Corporate Overview November 2017 1 Alnylam Forward Looking - - PowerPoint PPT Presentation

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Colin

Living with Porphyria

Corporate Overview

November 2017

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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 quarterly report on Form 10-Q 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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RNAi Therapeutics

New Class of Innovative Medicines

Harness natural pathway Catalytic mechanism Silence any gene in genome Upstream of today’s medicines Clinically proven approach

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

Alnylam Platform and R&D Safety

Building a Pipeline of Potentially Transformative Medicines

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Alnylam Clinical Development Pipeline

HUMAN POC* EARLY STAGE

LATE STAGE

REGISTRATION/ COMMERCIAL COMMERCIAL RIGHTS Patisiran

Hereditary ATTR Amyloidosis

• US, Canada,

Western Europe

Fitusiran**

Hemophilia and Rare Bleeding Disorders

• 50%

US, Canada, Western Europe

Inclisiran

Hypercholesterolemia

• Milestones &

Royalties

Givosiran

Acute Hepatic Porphyrias

• Global

Cemdisiran

Complement- Mediated Diseases

• Global

ALN-GO1

Primary Hyperoxaluria Type 1

• Subject to

partner option rights

ALN-TTRsc02

Hereditary ATTR Amyloidosis

• Subject to

partner option rights Focused in 3 Strategic Therapeutic Areas (STArs):

Genetic Medicines Cardio-Metabolic Diseases Hepatic Infectious Diseases

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Hereditary ATTR Amyloidosis

Patisiran

Leo

Living with hATTR Amyloidosis

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Hereditary ATTR (hATTR) Amyloidosis

DESCRIPTION

Orphan multi-system disease caused by mutant transthyretin (TTR) amyloid deposits in nerves, heart, GI tract, and other tissues

Significant morbidity and fatal within

2-15

years from symptom onset

PATIENT POPULATION*

~50,000

worldwide

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Mutant Transthyretin (TTR) is disease-causing protein Serum Biomarker TTR

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

• 20
• 40

Motor strength/weakness (192)

Reflexes (20) Quantitative Sensory Testing (80)

• r HRdb (2)

mNIS+7

Established Endpoint Neurological Impairment Score

Patisiran for hATTR Amyloidosis

Potential for Disease Modification by Reducing Pathogenic Protein

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APOLLO Phase 3 Study Design

Patient Population

• hATTR amyloidosis: any

TTR mutation, FAP Stage 1 or 2

• Neurological impairment

score (NIS) of 5-130

• Prior tetramer stabilizer

use permitted 2:1 RANDOMIZATION†

Patisiran 0.3 mg/kg IV q3w* Placebo IV q3W*

Primary Endpoint

• Change in mNIS+7 from

baseline at 18 months Secondary Endpoints

• Norfolk QOL-DN
• NIS-weakness
• R-ODS
• 10-meter walk
• mBMI
• COMPASS-31

Select Exploratory Endpoints

• EQ-5D QOL
• NIS+7
• Serum TTR levels
• Cardiac assessments
• Grip strength
• Skin biopsies for nerve fiber

density and amyloid

• ther mutations (including late onset V30M), and previous tetramer stabilizer use (tafamidis or diflunisal) vs. no previous tetramer stabilizer use

*To reduce likelihood of infusion-related reactions, patients receive following premedication or equivalent at least 60 min before each study drug infusion: dexamethasone; oral acetaminophen/paracetamol; H2 blocker (e.g., ranitidine or famotidine); and H1 blocker (e.g., diphenhydramine).

99% of patients who completed APOLLO study enrolled in Global OLE Study

• r

10

• 10
• 5

5 10 15 20 Better Worse LS mean (SEM) ∆Norfolk-QOL from baseline Baseline 9 Months 18 Months

p=1.10 x 10-10

• 10
• 5

5 10 15 20 25 30 35 Better Worse LS mean (SEM) ∆mNIS+7 from baseline Baseline 9 Months 18 Months

p=9.26 x 10-24

APOLLO Phase 3 Study Results

Patisiran Meets Primary and all Secondary Endpoints

mNIS+7 at 18 mos

• -6.0 point change relative to baseline
• 34.0 point difference relative to placebo
• 56.1% of patients improved

Norfolk-QOL at 18 mos

• -6.7 point change relative to baseline
• 21.1 point difference relative to placebo
• 51.4% of patients improved

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APOLLO Phase 3 Study Results

Patisiran Meets Key Exploratory Endpoints in Cardiac Subpopulation*

Biomarker Functional Echocardiographic

NT-proBNP 10MWT

• 350
• 300
• 250
• 200
• 150
• 100
• 50

50 100 150 200 250 300 350 Median ∆NT-proBNP from baseline at 18 mos (ng/L)

• 0.4
• 0.3
• 0.2
• 0.1

0.1 0.2 0.3 0.4 Mean ∆10-MWT gait speed from baseline at 18 mos (m/sec)

Longitudinal Strain

• 1.5
• 1.25
• 1
• 0.75
• 0.5
• 0.25

0.25 0.5 0.75 1 1.25 1.5 Mean ∆longitudinal strain from baseline at 18 mos (%)

LV Wall Thickness

• 0.12
• 0.1
• 0.08
• 0.06
• 0.04
• 0.02

0.02 0.04 0.06 0.08 0.1 0.12 Mean ∆LV wall thickness from baseline at 18 mos (cm)

p=7.74 x 10-8 ** p=0.0173** p=0.0154** p=7.42 x 10-9 **

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APOLLO Phase 3 Study Results

Encouraging Safety & Tolerability Profile

Overall, 13 deaths in APOLLO study; no deaths considered related to study drug

• Similar frequency of deaths in patisiran and placebo treatment groups
• Causes of death (e.g., cardiovascular, infection) consistent with natural history

Majority of AEs mild or moderate in severity

• Most common AEs more frequently observed in patisiran arm vs. placebo included peripheral edema (29.7% vs.

22.1%) and infusion-related reactions (18.9% vs. 9.1%)

• Both AEs decreased over time; IRR led to discontinuation in only 1 patient (0.7%); peripheral edema led to no discontinuations

Additional notable safety findings

• Encouraging safety & tolerability in cardiac subpopulation
• Deaths in 5.6% of patisiran patients and 11.1% of placebo patients
• No safety signals related to steroid pre-medication regimen or TTR knockdown
• No safety signals regarding liver function tests, hematology including thrombocytopenia, or renal dysfunction related to

patisiran Type of Adverse Event, Number of patients (%) Placebo (N=77) Patisiran (N=148) Adverse event (AE) 75 (97.4) 143 (96.6) Severe AE 28 (36.4) 42 (28.4) Serious adverse event (SAE) 31 (40.3) 54 (36.5) AE leading to treatment discontinuation 11 (14.3) 7 (4.7) AE leading to study withdrawal 9 (11.7) 7 (4.7) Death 6 (7.8) 7 (4.7)

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hATTR Amyloidosis and APOLLO Assessments

Clinical Manifestations APOLLO Assessments

• Heart failure
• Arrhythmias/syncope
• Impaired exercise tolerance
• NT-proBNP
• Echo longitudinal strain
• Echo LV thickness
• 10-MWT
• AE profile
• Loss of sensation
• Muscle weakness
• Impaired ambulation
• mNIS+7
• NIS-W subdomain
• QST subdomain
• Reflexes subdomain
• Norfolk-QOL
• R-ODS Disability
• 10-MWT
• Grip strength
• AE profile
• Orthostatic hypotension
• Syncope/falls
• Constipation/diarrhea
• Urinary retention/UTIs
• mNIS+7
• Postural BP subdomain
• Norfolk-QOL
• Autonomic subdomain
• mBMI
• COMPASS-31
• Orthostatic hypotension
• GI and bladder subdomains
• AE profile

Mutant & wild-type TTR in liver Misfolded mutant & wild-type TTR amyloid fibrils in circulation deposit in nerves and tissues of many organs Heart Sensorimotor Nerves Autonomic Nerves Patisiran

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hATTR Amyloidosis Population

Patient identification will be key element of commercial success

• ~50,000 hATTR amyloidosis patients worldwide with some endemic hot-spots
• Continuum of peripheral/autonomic neuropathy and cardiac symptoms
• Polyneuropathy phenotype believed to occur in 1:100K in non-endemic regions
• >50% of patients with neurologic phenotype assumed to have concomitant cardiomyopathy (“mixed phenotype”)
• >30% of patients with cardiac phenotype assumed to have concomitant neuropathy (“mixed phenotype”)

Estimated Global Population*

U.S. EUCAN ROW**

PN Mixed CM Prevalence Current Diagnosis Rate†

~3K 8-12K 15-22K ~10-30% ~7K 1-3K 2-4K ~20-50%

PN Mixed CM

~2K ~4K ~8K ~10-30%

PN Mixed CM

Alnylam Territories Sanofi Genzyme Territories

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Building a Customer-Centric Organization

Expect ~150 U.S./EUCAN employees in customer-facing activities:

• Medical affairs:
• Health economics/outcomes research
• Field-based MSLs
• Patient advocacy
• Medical communications
• Commercial:
• Marketing
• Account management
• Market access
• Market insights
• Patient services
• Country leadership

Engagement and Advocacy Educate Access Retain Support and Solutions Best or First-in-Class Product Profiles

RNAi Therapeutics Success

Diagnose

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Raising hATTR Awareness and Care

Diagnosis, education, patient support, and access are key priorities

Diagnosis Education Support Access

• Started 2014, expanded

in 2016

• Free genetic screening
• Now includes panels

for neuropathy, cardio

• >350 physicians enrolled;

>2000 tests

• Screened heart failure

patients for prevalence

• f TTR mutations
• Screened >1000,

identified 77 patients with hATTR mutations

https://hATTRbridge.com

HCP Website Patient Website

https://hATTRamyloidosis.com

Care Days

• Local support program in

partnership with local KOLs

• Agenda includes disease
• verview, tips for living

with hATTR, and support and resources

• 4 programs hosted in

2017; total attendance

• ver 100 people

Expanded Access Program

• Providing expanded access

to patisiran to patients who meet program criteria

• Now open at >15 sites in

U.S.; compassionate use

• ngoing in EU

Data

Big Data Projects

• Integrating data sources

to inform MD targeting for field engagement

Advocacy

• Working collaboratively

with patient advocacy groups to improve care for hATTR

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Inotersen ALN-TTRsc02

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DOSES PER YEAR

4

DOSES PER YEAR ANTICIPATED

Ongoing Study in Normal Healthy Volunteers

Mean max TTR KD of 97.1%; ~80% TTR KD at nearly 1 year after single 50 mg dose**

Most potent Alnylam RNAi therapeutic to date

Safety: Generally well tolerated in healthy volunteers (N=80)

• No SAEs or discontinuations due to AEs; all AEs mild or moderate
• 14 AEs in 8 subjects considered possibly related to treatment; majority mild
• Events included erythema, pain, and bruising at the injection site, rhinorrhea,

pruritis, cough, nausea, fatigue, genital rash and abdominal pain

• No clinically significant changes in physical exams, EKG or lab parameters (e.g.,

LFTs)

ALN-TTRsc02 Opportunity

Potential for Best-in-Class Profile

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Hemophilia and Rare Bleeding Disorders

Fitusiran

Venkat

Living with Hemophilia

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Hemophilia and Rare Bleeding Disorders

DESCRIPTION

Genetic deficiency resulting in inability to generate thrombin and stop bleeding

Global need due to frequent IV infusions, ability to manufacture, and cold chain PATIENT POPULATION*

Hemophilia A and B

200,000

~4,000

worldwide

with inhibitors

Highest need is prophylaxis for inhibitor patients and to avoid inhibitor

formation in all patients

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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

AT

FIX FVIII Plasma Biomarkers AT Lowering, Thrombin Generation

• 30

Fitusiran for Hemophilia

Potential to Restore Hemostasis in Hemophilia

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Fitusiran Phase 2 OLE Study Results*

38 5 10 15 20 25 30 35 40 ABR Summary of Median ABRs in Patients with Inhibitors

N=14 N=14 Pre-Study Observation

• Median duration in observation period: 6 months [range: 1 –11]
• Mean AT activity in observation period (relative to baseline): 18%

Initial Evidence for Potential Restoration of Hemostasis in Severe Hemophilia A and B

DURABILITY

Monthly SC fixed dose regimen

2 12 1.7 2 4 6 8 10 12 14 PPx OD Pre-Study ABR Summary of Median ABRs in Patients without Inhibitors

• Median duration in observation period: 13 months [range: 2 –19]
• Mean AT activity in observation period (relative to baseline): 22%

N=7 N=12 N=19 Observation

Ongoing Study in Hemophilia A & B Patients, Including Inhibitors; Currently on Hold

PLANNED NEXT STEPS

ATLAS Phase 3 results

in mid-to-late 2019

Updated Safety in Phase 2 OLE (N=33):

• 3 SAEs considered possibly related to study drug
• Fatal cerebral venous sinus thrombosis resulting in suspension of dosing and evaluation of enhanced

• Asymptomatic transaminase elevation in HCV infected patient and seizure in patient with seizure history
• Majority of AEs mild or moderate in severity, unrelated to study drug
• Mild ISRs in 6 (18%) patients
• ALT increases >3x ULN observed in 11 (33%) patients
• All asymptomatic, with no concurrent elevations of bilirubin >2x ULN
• Reversible; all patients had medical history of HCV
• No instances of anti-drug antibody formation

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• Adults and adolescents

with hemophilia A or B with inhibitors

• Currently manage bleeds

with on-demand bypassing agent therapy

• N~50

2:1 9 months fitusiran 9 months

• n-demand BPA

Primary Endpoints:

• ABR†

Secondary Endpoints:

• Spontaneous ABR
• Joint ABR
• QOL (Haem-A-QOL)

OR

• Adults and adolescents

with hemophilia A or B with

• r without inhibitors
• Currently manage bleeds

prophylactically

• N~100

7 months fitusiran 6 months PPX factor/BPA

• Adults and adolescents

with hemophilia A or B without inhibitors

• Currently manage bleeds

with on-demand (OD) factor replacement therapy

• N~100

2:1 Patients who complete the study may be eligible for fitusiran treatment in ATLAS-OLE study 9 months fitusiran 9 months

• n-demand factor

OR Primary Endpoints:

• ABR‡

Secondary Endpoints:

• Spontaneous ABR
• Joint ABR
• QOL (Haem-A-QOL)

Primary Endpoints:

• ABR in factor/BPA

and fitusiran period Secondary Endpoints:

• Spontaneous ABR
• Joint ABR
• QOL (Haem-A-QOL)

Fitusiran ATLAS Phase 3 Program

Initiated in July 2017; Currently on Hold*

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Acute Hepatic Porphyrias

Givosiran

Rose

Living with Porphyria

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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

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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 ALAS1 upstream of genetic defect

Up-regulation

• f ALAS1

Accumulation of toxic intermediates ALA and PBG

• 20
• 40

Givosiran for Acute Hepatic Porphyrias

Potential to Prevent Debilitating Attacks

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Givosiran Interim Phase 1 Study Results*

PLANNED NEXT STEPS

Phase 3 Interim Analysis

in mid-2018

DURABILITY

Monthly and possibly quarterly SC dose regimen

Initial Evidence for Clinical Activity in Recurrent Attack Porphyria Patients

FDA Breakthrough and EMA PRIME Designations

Cohort 1, Givosiran – Patient 3 Treatment Run-in

• 100
• 50

Safety: Generally well tolerated (N=9)

• No drug-related SAEs and no discontinuations due to AEs
• As reported previously, one patient developed acute pancreatitis complicated

by pulmonary embolism resulting in death, considered unlikely related to study drug

• Majority of AEs mild-moderate in severity
• AEs possibly related include ISRs, hypersensitivity, myalgia, headache,

moderate renal impairment (in patient with history of same), and erythema

• No clinically significant changes in vital signs, EKG, or clin labs

Ongoing Randomized, Double-Blind, Placebo-Controlled Study in Recurrent Attack Porphyria Patients

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N ~ 74 Patient Population

• Age ≥ 12 years
• Diagnosis of AHP
• ≥ 2 attacks within

prior 6 months

• Willing to

discontinue and/or not initiate hemin prophylaxis

1:1 RANDOMIZATION

Givosiran SC QM 2.5 mg/kg 6 months Placebo SC QM 6 months Primary Endpoint:

• Attacks requiring

hospitalization, urgent care visit, home IV hemin

Key Secondary Endpoints:

• ALA and PBG
• Hemin doses
• Symptoms
• QoL

OR

Open- Label Extension

Statistical Considerations

• 70 patients will have at least 90% power to detect 45% reduction in

annualized attack rate at 2-sided alpha of 0.05

• Unblinded interim analysis in 30 patients using endpoint of reduction in

urinary ALA level at 3 months

➢ No plan to stop early for efficacy or futility Interim analysis when 30 patients complete 3 months treatment - mid-2018 interim readout, supporting potential NDA at or around YE 2018 (if positive); potential FDA approval early-to-mid 2019

Global Footprint

Plan to conduct Phase 3 in ~22 countries

Givosiran Phase 3 Study Design; Plan to Initiate in Late 2017

Randomized, Double-Blind, Placebo-Controlled Study, Followed by Open-Label Extension

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Interim Analysis in Givosiran Phase 3 Study

If Positive, Supports Potential NDA at or Around YE 2018

Alignment with FDA that reduction of urinary ALA is reasonably likely to predict clinical benefit

• Interim analysis with ~30 patients after 3 mo dosing; expect data in mid-2018

Relationship of ALA Lowering with Annualized Attack Rate* ALA Lowering in Phase 1, Part C at 2.5 mg/kg qM

Annualized Attack Rate

Urinary ALA (mmol/mol creatinine)

Time, Days

• 120
• 90
• 60
• 30

ULN

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Other Clinical Programs to Watch

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Other Clinical Programs to Watch

PLANNED NEXT STEPS FOR INCLISIRAN:

Start Phase 3 Study

in late 2017

Inclisiran for Hypercholesterolemia*

51%

mean LDL-C lowering at Day 180 after two quarterly doses1

Cemdisiran for Complement-Mediated Diseases

Sustained control

• f disease hemolysis

with up to

67%

reduction in eculizumab dose in PNH patients2

• No SAEs, no discontinuations due to

• 1 AE of hemolysis in setting of URI;

• 1 AE of asymptomatic, transient grade 3

• No drug-related SAEs, no discontinuations

• Two patient deaths due to MI and stroke,

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

Up to

8-fold

increase in plasma glycolate in healthy volunteers3

ALN-GO1 for Primary Hyperoxaluria 1 (PH1)

• No SAEs, no discontinuations due to AEs
• All AEs mild or moderate, with exception
• f one subject with transient,

RECENT ACTIVITY FOR ALN-GO1:

First PH1 Patient Dosed

in March 2017

PLANNED NEXT STEPS FOR CEMDISIRAN:

Report Phase 2 aHUS Data

in late 2018

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Samantha

Regulatory Affairs, Alnylam

Guidance and Goals

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Fitusiran Patisiran Givosiran

Building commercial capabilities to prepare for upcoming product launches

• Patisiran in U.S., Canada, and Western

Europe

• Fitusiran co-develop/co-commercialize

in U.S., 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

~2018-2020

Transition to Potential Commercialization

Planned Rapid Launch Succession

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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

Alnylam 2017 Pipeline Goals

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Financial Summary and Guidance

2017 Q2 Financial Results

• Cash $1.25B
• Includes $355.2M of net proceeds from the May 2017 public offering
• Includes $21.4M of proceeds from Sanofi Genzyme’s purchase of common stock
• Includes $150.0M in restricted investments
• GAAP Revenues $15.9M
• Total GAAP Operating Expenses $136.4M
• Research and Development Expenses $90.6M
• General and Administrative Expenses $45.8M
• GAAP Net Loss $118.4M
• Non-GAAP Net Loss* $94.4M
• Shares Outstanding 91.7M

2017 Guidance

• Year-end cash >$1.0B
• Includes $150.0M in restricted investments

* Non-GAAP net loss excludes stock-based compensation expenses.

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Thank You