights; and possible safety or efficacyconcerns that could emerge as new data are generated in R&D, general business, financial and accounting risks and litigation.
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 otherpublic announcements and public filings made after the date of this information.
Dicerna™, GalXC™, and PHYOX™ are trademarks of Dicerna Pharmaceuticals, Inc.
Forward-looking Statements
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Build a fully integrated company by developing innovative RNAi-based therapies for high unmet medical needs and broadly capture the value of our GalXC platform
Vision 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 select programs through clinical proof-of-concept before seeking development and commercialization partners
• Enhance Value by partnering with therapeutic field leaders on discovery stage programs
Dicerna Vision and Strategy: Driving RNAi Therapies Forward for Patients
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• 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
The Foundation of Our Value
Dicer substrate (DsiRNA) RNAi trigger
GalNAc targetingligands
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CANDIDATE INDICATION RESEARCH PRECLINICAL CLINICAL POCTRIALS
REGISTRATION TRIALS PARTNER
DCR-PHXC Primary Hyperoxaluria —
DCR-HBVS Hepatitis B Virus —
DCR-undisclosed Rare Disease —
DCR-undisclosed Undisclosed —
DCR-LIV1 NASH Boehringer Ingelheim
DCR-LIV2 NASH Boehringer Ingelheim
DCR-CM1 Cardiometabolic Lilly
DCR-CM2 Cardiometabolic Lilly
DCR-CM3 Cardiometabolic Lilly
DCR-NEURO1 Neurodegeneration Lilly
DCR-NEURO2 Neurodegeneration Lilly
DCR-PAIN1 Pain Lilly
DCR-PAIN2 Pain Lilly
DCR-COMP1 Complement-mediated Alexion
DCR-COMP2 Complement-mediated Alexion
Dicerna Development Pipeline
ORPHAN PREVALENT5
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Primary Hyperoxaluria
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Disease Progression of PH Type 1 (PH1)
A family of rare, inherited, liver metabolic disorders resulting in oxalate overproductionPrimary Hyperoxaluria (PH)
Abnormal liver metabolism produces excess oxalate
Calcium oxalate crystals form in the kidneys
Decline in kidney function results in systemic oxalosis
Median age of onset of kidney failure is mid-20s
Patients require intensive daily dialysis while awaiting a liver-kidney transplant
PH Type 1: Most serious form of PHMedian age of kidney failure mid-20sSystemic oxalosis
PH Type 2: Very serious, chronic stones with significant risk of kidney failure
PH Type 3: Chronic stones, especially in youth
Peroxisome
Oxalate
GO
Primary hyperoxaluria 1
Glycolate
Glyoxylate
Primary hyperoxaluria 2 & 3
Glycine
LDH DCR-PHXC
AGT
HEPATOCYTE
GRHPR
Glyoxylate
Glycolate
Mitochondria
PathwayInputs
HOGA1 2 3
DCR-PHXC, under evaluation for the treatment of all forms of PH, silences LDHA, the final common pathway of oxalate production
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A two-part, single-ascending dose study (ClinicalTrials.gov: NCT03392896)
• Cohort 1 (1.5 mg/kg):- 3/5 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 = 51% (range: 28%-72%)
• Cohort 2 (3.0 mg/kg):- 4/5 participants’ 24Hr Uox values have reached normalization (<0.46 mmol/24Hr)
at one or more post-dose time points- Mean maximal 24Hr Uox reduction = 71% (range: 62%-80%)
• Cohort 3 (6.0 mg/kg):- As of March 14, 2019 data cut, 3 participants have 24Hr Uox results- Mean maximal 24Hr Uox reduction = 76% (range: 58%-100%)- One participant in this cohort reached normalization at one or more post-dose
time points- Two participants are still in follow-up, as their 24Hr Uox has not yet returned to
within 80% of the lowest baseline 24Hr Uox measurement
*Results based on availability of data as of March 14, 2019**These data were presented at the German Society of Pediatric Nephrology Meeting on March 28, 2019
PHYOX™1: An Ongoing Phase 1 Study of DCR-PHXC in PH1 and PH2
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• 18 PH1 and PH2 patients, open-label
Genetically confirmed diagnosis Uox ≥0.7mmol/24hr eGFR ≥30mL/min/1.73m2
• PH1 cohorts: 1.5, 3.0, 6.0 mg/kg• Mixed PH1 & PH2 cohort: variable dosing• 18 patients dosed as of today
(15 PH1, 3 PH2)
PHYOX1: A Placebo-Controlled, Single-Blind, Single-Center Phase 1 Study in 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)
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PHYOX – PH1 ONLY: PD and safety/tolerability results lay groundwork for pivotal trialPHYOX1: Uox Reduction in Patients After a Single Dose
Mean 24Hr Oxalate Over Time, Following Single Administration of DCR-PHXC
Mean Oxalate-to-Creatinine Ratio Over Time, Following Single Administration of DCR-PHXC
Most data points taken from 2 or fewer participants*Results based on availability of data as of March 14, 2019.
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8/13 patients achieve normalization or near-normalization; 8/13 with >50% Uox reductionScreening to Maximum Observed Reduction in Uox
Observed Uox Values (µmol/24hr)Screening to Maximal Reduction
% Reduction in UoxMaximal Reduction vs. Screening
Screening Maximal Reduction0
500
1000
1500
2000
2500
3000
Uox
(µm
ol/2
4hr)
<460normal
≥460 and <600near-normal
Screening Maximal Reduction0
10
20
30
40
50
60
70
80
90
100
% C
hang
e*Results based on availability of data as of March 14, 2019**These data were presented at the German Society of Pediatric Nephrology Meeting on March 28, 2019
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Coordinated program of Phase 2 pivotal trial and additional supportive trials
• PHYOX2 (PIVOTAL TRIAL): Double-blind, randomized, placebo-controlled trial (2:1 randomization) in approx. 36 patients with PH1 and PH2 (Q2 2019 initiation). Convenient, monthly fixed-dose regimen, enabling pre-filled syringes or autoinjectors at or shortly after product launch.
• PHYOX3 (ROLL-OVER STUDY): Patients from PHYOX trials may be re-enrolled into a long-term, multi-dose open-label extension trial, allowing readout of multi-dose data (Q2 2019 initiation)
• PH3 Patient Trial: Open-label study in approximately 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 (below age 6)
• Additional trials exploring dosing paradigms are also anticipated
DCR-PHXC: Moving into Regulatory Approval Trial in Q2 2019
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DCR-PHXC significantly expands to the patient pool compared to PH1-specific therapyDCR-PHXC is the Only RNAi Drug Candidate in Development for All PH Types
The Genetics of PH Current Diagnosis Rates
PH1 PH2 PH3
Genetic prevalence(per million) 8.23 5.08 12.58
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 Dicerna estimate peak sales between $500M and $1B
Pediatr Nephrol. 2003 Oct;18(10):986-91Am J Nephrol. 2005 May-Jun;25(3):276-81Am J Nephrol. 2005; 25:290-296
J Am Soc Nephrol. 2015 Oct;26(10):supp, and applied to population sizes
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Chronic Hepatitis B Virus Infection
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• 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
Hepatitis B: A Severe, Global Unmet Medical Need
Electron micrograph of HBV showing infectious viral particles (~42 nm) and non-infectious subviral “decoy” particles (~22 nm) and filaments
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Organization of the HBV genome enables effective RNAi targeting of multiple viral functions GalXC RNAi May Play a Key Role in Establishing a Functional HBV Cure
• Functional Cure of chronic HBV is currently the best treatment outcome
• 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
Current HBV Therapies Are Insufficient
The Promise of RNAi for HBV
• RNAi can simultaneously inhibit multiple viral activities due to overlapping transcripts
• RNAi can target viral transcripts and pgRNA from cccDNA and integrated genomes
DCR-HBVS Has Entered Clinical Development• Healthy volunteer dosing underway
• First chronic HBV patient dosing expected Q2 2019
3,221
EcoRI
preS1, preS2
and S
Polymerase
X gene
preCore,Core
1,376
2,856
834
1,6221,816
1,873
2,458
2,309
P gene: Polymerase. Viral genome production
S gene: Surface protein. HBsAg,
hepatocyte entry and immune decoy
X gene: Epigenetic
maintenance of viral genome
C gene: Core protein. Capsid
assembly; E antigen secretion
DCR-HBVS target site
Overlapping mRNAs and protein-coding regions enable targeting multiple HBV genes and proteins with a single GalXC trigger
AAAAA
Region of viral genome conservation
Viral mRNA transcript
Viral genome
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Driven by striking pharmacodynamic differences between targeting in the S versus X ORFsSingle Dose HBsAg Reduced to Below Lower Level of Detection in Preclinical Study
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• GalXC-HBVS: ≥3.9 log reduction, long duration of activity • X gene targeted: 3.0 log reduction, shorter duration of activity
• Immunohistochemical staining of mouse liver sections for HBV Core Protein (HBc) reveals extreme differences in subcellular localizationof 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
Time (days)
%HB
sAg
+/-
SEM
(Nor
mal
ized
to d
0)
-1 0 1 2 3 4 5 6 7 8 9 10 11 120.001
0.01
0.1
1
10
100
2/3 BLOQ 3/3 BLOQ
Vehicle Control
X Gene targeted treatment
GalXC-HBVS
3 mg/kg qWx3
HDI-HBV Plasmid Model (cccDNA-dependent)
HDI-HBV
Vehi
cle
Ctl.
GalX
C-HB
VS
HDI-HBV
X ta
rget
ed
Time (weeks)
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Includes placebo-controlled studies in both NUC-naïve and NUC-experienced patientsDCR-HBVS Clinical Program for Proof of Concept
Three Part Study in Healthy Volunteers and Chronic HBV Patients
• Group A: Single-dose-ascending dose study, placebo-controlled, in 30 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 eight patients with NUC-naïve chronic hepatitis B- 1 dose cohort at 3.0-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 Launched in Q1 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
• Dosed first healthy volunteer in January 2019 and first patient dosed in May 2019
• Interim data expected in Q4 2019
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Selected Dicerna GalXC™ ProgramsCollaborations With Lilly, Alexion and Boehringer Ingelheim
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Realizing Value Through Strategic Collaborations
Developing GalXC™ candidates with established pharmaceutical partners• Lilly: cardiometabolic, neurodegenerative and pain targets• Alexion: complement pathway targets• Boehringer Ingelheim: NASH targets
Expanding the range of the GalXC technology platform to go beyond liver tissue• Neural tissues: exclusive collaboration with Lilly to develop RNAi neural delivery
technology; Dicerna retains right to select rare diseases for Dicerna development
• Cardiometabolic tissue: non-exclusive collaboration with Lilly
Providing resources to drive our strategic programs• $252 million in upfront and option payments and equity at a premium among
the three collaborations
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Dicerna drivesto market
We seek to generate value across the full spectrum of GalXC clinical applicationsElements of Portfolio Strategy
Primary Hyperoxaluria
Undisclosed indication
ORPHAN DISEASE
Strategic Programs Partnered ProgramsHighest
ResourceInvestment
LowerResource
Investment
Dicerna drivesto clinical POC
Hepatitis BVirus
Undisclosed indication
COMMON DISEASE
Dicerna discoversPartner develops
COMMON DISEASE
Dicerna discoversPartner develops
AlexionCollaboration
DCR-COMP1DCR-COMP2
ORPHAN DISEASE
Key ValueDrivers
AdditiveValue
Lilly & BoehringerCollaborations
DCR-LIV1DCR-LIV2
DCR-CM1DCR-CM2DCR-CM3
DCR-NEURO1DCR-NEURO2
DCR-PAIN1DCR-PAIN2
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Building Value, Capturing Value, Enhancing Value
Advance DCR-PHXC for the treatment of primary hyperoxaluria (PH) Initiate PHYOX2, a pivotal multi-dose, double-blind, randomized, placebo-controlled trial Initiate PHYOX3, a long-term, multi-dose, open-label roll-over extension trial Report longer-term clinical data from PHYOX3
Advance DCR-HBVS for the treatment of patients with chronic hepatitis B virus (HBV) Dose first healthy volunteer in Phase 1 trial Dose first patient with non-cirrhotic chronic HBV in Phase 1 trial Report proof-of-concept data
Advance investigational GalXC™ therapy for the treatment of an undisclosed rare disease File clinical trial application
Achieve anticipated corporate milestones Evolve Board composition and expand leadership team to support continued growth
2019 Milestones
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