First Quarter 2017 Financial Results May 5, 2017 1 Agenda - - PowerPoint PPT Presentation

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Colin

Living with Porphyria

First Quarter 2017 Financial Results

May 5, 2017

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Agenda

Welcome

• Christine Regan Lindenboom

Vice President, Investor Relations & Corporate Communications

Q1 2017 Overview

• John Maraganore, Ph.D.

Chief Executive Officer

Alnylam Clinical Pipeline

• Akshay Vaishnaw, M.D., Ph.D.

Executive Vice President of R&D

Financial Results

• Michael Mason

Vice President, Finance and Treasurer

2017 Goals Update

• Barry Greene

President

Q&A Session

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Alnylam Forward Looking Statements

This presentation contains forward-looking statements, within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. There are a number of important factors that could cause actual results to differ materially from the results anticipated by these forward- looking statements. These important factors include our ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of our product candidates; pre-clinical and clinical results for our product candidates; actions or advice of regulatory agencies; delays, interruptions or failures in the manufacture and supply of our product candidates; our ability to obtain, maintain and protect intellectual property, enforce our intellectual property rights and defend

• ur patent portfolio; our ability to obtain and maintain regulatory approval, pricing and reimbursement for

products; our progress in establishing a commercial and ex-United States infrastructure; competition from

• thers using similar technology and developing products for similar uses; our ability to manage our growth

and operating expenses, obtain additional funding to support our business activities and establish and maintain business alliances; the outcome of litigation; and the risk of government investigations; as well as those risks more fully discussed in our most recent annual report on Form 10-K under the caption “Risk Factors.” If one or more of these factors materialize, or if any underlying assumptions prove incorrect, our actual results, performance or achievements may vary materially from any future results, performance or achievements expressed or implied by these forward-looking statements. All forward-looking statements speak only as of the date of this presentation and, except as required by law, we undertake no obligation to update such statements.

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Q1 2017 Overview

John Maraganore, Ph.D. Chief Executive Officer

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Strategic Context for 2017

APOLLO Phase 3 topline results expected in mid-2017

• If positive, plan to file NDA/MAA at year-end

Expect to advance three additional programs into Phase 3 studies

• Fitusiran, for the treatment of hemophilia
• Givosiran, for the treatment of acute hepatic porphyrias
• Inclisiran, for the treatment of hypercholesterolemia (in collaboration with The

Medicines Company)

Building world-class team and capabilities in preparation for potential transition to commercial stage

• Includes Quality, Medical Affairs, Manufacturing, and Commercial teams
• Buildup in North America and Western Europe, and then Global

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Alnylam Clinical Pipeline

Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D

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Alnylam ATTR Amyloidosis Portfolio

Committed to Continued Innovation for Patients Patisiran ALN-TTRsc02

• IV administration
• Phase 2 completed
• Phase 3 trial
• ngoing; fully enrolled with top-

line results expected in mid- 2017

• APOLLO-OLE study ongoing
• ESC “second generation”

chemistry

• Anticipate quarterly SC dose

regimen

• Phase 1 ongoing; initial positive

data presented December 2016

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ΔmNIS+7 from baseline to Month 24

• 35
• 30
• 25
• 20
• 15
• 10
• 5

5 10 15 20 25 30

Mean (SEM) ΔmNIS+7 from baseline at 24 mos~

• 35
• 30
• 25
• 20
• 15
• 10
• 5

5 10 15

Natural History (nonlinear; N=283)1#

Diflunisal Ph 3 Study2+

Placebo (N=66) Diflunisal (N=64)

Mean ΔmNIS+7 Across hATTR Amyloidosis Studies at 24 mos~

25.8 (9.4) 29.6 (3.1) 9.2 (2.7)

• 7.0

(2.0)

20 25 30

Patisiran Ph 2 OLE^ (N=26)

20 out of 27* patients (74%) with no change or an improvement in mNIS+7 at month 24 compared to baseline

• 1. Adams D et al. Neurology. 2015;85;675-682. 2. Berk JL et al. JAMA. 2013;310:2658-67.

Individual ΔmNIS+7 at Month 24 (n=26)

Patisiran Phase 2 OLE Final Study Results

Change in mNIS+7 at 24 Months

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Change in mNIS+7 from Baseline to Month 24

• 40
• 30
• 20
• 10

10 20

Individual ΔmNIS+7 at Month 24 (n=26)

Baseline NIS Tertiles N Baseline NIS Range Mean (SEM) ΔmNIS+7 from Baseline to Month 24 First Tertile 7 4-13

• 2.9 (2.0)

Second Tertile 10 16-42

• 9.4 (3.3)

Third Tertile 9 46-93

• 7.4 (4.3)

Patisiran Phase 2 OLE Final Study Results

Change in mNIS+7 at 24 Months by Baseline NIS Tertile

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• Blinded analysis of tandem skin punch biopsies performed at central lab; statistical significance

testing performed post-hoc

• Dermal amyloid content in both distal thigh and distal leg decreased over time relative to baseline
• Statistically significant decrease in absolute change for distal thigh at 6, 18 and 24 months and at all time points

for distal leg

Median Relative Change from Baseline in Dermal Amyloid Content Distal Thigh N Median Relative Percent Change (IQR)

6 months 22

• 52.5 (-75.7, 0)

12 months† 19

• 61.8 (-87.5, 0)

18 months 20

• 78.2 (-89.7, -8.3)

24 months† 19

• 23.8 (-78.3, 0)

Distal Leg N Median Relative Percent Change (IQR)

6 months 22

• 48.5 (-74.3, 0)

12 months 18

• 64.6 (-85.8, 0)

18 months† 18

• 67.5 (-91.3, -10)

24 months† 18

• 40.4 (-78.3, -21.6)

Distal thigh dermal amyloid content‡ in Patient 050-0003

• 4.58*
• 4.27
• 8.01*
• 3.81*
• 7.23*
• 9.48*
• 10.71*
• 6.38*
• 15
• 10
• 5

Distal Thigh

Distal Leg

* P<0.05

Mean Absolute Change from Baseline in Dermal Amyloid Content, %

6 months 12 months 18 months 24 months

Mean Absolute Change from Baseline in Dermal Amyloid Content

Patisiran Phase 2 OLE Final Study Results

TTR Amyloid Content in Skin: Lower Limb

Adams et al., AAN, April 2017

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Patisiran generally well tolerated in patients with hATTR amyloidosis out to 25 months

• No drug-related SAEs and majority of AEs were mild or moderate
• Drug-related AEs reported in ≥4 patients were infusion related reaction (22.2%) and flushing (22.2%),

all of which were mild

Results consistent with therapeutic hypothesis that patisiran can potentially halt or improve neuropathy progression

• Long-term patisiran administration resulted in improvement in neuropathy impairment score with mean

7.0-point decrease in mNIS+7 at 24 months

– Compares favorably to expected mean 26-30 point increase in mNIS+7 at 24mo estimated from analyses

• f separate historical data sets in untreated hATTR patients with similar baseline neuropathy impairment
• Improvement or no change in mNIS+7 observed in 20 of 27 (74%) patients
• In exploratory analyses, observed an increase in sweat gland nerve fiber density and a decrease in

dermal amyloid content in the distal thigh and leg relative to baseline

All eligible patients have enrolled into the APOLLO-OLE study and will continue to receive patisiran dosing

• As of May 5, 2017, more than 20 patients received ≥ 36 months of patisiran dosing; plan to present data

in late 2017

Plan to present APOLLO Phase 3 topline results in September

Patisiran Phase 2 OLE Final Study Results

Summary

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Fitusiran for Hemophilia

Potential to Restore Hemostasis in Hemophilia

Genetically validated, liver-expressed target gene Biomarker for POC in Phase 1 Definable path to approval and patient access

Established Endpoint Annualized Bleeding Rate (ABR)

AT FIX

Thrombin

Blood clot Hemophilia B Hemophilia A

AT

FIX FVIII Plasma Biomarkers AT Lowering, Thrombin Generation

AT Activity (%) Days

• 30

60 120 Peak Thrombin (nM)

Fitusiran Phase 1 results: Pasi et al., WFH, July 2016

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Preliminary Fitusiran ATLAS Phase 3 Program*

Plan to Initiate in Early 2017

• Adults and adolescents

with hemophilia A or B with inhibitors

• On-demand
• N~50

2:1

Fitusiran OD BPA

Endpoints:

• ABR
• Bypassing agent

(BPA) consumption

• Quality of life
• Safety

OR

• Adults and adolescents

with hemophilia A or B with or without inhibitors

• Prophylaxis
• N~100

Fitusiran PPX Factor/BPA

Endpoints:

• ABR
• Factor/BPA

consumption

• Quality of life
• Safety
• Adults and adolescents

with hemophilia A or B without inhibitors

• On-demand
• N~100

2:1

Fitusiran OD Factor

Endpoints:

• ABR
• Factor VIII or IX

consumption

• Quality of life
• Safety

OR

*Preliminary plans subject to further diligence and health authority feedback

All completers will be eligible for fitusiran treatment in Phase 3 OLE study (ATLAS-OLE)

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Acute Hepatic Porphyrias

DESCRIPTION

Family of ultra-rare orphan diseases causing incapacitating and potentially fatal attacks

Predominantly

female,

commonly misdiagnosed

Disease burden includes:

• Acute, Severe Abdominal Pain
• Frequent Hospitalizations
• Peripheral and Autonomic Neuropathy
• Neuropsychiatric Symptoms
• Chronic Pain

PATIENT POPULATION*

~5,000

Patients with sporadic attacks in U.S./EU

~1,000

Patients with recurrent attacks in U.S./EU

*ORPHANET; The Porphyria Consortium

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Genetically validated, liver-expressed target gene Biomarker for POC in Phase 1 Definable path to approval and patient access

Potential Endpoints

• Annualized attack rate
• ALA and PBG levels

Serum and Urinary Biomarkers ALA and PBG

Givosiran for Acute Hepatic Porphyrias

Potential to Prevent Debilitating Attacks

ALAS1 upstream of genetic defect

Up-regulation

• f ALAS1

Accumulation of toxic intermediates ALA and PBG

Mean (SEM) % ALA Knockdown Time (Months)

• 20
• 40

Givosiran Interim Phase 1 results: Sardh et al., ASH, December 2016

EMA PRIME Designation

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Robust and Sustained LDL-C Reductions with Inclisiran*

Phase 2 Results to Day 270 Following Two Doses

PLANNED NEXT STEPS FOR INCLISIRAN:

Start Phase 3 study

in mid-2017

Safety (N=501):

• No drug-related SAEs, no discontinuations due to AEs
• Two patient deaths due to MI and stroke, both

unrelated to study drug

• No LFT elevations related to study drug
• Majority of AEs mild or moderate in severity

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ALN-GO1

for Primary Hyperoxaluria 1 (PH1)

Other Programs to Watch

ALN-CC5

for Complement-Mediated Diseases

Sustained control

• f disease hemolysis

with up to

67%

reduction in eculizumab dose in PNH patients1

ALN-HBV

for Hepatitis B Virus (HBV) Infection

Pre-clinical results:3

up to

3.6 log10

HBsAg reduction

Up to

8-fold

increase in plasma glycolate in healthy volunteers2

Safety (N=32):

• No SAEs, no discontinuations due to AEs
• All AEs mild or moderate, with exception of
• ne subject with transient, asymptomatic CPK

elevation considered unrelated to study drug Safety (N=6):

• No SAEs, no discontinuations due to AEs
• 1 AE of hemolysis in setting of URI; moderate in

severity and considered unrelated to study drug

• 1 AE of asymptomatic, transient grade 3

elevation of LFTs; considered possibly related

RECENT ACTIVITY FOR ALN-GO1:

First PH1 Patient Dosed

in March 2017

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Q1 2017 Financial Results

Michael Mason Vice President, Finance and Treasurer

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Financial Summary and Guidance 2017 Q1 Financial Results

• Cash $962.2M
• Includes $150.0M in restricted investments
• GAAP Revenues $19.0M
• Total GAAP Operating Expenses $125.5M
• Research and Development Expense $87.0M
• General and Administrative Expense $38.5M
• GAAP Net Loss of $107.3M
• Shares Outstanding 86.1M

2017 Guidance

• Year-end cash >$700M
• Includes $150.0M of restricted investments

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2017 Goals Update

Barry Greene President

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Transition to Potential Commercialization

Planned Rapid Launch Succession

Givosiran

~2020

Patisiran

~2018

Fitusiran

~2019

Building commercial capabilities to prepare for potential product launches

• Patisiran in US, Canada, and Western

Europe

• Fitusiran co-develop/co-commercialize

in US, Canada, and Western Europe

• Givosiran globally

Manufacturing build-out to ensure consistent drug supply underway

• Alewife facility fully operational and

ready for patisiran launch

• Norton drug substance facility

expected to be commercially

• perational in 2020

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2017*

Early Mid Late

PATISIRAN

(hATTR Amyloidosis)

Phase 2 OLE data APOLLO Phase 3 top-line APOLLO Phase 3 results NDA/MAA filing

FITUSIRAN

(Hemophilia and RBD)

Phase 2 OLE data ATLAS Phase 3 program start

GIVOSIRAN

(Acute Hepatic Porphyrias)

Phase 1, Part C data Phase 3 study start

INCLISIRAN**

(Hypercholesterolemia)

ORION-1 Phase 2 data ORION-2 HoFH study start ORION-3 Phase 2 OLE study start ASCVD Phase 3 study start

ADDITIONAL CLINICAL PROGRAMS

Continue to advance early/mid-stage pipeline; Present clinical data

*Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4

Alnylam 2017 Pipeline Goals

**Based on The Medicines Company guidance as of January 2017

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Q&A Session

Q1 2017 Financial Results

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Thank You