Corporate Overview
Douglas Fambrough, CEO
September 28, 2016
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.
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About Dicerna
Dicerna has focused discovery and development efforts on our GalXC technology
Discovering New Pharmaceuticals with RNAi
• Subcutaneously delivered drugs
for liver gene silencing
• “One shot, once a month”
• Proprietary RNAi technology
• Broad therapeutic applicability
• Founded in 2007 based on
Rare Diseases
Chronic Liver Diseases
Cardiovascular Diseases
Liver Infectious Diseases
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proprietary RNAi technology
• Ticker DRNA
• Based in Cambridge, MA, with
approximately 50 employees
• Dicerna ended Q2 2016 with
~$69 million.
How GalXC Silences Liver Genes
 Extensively demonstrated in non-human primates
Passenger strand
 Delivered via subcutaneous injection
Guide strand
4
 Long duration of action, one month or greater
GalNAc-conjugated
tetraloop
 Very well tolerated, high therapeutic index
 Simple oligonucleotide manufacturing process
Portfolio Development Strategy for GalXC
Delivering RNAi-based breakthrough therapies to improve lives
• Dicerna Development Programs – rare diseases
Genetically and molecularly defined diseases with high unmet need and efficient development paths
Rare Diseases
• Partnering focused efforts – large population size disorders
Where subcutaneous RNAi present a compelling commercial profile
Primary
Hyperoxaluria
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Chronic Liver
Diseases
Cardiovascular
Diseases
Liver Infectious
Diseases
Fibrotic liver
disease
Hypercholesterolemia
(PCSK9)
Chronic
hepatitis B
infection
GalXC Development Pipeline
Product Candidate
Indication
Stage of Development
GalXC
2017
GalXC
2016
Research
DRNA 16.1: DCR-PHXC
Primary Hyperoxaluria
DRNA 16.2: DCR-undisclosed
Orphan Genetic Disease
DRNA 16.3: DCR-PCSK9
Cardiovascular Disease
Preclinical
Clinical POC
studies
Dicerna has the capacity to launch 3
new GalXC programs each year
Dicerna has developed an extensive library of GalXC molecules across our Tx areas with
high potency in rodents, ready for optimization and full candidate qualification.
6
Dicerna Rare Disease Programs:
Primary Hyperoxaluria Type 1
Undisclosed Targets
Dicerna’s Opportunities in Rare Diseases
Rare Diseases
• Primary
Hyperoxaluria
• Additional
opportunities
Dicerna’s strategy is to retain substantial
rights to key rare disease programs
Rare diseases are an ideal case for GalXC-based therapies
•
•
•
•
•
•
High unmet medical need
A single known genetic cause
Easily identifiable patient population
Easily assayed biomarkers
Centers of excellence for treatment
Supportive advocacy organizations
To date Dicerna has qualified 10 rare disease targets
including both first-in-class and validated target opportunities
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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)
Systemic oxalosis in PH1
Bone
Bone & Kidney
Skin
Kidney
Calcium oxalate crystals form, inducing nephrolithiasis &
nephrocalcinosis (Cochat, 2013)
Subsequent decline in kidney function results in systemic oxalosis
(Cochat 2013)
Median age of onset of kidney failure is 23 yrs (van der Hoeven, 2012)
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)
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CONFIDENTIAL
Photographs reprinted by permission from
Macmillan Publishers Ltd:
Nature Reviews Nephrology 8 (2012) pg. 467
Primary Hyperoxaluria Type 1
Epidemiology
Over 1,000 PH1 patients in two registries
330 PH1 pts
July 2015
683 PH1 pts
30%
July 2015
P. Cochat et al. 2013. NEJM 369;7; Hopp et al, 2015 JASN ePub; http://www.rarekidneystones.org/hyperoxaluria; http://www.oxaleurope.org
How large is the addressable market?
10
Eligible Pts. ('27)
917
1,347
1,097
3,357
86
14,982
104
3,714
3,905
319
137
Predicted incidence based on US allele freq. of 6.6 per million (Hopp 2015),
adjusted for PH1 lifespan (~65 yrs. (Mandrile 2014) which is ~81% of normal).
ME/Africa is doubled due consanguinity (estimate); may actually be as high as
10x. Assumes that van der Hoeven 2012 (Netherlands) represents max possible
diagnosed prevalence, which is functionally similar to penetrance; after
adjusting for consanguinity in Netherlands, diagnosed prevalence is 2.6 per M.
18%
34%
http://www.rarekidneystones.org/hyperoxaluria/physicians.html; Tang 2014, Kidney International
Potential for Accelerated Approval
Nearly 15k eligible patients worldwide in peak
year of sales (2027)
Country
US
EU28
LATAM
ME/Africa
AZ/NZ
Canada
China
India
Japan
So. Korea
18%
Adult 20+
Early Child 0-4
Estimated prevalence & genotypic incidence:
1-3 cases per million pop (diagnosed today in EU countries)
1 case per ~150,000 births (based on disease allele frequency)
Juvenile 10-19
Median age of diagnosis is 12 years
Late Child 5-9
PH1 is an ultra rare disease
Urinary oxalate excretion rate
of >2 mmol/1.73m2/24hr
associated with a significantly
lower rate of end stage renal
disease (ESRD)
~2,000
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)
GalXC HAO1 is Efficacious in the Mouse Genetic Model of PH1
HAO1 silencing generates the expected urinary oxalate reduction and urinary glycolate increase
A single SC dose of GalXC HAO1 produced strong effects on urinary biomarkers in
Agxt-/- PH1 disease model mice
Oxalate Reduction
3000
1000
disease oxalate level
600
400
normal oxalate level
200
1 m g /k g
( m g /g C r e a tin in e /2 4 h r )
800
2400
2100
1800
1500
1200
900
600
1 m g /k g
300
3 m g /k g
3 m g /k g
W eeks
0
dose
1
2
3
4
W eeks
0
0
11
2700
U r in e G ly c o la te
O x a la te /C r e a tin in e (m g /g )
Glycolate Elevation
5
6
7
0
1
2
3
4
5
6
7
Monthly Regimens for DCR-PHXC Lead in Non-Human Primates
DCR-PHXC precursor in long-term non-human primate studies at 2mg/kg and 4 mg/kg
Monthly Dosing with Washout
Multi-Dose Regimens in Non-Human Primates
%
1 0 0
2 mpk QMx4
7 5
First
Dose
Last
Dose
Day
180
5 0
2 5
ongoing
to 7.5
months
1 0
0
0
1
2
3
4
Months
First Dose
12
Multi-dose Tx Regimens
4 mpk QMx4
(rel
( r eto
l t pre-dose)
o p re -d o s e )
U D T # 1
m RRemaining
N A R e m a in
% mRNA
in g
Dosing
Regimens:
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• Both 2 and 4 mg/kg groups achieved ≥85%
mRNA silencing by two months
• 95% maximum mRNA silencing
• ~88% average mRNA silencing two months
after the last dose (4 mg/kg)
Last Dose
Monkey gene silencing data suggests only 2 mg/kg monthly or >2 mg/kg at longer
dosing intervals would be efficacious
DCR-PHXC Primary Hyperoxaluria Development Plan
• PHYOS observational study underway, establishing disease baseline and progression characteristics
• Prior DCR-PH1 (IV administered) clinical work has validated disease pathway biology
• DCR-PHXC will have an IND/CTA filing in late 2017
PHYOS
DCR-PHXC Development
• Natural history and clinical course of
patients with PH1
• Urine & plasma biomarkers
• Quality-of-life and economic burden of
disease
• 18 patients enrolled to date
• IND/CTA late 2017
• Will incorporate learnings from DCR-PH1
• Endpoints:
- PD (oxalate & glycolate biomarkers)
- Safety & Tolerability
- PK
Dosing Regimen: Single ≤1 ml subcutaneous injection
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Dicerna Rare Disease Programs:
Primary Hyperoxaluria Type 1
Undisclosed Targets
DCR-16.2 Rare Disease Characteristics
Indications and clinical characteristics
A complex rare disease characterized by multi-organ complications.
Disorder causes progressive decline in multiple organs despite standard of care.
Assessments
Technical
Commercial
Opportunity
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Parameters
Investment Thesis
Validation
Silencing of gene target in mice reduces or eliminates major pathology of disease
Biomarker
Sustained increased concentration of single plasma biomarker is the most significant disease
risk factor
High Unmet Need
No approved drug therapy US, EU or JP
The median survival time from diagnosis is less than 10 years
Patient Numbers
Uncertain epidemiology, but publications suggest as many as 10,000 - 15,000 patients in the
US and EU
Competition
First-in-class opportunity
Challenging target for small molecules and antibodies
Patient Advocacy
Active patient groups and growing disease awareness
GalXC DCR-16.2 Rare Disease Potent Silencing in Non-Human Primates
One subcutaneous dose at 3 mg/kg was administered on Day 0, liver biopsies taken on Day 21 and 63
% T a r g e t m R N A R e m a in in g
GalXC Lead Comparison in NHP at Days 21 & 63
primates as part of candidate selection
process
100
• All candidates show >95% mRNA silencing
PBS
after a single 3 mg/kg subcutaneous
injection
U D T # 4 -1
75
U D T # 4 -2
U D T # 4 -3
• No loss of gene silencing after more than
50
two months, suggests very infrequent
dosing may be possible
25
• Program on track for formal program launch
10
0
0
3
6
w eeks
16
• Three lead constructs tested in non-human
9
12
with final candidate in 2016
GalXC Undisclosed Target for Rare Disease
Indications and clinical characteristics
Metabolic disorder causing progressive decline in liver function despite standard of care.
Long-term outcome includes progressive liver fibrosis and cirrhosis.
Assessments
Technical
Commercial
Opportunity
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Parameters
Investment Thesis
Validation
Clear predictive causality from pathway has been verified using in-house animal models
Biomarkers
Common plasma disease markers combined with emerging imaging techniques
High Unmet Need
No efficacious therapeutic options available
Symptoms and disease management negatively impacts patient and family quality of life
Patient Numbers
Estimated US/EU prevalence of 3,000 - 5,000 patients
Competition
First-in-class opportunity
Challenging target for small molecules and antibodies
GalXC Undisclosed Target: Treatment in a Mouse Model of Liver Disease
Visualization of liver damage; GalXC conjugate efficacy in vivo
Mouse Model
PBS
Patient Liver
Human
20X
20X
20X
GalXC
Normal
20X
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Significantly improved liver morphology with GalXC treatment
Dicerna Large Population
Disease Programs:
PCSK9
HBV
Chronic Liver Diseases (CLD)
Dicerna’s Opportunities in Large Population Disorders
Chronic Liver
Diseases
• HMGB1 for fibrotic
liver diseases
Cardiovascular
Diseases
• PCSK9 targeted
therapy for hypercholesterolemia
Liver Infectious
Diseases
• HBV targeted
therapy for chronic
hepatitis B infection
Dicerna’s strategy is to work with partners to develop
therapies for large patient populations
GalXC-based therapies can have a major impact
• Simple, infrequent SC dosing paradigm may bring
convenience and compliance benefits
• Exquisite target and tissue specificity nearly
eliminates off-target effects
• GalXC therapy has demonstrated a high
therapeutic index in animal studies
To date Dicerna has qualified >20 disease targets in
these major therapeutic areas
Some targets are relevant to rare disease
subpopulations
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GalXC PCSK9: Atherosclerotic Cardiovascular Disease (CVD)
Unmet medical need to reduce recurrent CV events in statin-refractory CVD patients
Market Opportunity:
Competition:
35M statin treated patients in U.S.
with hypercholesterolemia1,2
PCSK9 GalXC is being developed for the $10B+ statin-refractory CVD market with the goal of
improved convenience and adherence (less frequent dosing) compared to mAbs.
23M (2/3) without CVD
12M (1/3) with CVD1,2,3
Partnering Opportunities:
Addressable U.S. Patient Population:
> 4.5M (>37%) CVD patients not at LDL
goal of 70 mg/dL on statin alone4
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1.
2.
3.
4.
5.
Qiuping Gu, et al. NCHS Data Brief. 2014, No. 177.
CDC. Age and Sex Composition in the United States, 2012.
CDC. Summary Health Statistics: National Health Interview Survey 2014.
Wiviott SD, et al. J Am Coll Cardiol. 2005;46(8):1411-1416
Cannon CP, et al. NEJM. 2015; 372 (25).
PCSK9 agents complement portfolios that include other classes shown to reduce CV events;
many pharmaceutical companies would benefit from having PCSK9 GalXC, especially those with
marketed or late-stage mAbs that are likely to be disrupted by emerging long-duration oligos.
6. Eliano PN, et al. Annals of Internal Medicine. 2015; 163 (1).
7. Unpublished data. Alnylam Pharmaceuticals; 11.11.15 Press Release.
HBV: GalXC May Play a Key Role in Establishing a Functional Cure
Over 350 million people are chronically infected worldwide
Organization of the HBV Genome:
Overlapping Polycistronic mRNA Targets
Nearly 3 Log reduction in HBsAg after GalXC-HBV treatment
3mg/kg QW x 3
RRelative
e la t iv e HHBsAg
B s A g (pre-dose)
(p re -d o s e )
3,221 1
2,856
Polymerase
EcoRI
2,458
834
2,309
1000
%HBsAg +/- SEM
preS1,
preS2
and S
Control
100
10
1
GalXC-HBV(S)
1,622
1,816
1,873
X gene
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0
3
6
9
2
5
7
14
14
13
12
11
11
98
91
84
10
D ay
77
70
63
56
49
42
35
28
21
14
0
preCore,
Core
7
0 .1
Pre-dose HBsAg titer range 1.8 – 13 ug/mL
1,376
HBV:2912
3 mg/kg
qW x 3
Establishing New Therapies for CLD
Using GalXC to target chronic liver disease at its source
Uncovering New Therapeutic
Approaches by Targeting Hepatocytes
• GalXC targets hepatocytes, silencing injury-
responsive genes that release profibrotic signals
• CLD presents a large opportunity space,
encompassing complex polygenic diseases like
NASH and rare monogenic diseases
• Rapid GalXC generation time allows efficient
exploration of a large target space across
multiple disease models:
High fat and other diets
Genetic knockout models
Carbon tetrachloride and other
hepatotoxicity models
Complete and partial bile duct ligation
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Therapeutic Rationale
Possible gene targets
ACC1/2
ASK1
CASP1
CB1
COL1A1
CTGF
CTNNB1
CYP27A1
CYP7A1
DGAT2
FOXF1
HIC5
HMGB1
HSP47
LOX
LOXL2
MYC
OPN
PLIN5
PNPLA3
SERPINA1
SHH
SMAD 2/3/7
SNAI1
SRBP1C
TGFβ
TM6SF2
Others
…and more
GalXC Prevents Liver Damage in Partial Bile Duct Ligation Model
Sirius red staining for collagen after potent silencing of an undisclosed target
GalXC 10mg/kg
Day 0: Surgical
partial bile
duct ligation Day 1
Sac
Day 8
Day 15
Day 22 Day 23
% S ir iu s R e d S t a in in g
200
150
100
50
0
Animal
A3 1
Fibrotic collagen staining
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Image analysis
Animal
A4 2 Animal
B 3 3 Animal
B4 4
Untreated
Animal
B5 5
GalXC Treated
Each data point is quantification of staining
from a representative liver tissue section
Our Vision for GalXC
Delivering RNAi-based breakthrough therapies to improve lives
• Powerful Capability – durable liver gene silencing we believe will be “one shot, once a month”
• Expansive Opportunity – multiple gene targets across four disease areas
Rare Diseases
Primary
Hyperoxaluria
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Chronic Liver
Diseases
Cardiovascular
Diseases
Liver Infectious
Diseases
Fibrotic liver
disease
Hypercholesterolemia
(PCSK9)
Chronic
hepatitis B
infection
Key Milestones
2016 GalXC Subcutaneous Platform Milestones
• DCR-PHXC program launched
• DCR-16.2 Rare disease candidate declaration and program launch
• DCR-16.3 PCSK9 candidate declaration and program launch
2017 GalXC Subcutaneous Platform Milestones
• Multiple GalXC candidate declarations
• IND/CTA filing for DCR-PHXC
2018 GalXC Subcutaneous Platform Milestones
• DCR-PHXC clinical proof of concept
• Additional GalXC INDs/CTA
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