Patisiran and ALN-TTRsc02, Investigational RNAi ... · for the Treatment of Hereditary Transthyretin-Mediated (hATTR) Amyloidosis ... (IND or CTA Filed-Phase 2) ... tests vs baseline

LeoLiving with hATTR Amyloidosis

Patisiran, an Investigational RNAi Therapeutic

for the Treatment of Hereditary Transthyretin-

Mediated (hATTR) Amyloidosis

Thursday, August 3, 2017

2

Agenda

Welcome• Joshua Brodsky, Associate Director, Investor Relations and Corporate Communications

Introduction• Eric Green, Vice President, General Manager, TTR Program

Path to Diagnosis• Dr. Michael Polydefkis, M.D., Director, Cutaneous Nerve Lab, Professor of Neurology,

Johns Hopkins University School of Medicine

Overview of Disease and Patisiran Data• Jared Gollob, M.D., Vice President, Clinical Research

Commercial Opportunity and Preparation• Eric Green, Vice President, General Manager, TTR Program

Q&A Session

3

Reminders

Event will run for approximately 75 minutes

Q&A Session at end of presentation

• Submit questions at top of webcast screen

• Questions may be submitted at any time

Replay, slides and transcript available at www.alnylam.com

4

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

our 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

others 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

5

Agenda







Q&A Session

6

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

7

HUMAN POC* EARLY STAGE(IND or CTA Filed-Phase 2)

LATE STAGE (Phase 2-Phase 3)

REGISTRATION/

COMMERCIAL

COMMERCIAL

RIGHTS

PatisiranHereditary ATTR

Amyloidosis ● US, Canada,

Western Europe

FitusiranHemophilia and Rare

Bleeding Disorders ●50%

US, Canada,

Western Europe

Inclisiran Hypercholesterolemia ● Milestones &

Royalties

GivosiranAcute Hepatic

Porphyrias ● Global

ALN-CC5Complement-

Mediated Diseases ● Global

ALN-GO1Primary

Hyperoxaluria Type 1 ●Subject to

partner option

rights

ALN-TTRsc02Hereditary ATTR

Amyloidosis ●Subject to

partner option

rights

ALN-HBVHepatitis B Virus

Infection ● Global

Focused in 3 Strategic Therapeutic Areas (STArs):

Genetic Medicines

Cardio-Metabolic Diseases

Hepatic Infectious Diseases

Alnylam Clinical Development Pipeline

As of July 2017

*POC, Proof of concept - defined as having demonstrated target gene knockdown and/or additional evidence of activity in clinical studies

8

HUMAN POC* EARLY STAGE(IND or CTA Filed-Phase 2)

LATE STAGE (Phase 2-Phase 3)

REGISTRATION/

COMMERCIAL

COMMERCIAL

RIGHTS

PatisiranHereditary ATTR

Amyloidosis ● US, Canada,

Western Europe

FitusiranHemophilia and Rare

Bleeding Disorders ●50%

US, Canada,

Western Europe

Inclisiran Hypercholesterolemia ● Milestones &

Royalties

GivosiranAcute Hepatic

Porphyrias ● Global

ALN-CC5Complement-

Mediated Diseases ● Global

ALN-GO1Primary

Hyperoxaluria Type 1 ●Subject to

partner option

rights

ALN-TTRsc02Hereditary ATTR

Amyloidosis ●Subject to

partner option

rights

ALN-HBVHepatitis B Virus

Infection ● Global

Focused in 3 Strategic Therapeutic Areas (STArs):

Genetic Medicines

Cardio-Metabolic Diseases

Hepatic Infectious Diseases

Alnylam Clinical Development Pipeline

As of July 2017

*POC, Proof of concept - defined as having demonstrated target gene knockdown and/or additional evidence of activity in clinical studies

9

Alnylam ATTR Amyloidosis Portfolio*

Committed to Continued Innovation for Patients

hATTR amyloidosis

• IV administration

• Phase 2 completed

• Phase 2 Open-Label Extension

(OLE) study completed

• Phase 3 trial ongoing;

fully enrolled with top-line results

expected in mid-2017

• APOLLO-OLE study ongoing

• Expanded Access Protocol (EAP)

ongoing in the US

patisiran ALN-TTRsc02

ATTR amyloidosis• ESC “second generation”

chemistry

• Expect clamped TTR knockdown

with very low volume, quarterly SC

dose regimen

• Phase 1 ongoing; initial data

presented Dec’16

*In October 2016, Alnylam decided to discontinue development of revusiran, which used STC “first

generation” GalNAc chemistry and was being developed for treatment of hATTR with cardiomyopathy

10

Agenda







Q&A Session

11

hATTR Amyloidosis: Genotypic–Phenotypic Presentation

• >120 amino acid substitutions have been reported in patients with hATTR amyloidosis1

• Presentation can vary by TTR mutation, but mixed phenotype is commonly reported2,3

Phenotype

V30MEarly onset

S77Y

C10R

S50R

G47A

E89Q V30MLate onset

I68L

L111M

T60A

H88R

I107V

V122I

F33L

F64L

W41L

A36P

Neurologic Cardiac

Patients with polyneuropathy may also

present with, or develop, cardiomyopathy

Patients with cardiomyopathy may also

present with, or develop, polyneuropathy

1. Rowcenzio et al. Hum Mutat 2014;35:E2403–122; 2. Rapezzi et al. Eur Heart J 2013;34:520–8;

3. Semigran et al. J Am Coll Cardiol 2016;68:173–75

12

Multiple symptoms of hATTR amyloidosis can complicate

diagnosis

Diagnosis of ATTR amyloidosis is often delayed

Wide variety of symptoms mean underlying cause is hard to detect2

For many patients diagnosis can take years1

83%

35%

42%

30%

23%

71%

75%

SENSOIMOTOR INVOLVEMENT

CARPAL TUNNEL SYNDROME

GI PROBLEMS

DIZZINESS

URINATION PROBLEMS

ECHOCARDIOGRAPHIC ABNORMALITIES

ECG ABNORMALITIES

Symptoms at presentation (n=186)3

ECG, electrocardiogram

1. Adams et al. Curr Opin Neurol 2012;25:564–572; 2. Hanna. Curr Heart Fail Rep 2014;11:50–57;

3. Rapezzi et al. Eur Heart J 2013;34:520–528

13

Path to Diagnosis

22PCP

5Neuro

2

Cardiologist

18ATTR MD

1

Eye Doctor

✓DX

18

2

1

XMisDx

1

6

7

21

2

2

PCP

5Neuro

✓DX

1

4

1

2

Gastroenterologist

2

2

Cardiologist

1

1

2

Orthopedist

2

XMisDx

2

9ATTR

MD

2

5

1

9

12

1

1

Geneticist1

1

1

Vascular

1

1

1

Oncologist

1

Surgeon

1

1 2

Neurologist

1

1

2

Cardiologist1

8ATTR

MD

✓DX

8

3

1

1

1

111

Urologist

1

Neurologist

1

Geneticist

2

Surgeon

✓

1

Surgeon

Surgeon

1 ✓

✓

9

1

Gastroenterologist

1

Neurologist1

ATTR

✓

45JOURNEYS

Long patient odyssey for majority

of patients despite family history

14

Potential Diagnostic Criteria for Confirmation of hATTR

Amyloidosis

Onset of symptoms

and/or signs

Family history

Genetic testing

Changes in physiologic

tests vs baseline

Biopsy evidence of

amyloid

Assessments to support diagnosis of hATTR amyloidosis1,2

Confirmation of diagnosis is by TTR genotyping3 alone or with tissue biopsy4

1. Adams et al. Rev Neurol (Paris) 2016;172:645–52; 2. Ruberg & Berk. Circulation 2012;126:1286–300;

3. Obici et al. Curr Opin Neurol 2016;29(Suppl 1):S27–35; 4. Adams et al. Curr Opin Neurol 2016;29 (Suppl 1):S14–26

15

“Red Flag” Symptom Cluster Recommended for hATTR

Amyloidosis Presenting With Polyneuropathy

Progressive

symmetric

sensory motor

neuropathy

Family history

Early autonomic dysfunction

GI complaints

Unexplained weight loss

Cardiac hypertrophy, arrhythmias,

ventricular blocks, or cardiomyopathy

Renal abnormalities

Vitreous opacities

≥1 of

Additional alert signs:• Rapid disease progression

• Lack of response to prior therapies

Based on Conceição et al. J Peripher Nerv Syst 2016;21:5–9

16

“Red Flag” Symptom Cluster Recommended for hATTR

Amyloidosis Presenting With Cardiomyopathy

Evidence of

right-sided

heart failure

Thick interventricular septum,

“speckled” myocardium by Echo

Low/decreasing QRS voltage on ECG

Subendocardial late gadolinium

enhancement by CMRI

Heart failure with preserved ejection

fraction (without hypertension)Hypotension in

person with

previous

hypertension

or

Sensory involvement,

autonomic dysfunction

CMRI, cardiac magnetic resonance imaging; ECG, electrocardiogram; Echo, echocardiography

Based on Dharmarajan & Maurer. J Am Geriatr Soc 2012;60:765–74

≥1 of

Family history

Additional alert signs:• Intolerance of commonly used

cardiovascular medication

Bilateral carpal tunnel syndrome

17

74 year old woman without significant past medical history

• 4 years prior: presents to GI physician with complaint of diarrhea

• Physical exam: physician notes a murmur and refers to a cardiologist

• Continued work-up

• Echocardiogram: suggestive for amyloid

• Fat pad biopsy: amyloid

• Genetic testing: transthyretin Thr60Ala variant

“Stopped seeing physicians, they had nothing to offer”

• Currently:

• Well controlled class II heart failure

• Progressive peripheral neuropathy that limits daily function (NIS = 42)

Case 1: “The Serendipitous Diagnosis”

18

Case 2: “Family History”

63 year old man who enjoyed excellent health

• 3 years prior: knee pain, stopped refereeing hockey games

• Underwent a TKR but did not recover as expected

• 2 years prior: Foot infection requiring IV antibiotics

• Toe amputation

• Noticed numbness in his feet and shortly thereafter his hands.

• 1 year prior: Difficulty with fine motor tasks (buttoning shirt)

• Difficulty walking up stairs - stair lift installed

• Neurologist: Dx: advanced sensorimotor neuropathy– Patient’s father had been seen a decade earlier with an unexplained progressive neuropathy.

He spent the last few years of his life in a nursing home with severe impairment.

He died ~8 years after symptom onset.

• Continued work up:

• Patient underwent a nerve biopsy: amyloid

• Genetic testing: V30M

• NIS = 101

19

Case 3: “Evolving Diagnostic Tools”

A 59-year-old athletic, former Division-1 athlete • 2 years prior: lagging behind during a family outing

• 1.5-years prior: mild foot drop was noted

• 8 months prior: difficulty walking on uneven ground, difficulty maintaining balance on his bike

• Previous evaluation: • B12, TSH, SPEP/IFE

• Athena sensorimotor neuropathy (GM1, GALOP, MAG, Hu, sulfatide) and CMT genetic panels)

• A1C = 6.5%

• Dx: Diabetic polyneuropathy

• 2-year history of ED and tendency towards constipation

• Continued work up:• PE: bilateral foot drop; NIS=84

• NCV: Sural responses absent; ↓ Peroneal and tibial CMAP (0.5-1.0mV) with ↓ CV (34-36m/s).

• Median & ulnar motor responses and EMG: normal

} all negative

20

Biopsy Results

↓ IENFD, SGNFD

Case 3: “Evolving Diagnostic Tools,” continued

21

Biopsy Results

↓ IENFD, SGNFD

Congo red staining:

• Dermal staining with birefringence

• Amyloid Arrector pili


22

Biopsy Results

↓ IENFD, SGNFD

Congo red staining:



Nerve / muscle bx


23

Biopsy Results

↓ IENFD, SGNFD

Congo red staining:



Nerve / muscle bx

Genetic testing

• hATTR: Leu58His

• No previously known family history


24

Biopsy Results

↓ IENFD, SGNFD

Congo red staining:



Nerve / muscle bx

Genetic testing

• hATTR: Leu58His

• No previously known family history

Conclusions:

• First case of hATTR diagnosed by skin bx

• hATTR can be variable: no pain, little dysautonomia


25

• hATTR has a heterogeneous presentation

◦ Diagnosed in their 50’s, 60’s and 70’s

◦ Presenting with GI, cardiac and peripheral nerve manifestations

◦ Tissue diagnosis by fat pad biopsy, nerve biopsy and skin biopsy.

• Amyloid deposition in the skin correlates with axon loss

• Amyloid burden in skin biopsy correlates with disability

Conclusions

26

Agenda







Q&A Session

27

CNS Manifestations

• Progressive dementia

• Headache

• Ataxia

• Seizures

• Spastic paresis

• Stroke-like episodes

GI Manifestations

• Nausea and vomiting

• Changes in GI motility (i.e., diarrhea, constipation,

gastroparesis, early satiety)

• Unintentional weight loss

Autonomic Neuropathy

• Orthostatic hypotension

• Recurrent urinary tract infection

(due to urinary retention)

• Sexual dysfunction

• Sweating abnormalities

Peripheral Sensory-Motor Neuropathy

• Neuropathic pain

• Altered sensation (i.e., change in sensitivity to pain and temperature)

• Numbness and tingling

• Muscle weakness

• Impaired weakness

• Difficulty walking

Carpal tunnel syndrome

Ocular Manifestations

• Vitreous opacification

• Glaucoma

• Abnormal conjunctival vessels

• Papillary abnormalities

Nephropathy

• Proteinuria

• Renal failure

Cardiac Manifestations

• Conduction block

• Cardiomyopathy

• Palpitations and arrhythmia

• Mild regurgitation

• Shortness of breath

• Edema

GI, gastrointestinal


hATTR Amyloidosis: A Multisystemic Disease

28

hATTR Amyloidosis Spectrum of DiseaseGenotype-Phenotype Association

Neurologic Cardiac

Patients with polyneuropathy may also

present with, or develop, cardiomyopathy

Patients with cardiomyopathy may also

present with, or develop, polyneuropathy

Based on Rapezzi et al. Eur Heart J 2013;34:520–8; Semigran et al. J Am Coll Cardiol 2016;68:173–75

hATTR Amyloidosis

Predominantly Neurologic Predominantly Cardiac

V30MEarly onset

F33L S50R A36P E89Q I107V H88R L111M V122I

S77Y E89L G47A F64LV30M

Late onset W41L T60A I68L

• Orphan multi-system disease caused by mutant transthyretin (TTR) amyloid

deposits in nerves, heart, GI tract, and other tissues

• Range of clinical presentations including neuropathy and cardiomyopathy,

with most patients having a mixed presentation of symptoms

29

Patients with

polyneuropathy

aka

Familial amyloidotic

polyneuropathy

(FAP)

Historical Nomenclature of hATTR Amyloidosis

hATTR amyloidosis previously described by predominant clinical manifestation

However, many patients present with, or develop, concurrent cardiac and

neurologic impairments, such that FAP and FAC terminology can be misleading

Cardiac wall thickening, atrial arrhythmias,

conduction disease, heart failure

Sensory neuropathy, motor neuropathy,

autonomic dysfunction (eg, GI events)

Patients with

cardiomyopathy

aka

Familial amyloidotic

cardiomyopathy

(FAC)

Mohty et al. Arch Cardiovasc Dis 2013;106:528–40; Conceição et al. J Peripher Nerv Syst

2016;21:5–9; Shin et al. Mt Sinai J Med 2012;79:733–48

30

Amyloid Polyneuropathy: Clinical Manifestations

Photos courtesy of Alejandra Gonzalez Duarte (Mexico), Isabel Conceicao (Portugal) and

David Adams (France)

Sensory Loss and

Thermal Burns Muscle Weakness and Wasting

Joint

Damage

“Mal dos pesinhos”

31

Assessment of Polyneuropathy in hATTR Amyloidosis:

Neuropathy Impairment Scores

mNIS+7

(304 points)

Motor strength/

weakness

(192)

Reflexes (20)

QST (80)

Σ 5 NCS (10)

Postural BP (2)

NIS

(244 points)

Motor strength/

weakness

(192)

Reflexes (20)

Sensation (32)

Hig

he

r s

co

re in

dic

ate

s w

ors

en

ing

of

dis

ea

se

NIS-LL

(88 points)

Motor strength/

weakness

(64)

Reflexes (8)

Sensation (16)

NIS+7

(270 points)

Motor strength/

weakness

(192)

Reflexes (20)

Sensation (32)

Σ 5 NCS (18.6)

VDT + HRdb (7.4)

Motor strength/

weakness

(192)

Reflexes (20)

Σ 5 NCS (18.6)HRdb (3.7)

mNIS+7Ionis

(346.3 points)

0

350

QST (80)

Sensation (32)

BP, blood pressure; VDT, vibration detection threshold

Adams et al. Neurology 2015;85:675–82; Suanprasert et al. J Neurol Sci 2014;344:121–8; Dyck et al. Muscle Nerve 2017.

Jan 7 [Epub ahead of print]

32

Multiple Assessments Are Needed to Fully Capture the

Multisystemic Burden of hATTR Amyloidosis

Motor function

• NIS-weakness (upper and

lower limb, cranial nerves)

• 10-meter walk test

• Grip strength

Nutritional status

• mBMI

Cardiac changes

• Echocardiogram

• Cardiac biomarkers

(NT-proBNP, troponin)

QoL and physical functioning

• Norfolk-DN QoL

• EQ-5D

Autonomic symptoms

(GI symptoms, postural

hypotension)

• COMPASS-31

Disease Pathophysiology

• Nerve fiber density

• Amyloid burden

Ambulation changes

• FAP Stage / PND Score

Activity and social functioning

• R-ODS

These additional clinical assessments can help to understand the full impact of the disease

on the patient and enhance measurement of disease response to novel therapeutics

33

Assessment of Quality of Life (QoL) in hATTR Amyloidosis:

Norfolk QoL-DN Questionnaire

35-item patient-reported questionnaire with 5 question domains:

• Activities of daily living, physical functioning/large-fiber neuropathy,

small-fiber neuropathy, autonomic neuropathy, and symptoms

• Maximum impairment: 138

In hATTR amyloidosis with polyneuropathy, significant correlation between Norfolk total

QoL score and disease stage, disease duration, NIS, and nerve-fiber function1,2

Healthy

volunteers

Stage I, independent ambulation; Stage 2, assistance required when walking; Stage 3, wheel-chair or bed bound

1. Vinik et al. J Peripheral Nerv Syst 2014;19:104–14; 2. Coehlo et al. Muscle Nerve 2017;55:323–32

0

20

40

60

80

100

120

Healthyvolunteers

(n=16)

Stage I(n=29)

Stage 2(n=16)

Stage 3(n=16)

Me

an

un

its

Mean total QoL scores across disease stages2

0

10

20

30

40

50

HV Stage 1 Stage 2 Stage 3

Me

an

un

its

Individual domain scores across disease stages1

Physicalfunctioning/large-fiber neuropathyADL

Symptoms

Small-fiberneuropathy

Autonomicneuropathy

Activities of

daily living

34

Assessment of Everyday Functioning:

Rasch-built Overall Disability Scale (R-ODS)

24-item patient-reported outcome instrument

• Has been used to measure activity and social participation limitations in patients

with Guillain–Barré syndrome, CIDP, and gammopathy-related polyneuropathy1

• No limitations: 48

Patients with hATTR amyloidosis reported difficulty performing

everyday activities2 including:

Washing

dishes

Fastening

buttons

Turning key

in a lock

Moving a

chair

Walking

~0.5 miles

CIPD, chronic inflammatory demyelinating polyradiculoneuropathy

1. Van Nes et al. Neurology 2011;76:337–45; 2. Patient voice survey for patients with ATTR amyloidosis, presented at

ATTR/Familial Amyloidosis Support Meeting, 2015 Supported by the Amyloidosis Foundation and Amyloidosis Support Groups

35

Patisiran Phase 2 OLE Study Design

Timelines are not to scale

hATTR amyloidosis patients previously dosed on Phase 2 trial eligible to roll over

onto Phase 2 OLE study

• Up to 2 years of dosing, 0.30 mg/kg every 3 weeks, with clinical endpoints evaluated every 6

months

• Primary objectives: Safety and tolerability of long-term dosing with patisiran

• Secondary objectives: Effects on neurologic impairment (mNIS+7 and NIS), quality of life, mBMI,

disability, mobility, grip strength, autonomic symptoms, nerve fiber density in skin biopsies, cardiac

involvement (in cardiac subgroup), serum TTR levels

W1 W2 W3

Adverse events

Serum TTR levels

mNIS+7, other

clinical measures

W1 W2 W3 W1 W2 W3

every 6 months

Cardiac biomarkers

d 0, 1, 3, 7, 17, 84, 168, 182, 231, 234…

0

0

0

0

W1 W2 W3 W1 W2 W3

Echo

d 0 (baseline)

d 0 (baseline)

d 0 (baseline)

every 3 months

every 6 months

OLE

Dose 1

OLE

Dose 2

OLE

Dose 3

OLE

Dose 4

OLE

(out to 2 years)

Patisiran dosing:

0.30 mg/kg IV q3w

36

• 7 patients (25.9%) with 10 reports of serious adverse

events (SAE); not related to study drug

◦ One discontinuation for gastroesophageal cancer at ~20

months; patient subsequently died

◦ One death due to myocardial infarction after patient completed

24 months of treatment

◦ One patient with 3 reports (distal femur fracture/proximal tibia

fracture/osteonecrosis/ligament rupture, dehydration/acute

prerenal failure/urinary tract infection and thermal burn)

◦ One patient with 2 reports (ankle fracture/foot fracture/

osteonecrosis and ankle arthrodesis)

◦ One patient with venous thrombosis of the lower limb

◦ One patient with foot abscess and osteomyelitis

◦ One patient with pacemaker implantation due to amyloid

cardiomyopathy

• Majority of AEs were mild or moderate

◦ 5 patients (18.5%) had severe AEs not related to study drug

◦ Related AEs reported in ≥4 patients were infusion related

reaction (22.2%) and flushing (22.2%), all of which were mild

• No clinically significant changes in liver function tests,

renal function, or hematologic parameters, including

platelets

Adverse Events (AE) reported in

≥10% of patients

AE by Preferred Term Patisiran (N=27)

Flushing 7 (25.9%)

Diarrhea 6 (22.2%)

Infusion related reaction 6 (22.2%)

Nasopharyngitis 6 (22.2%)

Urinary tract infection 6 (22.2%)

Vomiting 6 (22.2%)

Wound 6 (22.2%)

Nausea 5 (18.5%)

Insomnia 4 (14.8%)

Neuralgia 4 (14.8%)

Pyrexia 4 (14.8%)

Anemia 3 (11.1%)

Bronchitis 3 (11.1%)

Cataract 3 (11.1%)

Infusion site extravasation 3 (11.1%)

Edema peripheral 3 (11.1%)

Macular degeneration 3 (11.1%)

Musculoskeletal pain 3 (11.1%)

Osteoporosis 3 (11.1%)

Patisiran Phase 2 OLE Final Study Results

Summary of Safety and Tolerability

Adams et al. Neurology 2017; 88:16 Supplement S27.004

37

Δm

NIS

+7

fro

m b

as

eli

ne

to

Mo

nth

24

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

Me

an

(S

EM

) Δ

mN

IS+

7 f

rom

ba

se

lin

e a

t 2

4 m

os

~

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

Natu

ral H

isto

ry

(no

nli

ne

ar;

N=

28

3)#

Diflunisal

Ph 3 Study+

//

Pla

ce

bo

(N=

66

)

Dif

lun

isa

l

(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)

Mean 7.0-point decrease in mNIS+7 at 24 months

20 out of 27* patients (74%) with no change or an improvement in

mNIS+7 at month 24 compared to baseline

SEM: Standard Error of the Mean; *One patient discontinued prior to the Month 24 assessment and is included in the denominator

~Assessments drawn from studies in patients with similar baseline neurologic impairment and not based on head-to-head studies

#Predicted progression of median NIS value from Gompertz curve fit (Adams D et al. Neurology. 2015;85;675-682)

+Linear interpolation from 2-year NIS progression measurement in longitudinal analysis set (Berk JL et al. JAMA. 2013;310:2658-67)

^Patisiran results similar in patients with/without concurrent TTR stabilizer therapy; mNIS+7 using full mNIS+7 set; partial imputation was used to recover mNIS+7 data

points where components were missing at one or more replicate measurements (per patient/visit)


Individual ΔmNIS+7 at Month 24 (n=26)


Change in mNIS+7 at 24 Months

38

Median Relative Change from Baseline

in Dermal Amyloid Burden

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)

IQR, Interquartile Range; †1 patient excluded due to baseline value of 0

and a non-zero post-baseline value

Baseline

24 months

Distal thigh dermal amyloid

burden‡ in patient

‡Red: Amyloid by Congo red staining

-4.58* -4.27

-8.01*

-3.81*

-7.23*

-9.48*-10.71*

-6.38*

-15

-10

-5

0

Distal Thigh(Baseline amyloid burden (n=24): 10.9%)

Distal Leg(Baseline amyloid burden (N=24): 15.8%)

* P<0.05

Mean

Ab

so

lute

Ch

an

ge f

rom

Baselin

e in

Derm

al A

mylo

id C

on

ten

t, %

6 months 12 months 18 months 24 months

N=22

N=18

N=20

N=20

N=19

N=20

N=19

N=22

Mean Absolute Change from Baseline

in Dermal Amyloid Burden


TTR Amyloid Burden in Skin: Lower Limb

• Amyloid detected in ~80% of skin biopsies at baseline

• Dermal amyloid burden in 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


39

Sweat gland nerve fiber density (SGNFD): • Statistically significant increase in distal thigh at 6, 12, 18, and 24 months

and in distal leg at 24 months

Distal thigh sweat gland innervation†

†Green: PGP 9.5 (nerve fibers)Red: CD31 (blood vessels); Blue: DAPI (nuclei)

Scale: 50 microns; Patient: 010-0004

Baseline

24months

IENFD, Intraepidermal nerve fiber density; SGNFD, sweat gland nerve fiber density; SEM: Standard Error of the Mean

*2-sided p-values from paired t-test comparing post-baseline vs baseline

Adams et al. Neurology 2017; 88:16 Supplement S27.004 and Polydefkis, et al. J Peripher Nerv Syst 2017; Peripheral Nerve Society Meeting July

8–12, 2017 Sitges, Barcelona, Spain


Nerve Fiber Density: Lower Limb

Mean

(S

EM

) C

han

ge F

rom

Baselin

e

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0

Months

0 6 12 18 24

N=19

P=0.0072*

N=20

P=0.0008*

N=21N=18

N=19

N=24

N=24

N=22

P=0.0323*

N=20

P=0.0037*

N=19

P=0.0025*

Distal Leg (meters/mm3)

Distal Thigh (meters/mm3)

Sweat Gland Nerve Fiber Density (SGNFD): Change from Baseline

Intraepidermal nerve fiber density (IENFD):• Stable throughout the 2-year treatment period; mean change from baseline consistent from 6 through 24 months

IENFD (fibers/mm)

Baseline Δ Baseline to Month 24

N Mean (SD) N Mean (SEM)

Location: Thigh 24 10.2 (2.0) 20 -1.8 (0.6)

Location: Leg 24 3.5 (1.3) 19 -0.1 (0.4)

40

Phase 3 Study (APOLLO) of Patisiran

Phase 3 and OLE* Ongoing

(n=225)

Patient population

• hATTR amyloidosis:

any TTR mutation,

FAP Stage 1 or 2

• Neuropathy Impairment

Score (NIS) of 5–130

• Prior TTR tetramer

stabilizer use permitted

2:1

RA

ND

OM

IZA

TIO

N

Patisiran IV

infusion once

every 3 weeks,

0.30 mg/kg

Placebo IV

infusion once

every 3 weeks

Primary endpoint

• Change in mNIS+7 from baseline

at 18 months

Secondary endpoints

• Norfolk QoL-DN

• NIS-weakness

• Rasch-built Overall Disability

Scale (R-ODS)

• 10-meter walk test

• mBMI

• COMPASS-31

Exploratory endpoints

• EQ-5D QoL

• Grip strength

• Cardiac assessments

• Serum TTR levels

• Dermal amyloid burden and nerve

fiber density in skin

*Patients who complete the study may be eligible for patisiran treatment in Phase 3 OLE study (APOLLO-OLE; NCT01960348)

OR

18 monthsClinicaltrials.gov # NCT01960348

Statistical Considerations

• Placebo-estimated mNIS+7 progression rate of 17.8 points/year derived

from natural history study of 283 hATTR patients with polyneuropathy1

• 90% Power to detect as little as 37.5% difference in ΔmNIS+7 between

treatment groups with 2-sided alpha=0.05

• Based on original target enrollment of 200 patients

EQ-5D, EuroQoL 5-Dimensions questionnaire; IV, intravenous

Adams et al. ISA 2016 (Abs PA82)

41

Ionis Reported NEURO-TTR Phase 3 Topline Results

Statistically significant benefit observed for inotersen-treated patients as compared to placebo in both mNIS+7 and Norfolk QOL-DN endpoints at 15 months

• p<0.0001 and p=0.0006, respectively

• Statistically significant differences also observed for both endpoints at eight months

• Benefit in disease progression achieved regardless of TTR mutation and in both Stage 1 and Stage 2 patients

Key safety findings included thrombocytopenia and renal SAEs

• Three patients had SAEs of thrombocytopenia◦ Two patients recovered, and one patient died due to intracranial hemorrhage

◦ One additional patient discontinued inotersen treatment due to lower grade thrombocytopenia

• Four patients discontinued inotersen treatment due to renal observations◦ Two patients met a predefined renal stopping rule, and two experienced renal SAEs, one of whom

experienced chronic renal insufficiency

◦ One placebo-treated patient also met a predefined renal stopping rule

• Enhanced monitoring implemented during study to support management of these issues; Ionisanticipates that regulators will require safety monitoring in inotersen prescribing information if approved

• Treatment-emergent AEs considered related to treatment were seen more commonly with inotersen than placebo

• Detailed review of safety data ongoing

*Topline results from NEURO-TTR Phase 3 study of inotersen: http://ir.ionispharma.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=2272828

http://ir.ionispharma.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=2272828

42

ALN-TTRsc02 OpportunityPotential for Best-in-Class Profile

Revusiran*/Inotersen ALN-TTRsc02

52DOSES PER

YEAR4 DOSES PER YEAR

ANTICIPATED

Ongoing Study in Normal Healthy VolunteersMean max TTR KD of 97.1 ± 0.5%; >80% TTR KD at Day 90 after single 50 mg dose**

Safety: Generally well tolerated in healthy volunteers (N=48)

• No SAEs or discontinuations due to AEs; all AEs mild or moderate

• 9 AEs in 5 subjects considered possibly related to treatment; all mild

• ISRs reported in 2 subjects – symptoms mild and transient

• No clinically significant changes in physical exams or lab parameters

(e.g., LFTs)

Most potent

Alnylam

RNAi therapeuticto date

*Alnylam discontinued development of revusiran in October 2016

**Data cut-off 26Oct2016; reported at Alnylam R&D Day in December 2016

43

Me

an

[+

/- S

EM

] T

TR

Re

lative

to

Ba

se

line

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Days since first dose

0 40 80 120 160 200 240 280 320

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Cohort Placebo (N=20) TTRSC02 (5mg) (N=6)TTRSC02 (25mg) (N=6) TTRSC02 (Optional; 25mg) (N=6)TTRSC02 (Subjects of Japanese descent; 25mg) (N=6) TTRSC02 (50mg) (N=6)TTRSC02 (Optional; 50mg) (N=6) TTRSC02 (Subjects of Japanese descent; 50mg) (N=6)TTRSC02 (100mg) (N=6) TTRSC02 (200mg) (N=6)TTRSC02 (300mg) (N=6)

ALN-TTRsc02 Phase 1 Preliminary Study Results

Single Ascending Dose Study in Healthy Volunteers

• No SAEs and no discontinuations due to AEs

• All AEs mild or moderate in severity

◦ 14 AEs in 8 subjects considered possibly related to treatment; majority mild

◦ Events included injection site erythema, injection site pain, injection site bruising, rhinorrhea, pruritus, cough, nausea, fatigue, genital rash and abdominal pain

◦ No clinically significant changes in lab parameters, EKG or physical exam

As of data cutoff on 31May2017

44

Summary

• hATTR amyloidosis is a multisystemic disease with multiple different clinical manifestations of polyneuropathy, often accompanied by cardiac involvement, which could lead to progressive disability, diminished quality of life, and death

• Composite neuropathy impairment scores such as mNIS+7, along with additional clinical and biomarker endpoints, have the potential to demonstrate the clinical benefit of novel therapeutics in this disease

• The patisiran Phase 2 OLE study results suggest that TTR lowering has the potential to have a disease-modifying effect on the polyneuropathy in hATTR amyloidosis, as shown by the effects on mNIS+7, dermal amyloid burden, and sweat gland nerve fiber density

• The emerging results of randomized Phase 3 trials with patisiran and inotersen will further elucidate the utility of these and other endpoints in assessing the magnitude and clinical meaningfulness of the response to treatment

• ALN-TTRsc02 offers the potential of a best-in-class profile of quarterly, low-volume dosing with clamped knockdown of TTR

45

Agenda







Q&A Session

46

Key Targeted Milestones for Patisiran

APOLLO Data – Mid-’17

NDA / MAA Filed – Late’17

US / EU Launch – 2018

47

Alnylam to Commercialize in US / Canada / W.Europe

Collaboration with Sanofi Genzyme in Rest of World

Patisiran to be commercialized by Alnylam in its territories

Sanofi Genzyme

Alnylam

Note: Note to scale

Cambridge, MAMaidenhead, UK

Zug, Switzerland

48

hATTR Amyloidosis Market Landscape

Limited available therapies; no approved drugs that halt disease

progression and improve patient quality of life

• US: No approved drugs; limited use of diflunisal off-label

• EU: tafamidis approved for Stage 1 polyneuropathy patients only; limited access

(e.g., not reimbursed in UK)

Cortese et al.1

N 61

Baseline NIS-LL 28 ± 5

Month 6 +4.5 (62% of patients)



Randomized controlled trial in 61 patients with hATTR Amyloidosis

NIS-LL = neuropathy impairment score-lower limb

◦ Multiple studies that document disease

progression during tafamidis treatment1-5

• Orthotopic liver transplantation (OLT)

use declining worldwide6

◦ Generally limited to younger patients

with V30M mutation

◦ Involves significant risks and may still

result in disease progression

◦ Contraindicated for patients with

cardiomyopathy

• Few investigational therapies in

clinical development

1. Cortese A, et al. J Neurol 2016; 263:916-914; 2. Plante-Bordeneuve V, et al. J Neurol 2017; 264:268-76

3. Coelho T et al. Neurology 2012; 79:785-92; 4. Lozeron et al. Eu J Neurol 2013; 20:1529-54

5. Merlini G, et al. J Cardiovasc Transl Res 2010; 6:1011-20 6. Suhr O, et al. Transplantation 2016;100: 373–381

49

hATTRAmyloidosis

Predominantly Neurologic Predominantly Cardiac

V30MEarly onset

F33L S50R A36P E89Q I107V H88R L111M V122I

S77Y E89L G47A F64LV30M

Late onset W41L T60A I68L

hATTR Amyloidosis Market Opportunity

Patisiran has potential to address unmet medical needs

• Evidence for potential halting or improvement of neuropathy in Phase 2 OLE study

• APOLLO Phase 3 study will evaluate mNIS+7 and multiple secondary endpoints

~50,000 patients WW

• ~10,000 with predominant

polyneuropathy plus

~20%-30% of remainder

with mixed phenotype

• Some mutations endemic

to certain regions

1. Hawkins PN, et al. Ann Med. 2015;47 (8 ):625 ‐ 638; 2. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31;

3. Rapezzi C, et al. Eur Heart J. 2013;34 (7 ):520 ‐ 528; 4. Adams D, et al. The XVth International Symposium on

Amyloidosis. Uppsala, Sweden: ISA International Society of Amyloidosis; July 3 ‐ 7, 2016. PA 82; 5. Coelho T, et al.. Curr

Med Res Opin. 2013;29:63 ‐ 76

• Often misdiagnosed due to heterogeneity of disease

◦ Variable age of onset, disease penetrance, symptoms at presentation, and comorbidities

◦ Efforts underway to improve diagnosis rates and enable earlier intervention

Based on Rapezzi et al. Eur Heart J 2013;34:520–8; Semigran et al. J Am Coll Cardiol 2016;68:173–75

50

Succeeding in Rare Disease Requires a Specific Road Map

Engagement

and Advocacy

Educate

Access

Retain

Support and

Solutions

Best or First-in-Class

Product Profiles

RNAiTherapeutics

SuccessDiagnose

51

Digital Educational Initiatives

Recently launched two websites for disease education

https://hATTRamyloidosis.com/ https://hATTRbridge.com/

Health care professionals Patients and their families

https://hattramyloidosis.com/

https://hattrbridge.com/

52

Scientific Leadership and Education

• >20 primary abstracts and publications since 2013• Including manuscripts in New England Journal of Medicine, Neurology

and Orphanet Journal of Rare Diseases

• Attendance at >55 international, regional and

local congresses and ~4,000 peer

engagements

• Symposia and facilitation of dialogue among

specialists to increase awareness of disease

burden

53

Alnylam ActTM

No-charge third-party genetic testing and counseling program*

Individuals with a suspected diagnosis or a confirmed family history of

hATTR amyloidosis are eligible to take part in the

Genetic Screening performed by CLIA-certified

clinical diagnostic laboratory

• Three testing options now available via saliva or blood

◦ Neuropathy Panel

◦ Cardiomyopathy Panel

◦ Single TTR Gene Testing

Genetic counseling offered by a genetics services provider

• Counseling available before, during or after genetic testing

Exploring a supported diagnostic program in the EU

*Available in the United States Only

**Since program inception and as of July 22, 2017.

CLIA - Clinical Laboratory Improvement Amendments

At no time does Alnylam receive patient-identifiable information.

More information regarding

this program available at:

www.alnylamact.com

~2,000Tests

Submitted**

>300Accounts**

54

Patient Advocacy

Mutual goals of increasing awareness, enabling earlier diagnosis,

advancing the development of potential new therapies, and designing

initiatives that support the unique needs of patient communities

France Germany

Italy

United States

Spain

Sweden

Netherlands

Canada

2017 activities:

• Patient education: three educational webinars supported

• Initiatives that support the unique needs of patient communities: three Care Days hosted, in conjunction ThinkGenetic, across the US

• Advancing the development of potential new therapies:>25 Advocacy Support Meetings attended

• Collaboration with and support of a variety of patient support groups

55

CNS Manifestations

• Progressive dementia

• Headache

• Ataxia

• Seizures

• Spastic paresis

• Stroke-like episodes

GI Manifestations

• Nausea and vomiting

• Changes in GI motility (i.e., diarrhea, constipation,

gastroparesis, early satiety)

• Unintentional weight loss

Autonomic Neuropathy

• Orthostatic hypotension

• Recurrent urinary tract infection

(due to urinary retention)

• Sexual dysfunction

• Sweating abnormalities

Peripheral Sensory-Motor Neuropathy

• Neuropathic pain

• Altered sensation (i.e., change in sensitivity to pain and temperature)

• Numbness and tingling

• Muscle weakness

• Impaired weakness

• Difficulty walking

Carpal tunnel syndrome

Ocular Manifestations

• Vitreous opacification

• Glaucoma

• Abnormal conjunctival vessels

• Papillary abnormalities

Nephropathy

• Proteinuria

• Renal failure

Cardiac Manifestations

• Conduction block

• Cardiomyopathy

• Palpitations and arrhythmia

• Mild regurgitation

• Shortness of breath

• Edema

GI, gastrointestinal


hATTR Amyloidosis: A Multisystemic Disease

Gastroenterologists

Pathologists

Neuromuscular

specialists /

neurologists

Heart Failure Specialists

/ Cardiologists

Ophthalmologists

56

US Go-to-Market Strategy

US Expected to be Alnylam’s First Launch

Patisiran expected to enter a competitive US market in a disease state

with significant unmet need and low physician and patient awareness

Our stakeholder-facing teams will interact with a wide variety of

external stakeholders:

• Health Care Professionals and Office Staff

• Patients and Caregivers

• Advocacy Organizations

• Payers

Patisiran will be supported by a number of stakeholder-facing roles

with an overall footprint similar to current orphan disease products

• High coordination across the field-based teams and HQ-based Patient Services

57

Actively Building EU Teams and Infrastructure

Focusing on EU5, Plus Endemic Countries: Sweden and Portugal

Head of EU in place

Regional Support

• Market Access

• G&A

• Supply Chain

Country organizations

being built

• Country Manager

• Medical Affairs

• Sales and Marketing

• Local Market Access

58

2017*

Early Mid Late

PATISIRAN (hATTR Amyloidosis)

Phase 2 OLE data

APOLLO Phase 3 top-line

APOLLO Phase 3 results

NDA/MAA filing

Patisiran

Conclusions

hATTR amyloidosis is similar to other ultra-rare diseases:

• Difficult to find patients, who are often hidden among more common diseases increase disease

awareness and patient diagnosis

• Difficult to know true market opportunity until treatment options available and concerted efforts to educate

and treat patients are in place

Given Phase 2 OLE experience and recent inotersen efficacy data, we are encouraged

by the potential for positive APOLLO results in mid-2017

Alnylam is preparing for commercialization in our territories beginning in 2018,

assuming approvals by health authorities

Working closely with Sanofi Genzyme to enable the delivery of patisiran to patients

around the world

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

59

Agenda







Q&A Session

60

Upcoming RNAi Roundtables

Revusiran investigation results

• Wednesday, August 9, 12:30 pm ET

Platform advances in RNAi therapeutics

• Wednesday, August 23, 3:30 pm ET

Givosiran, in development for the treatment of acute hepatic porphyrias

• Thursday, September 7, 10:30 am ET

Fitusiran, in development for the treatment of hemophilia and rare

bleeding disorders

• Tuesday, September 12, 10:30 am ET

Additional details for upcoming RNAi Roundtables, including speakers, dates and times, will be

provided on the Capella section of the Company's website, www.alnylam.com/capella.

http://www.alnylam.com/our-science/capella/

LeoLiving with hATTR Amyloidosis

Thank you

Documents

Patisiran and ALN-TTRsc02, Investigational RNAi ... · for the Treatment of Hereditary Transthyretin-Mediated (hATTR) Amyloidosis ... (IND or CTA Filed-Phase 2) ... tests vs baseline