Living with hATTR Amyloidosis - Alnylam ATTR Amyloidosis (Familial amyloidosis with polyneuropathy, or FAP) Mário Corino da Costa Andrade1906-2005. First large report on the disease

1

LeoLiving with hATTR Amyloidosis

Overview of Transthyretin amyloid (ATTR) amyloidosis

Ole B Suhr, Professor, M.D.Department of Publich Health andClinical MedicineUmeå University and University HospitalUmeå, Sweden.

Hereditary ATTR Amyloidosis(Familial amyloidosis with polyneuropathy, or FAP)

Mário Corino da Costa Andrade1906-2005. First large report on the disease

Brain 1952;75: 408-27First Swedish case. Andersson R, Kassman T. Acta Ophthalmol (Copenh) 1968; 46: 441-7.

Araki S et al. 1968 Arch Neurol. Chic) 18:593(picture courtesy of Ando Y)

In search of the protein (1980)

Amyloid and amyloidosis, 1980, Pavoa Vasim, Portugal

1. Tawara S. et al. Biochem Biophys Res Commun 1983; 116: 880-8. 2. Saraiva MJ et al. J Lab Clin Med 1983; 102: 590-603. 3. Connors LH et al. Amyloid 2003; 10: 160-84. 4. Westermark P et al. Proc Natl Acad Sci U S A 1990; 87: 2843-5. Hawkins et al. Ann Med 2015;47:625–38

Hereditary forms oftransthyretin amyloidosis (more than 130 mutations described)3

Senile systemic amyloidosis4

wild type TTR

Transthyretin (prealbumin)1,2

Produced by the liver (brain, eye).

» Nervous

– Autonomic-somatic neuropathy

– Central nervous symptoms

» Cardiac

– Arrhythmia

– Cardiomyopathy

» Gastrointestinal

» Kidney

» Eyes

» Misc: Charcot joint, carpal tunnel syndrome

Pictures courtesy of: Andersson R,Westermark P, and Ando Y.

Symptoms of disease

Case report» Woman of African descent

» At the age of 33 breast cancer, operated, recurrence at the age of 36, re-operated. Heart enlargement noted

» At the age of 39, onset of diarrhea, nausea, and vomiting, nutritional problems receive an endoscopic gastro-enterostomy. Develops faecal incontinence

» At the age of 41, disabling pain and progressive neuropathy

» At the age of 42, cardiac arrest, resuscitated by husband, receives a pacemaker.

» Biopsy: TTR-amyloidosis

» Gene testing: Ala45Gly

Evaluation at our centre:

» Positive bone scintigraphy for amyloidosis.

» Wheelchair bound, advanced autonomic neuropathy

» Adrenal insufficiency

» Too advanced disease for Tafamidis treatment

Bone-scintigraphy/CT

Treatment:

Does not tolerate Diflunisal

Heart/liver transplantation

discussed, but dies after a

new cardiac arrest at the age

of 42

Survival estimated to between 3 and 15 years from onset of symptoms

Swiecicki PL et al. Amyloid 2015;22: 123-31. Sattianayagam et al. Eur Heart J 2012; 33:1120-7. Benson MD et al. Am J Cardiol 2011; 108: 285-9. Connors LH et al. Am Heart J 2009; 158: 607-14. Kyle RA et al. Am J Med 1996;395–400. Ng B et al. Arch Intern Med 2005;165:1425–9.

Predominantly

heart

complications Predominantly

nerve

complications

Steady increase of new mutations in the Swedish population

(10 mutations during the last 10 years); likely related to increased disease awareness

Country ~ Number of Cases of hATTR with Polyneuropathy

USA 32002

Portugal 20003

Sweden 2503

Rest of EU-27 45004

Brazil >6005

Japan 4006

Estimated 10-15,000 afflicted patients worldwide1

Epidemiology of hATTR Amyloidosis with Polyneuropathy

Suggested pathway for amyloid formation1, and possible treatments

1. Halt production of circulating mutant TTR: Liver transplantation2

2. Decrease production of circulating TTR: Gene silencing3,4

3. Stabilise the TTR tetramer: Diflunisal, Tafamidis 5,6

4. Removal of Amyloid deposits: antibodies, Doxycycline 7,8

TTR-tetramer

Misfolded monomers

Full length TTR

B-fibrils1, 2 3

4

1. Hammarstrom P et al. Science 2003; 299: 713-6. 2. Holmgren G et al. Clin Genet 1991; 40:242-62. 3. Ackermann et al. Amyloid 2012;19(S1):43–4; 4. Coelho et al. N Engl J Med 2013;369:819–29. 5. Berk et al. JAMA 2013;310:2658–67. 6. Coelho T. et al. Neurology 2012; 79: 785-92. 7. Richards DB et al. N Engl J Med 2015; 373: 1106-14. 8. Cardoso I. et al. FASEB J2006; 20: 234-9.

None of the available treatments address CNS or eye complications

Factors related to amyloid fibril formation

» Concentration of amyloidogenic protein. The amyloid fibril formation process is concentration dependent1

» Mutant protein decreases stability2

» Age:

– Decreased efficacy of the immune system: antibody formation against misfolded protein3

– Decreased efficacy of housekeeping system for misfolded proteins4

1. Lachmann HJ et al. N Engl J Med 2007; 356: 2361-71. 2. Hammarstrom P et al. Science. 2003;299(5607):713-6.3. Obayashi K et al. Clin Chim Acta. 2013;419:127. 4. Santos SD et al. Journal of neuropathology and experimentalneurology. 2008;67(5):449-55

Importance of the concentrationof the amyloidogenic protein:

Regression of amyloidAA-amyloidosis

Henning Waldenströn, Acta Chir Scandinavia VolLXIII (1928)

From the department of surgical tuberculosis at St. Göran's Hospital, Stockholm, Sweden

Case III

Liver sizeOutline by ink

16/3 -25+++ hist.

1/4 -253% Proteinuria

1. Liver transplantation for ATTR amyloidosis

» Why perform liver transplantation and exchange a healthy liver?

– To decrease - eliminate the production of the amyloidogenicmutated transthyretin.

First liver transplanted ATTR amyloidosis patient.

Holmgren G et al. Clin Genet 1991; 40: 242-62.

Mutant TTR

0.

25.

50.

75.

100.

0. 5. 10. 15. 20.

Patient surv

ival (%

)

All TTR mutations (n=2044)

0.

25.

50.

75.

100.

0. 3.75 7.5 11.25 15.

Patient surv

ival (%

)

Years after transplantation

Val30Met - Early onset

Val30Met - Late onset

Non-Val30Met - Early onset

Non-Val30Met - Late onset

n=1342

n=170

n=109n=81

Ericzon BG et al. Transplantation 2015; 99: 1847-54.

3. TTR Stabiliser: Tafamidis/Diflunisal

Tafamidis trial: Efficacy in per

protocol analysis, but deterioration

on group level with time.

Efficacy only shown for ATTR

Val30Met amyloidosis patients in

stage I (walking without support)1,2,3.

Tafamidis is not approved in the US

Diflunisal trial: efficacy over 24

months demonstrated in a Phase

3 study, but deterioration noted in

treated patients. Long-term

outcome unknown. Not indicated

for hATTR amyloidosis

1. Coelho T et al. Neurology 2012; 79: 785-92. 2.

Coelho T et al.. J Neurol 2013; 260: 2802-14. 3.

Waddington Cruz M et al. Amyloid 2016; 23: 178-

83. 1 Berk JL et al JAMA 2013; 310: 2658-67.

Lack of efficacy of current treatments? additionalpathways for ATTR formation?

TTR-tetramer

Proteolytic clea-vage at residues46, 49 and 52

AmyloidogenicN-terminal fragment

A-fibrils

B-fibrils

Kelly JW et al. Adv Protein Chem 1997; 50: 161-81. Hammarstrom Pet al. Science2003; 299: 713-6. Thylen C et al. EMBO J 1993; 12: 743-8. Bergstrom J et al. Lab Invest 2004; 84: 981-8. Ihse E et al. Amyloid 2013; 20: 142-50. Mangione PP et al. Proc Natl Acad Sci U S A 2014; 111: 1539-44.

Misfolded monomersFull length TTR

The majority of ATTR amyloidosis patients currently without

effective treatment, a considerable unmet medical demand

Conclusions

» Currently, only a minor proportion of patients have a mutation/disease stage/phenotype that is suitable for available treatments

» Decrease production of the amyloidogenic protein (TTR), a promising therapeutic method that appears not to depend on amyloid formation pathways.

» However, no treatments are able to depress the amyloid formation caused by local TTR production in the eye or brain

Thank You!

20

Patisiran

Akshay K. Vaishnaw

Executive Vice President, R&D and Chief Medical Officer

21

Hereditary ATTR Amyloidosis (hATTR)

DESCRIPTION

Orphan disease caused by

mutant transthyretin (TTR)

amyloid deposits in nerves,

heart, gastrointestinal tract,

and other tissues

hATTR Amyloidosis with

polyneuropathy

10,000

hATTR Amyloidosis with

cardiomyopathy

40,000

Significant morbidity and fatal within

2-15 years from

symptom onset

PATIENT POPULATION*

~50,000worldwide

* Ando et al., Orphanet J Rare Dis, 2013; Ruberg et al., Circulation, 2012

22

Hereditary ATTR Amyloidosis with Polyneuropathy

Photos courtesy of Yukio Ando (Japan)

Inexorably Progressive Fatal Disease

Stage 1 Stage 2: Early Stage 2: Late Stage 34-5 yrs 2-3 yrs 1-2 yrs

23

Patisiran: Simple Approach to Treating a Complex DiseaseShutting Off Production of Disease-Causing Protein

Production of mutant and

wild type TTR

Neuropathy, cardiomyopathy

Organ deposition of monomers,

amyloid (β-pleated) fibril

Unstable circulating TTR

tetramers

Neuropathy, cardiomyopathy

stabilization or improvement

Organ deposition of monomers,

amyloid (β-pleated) fibril

prevented, clearance

promoted

Unstable circulating TTR

tetramers reduced

23

Patisiran acts to knock down both

mutant and wild type TTR production

Liver transplantation stops

mutant TTR production

Tafamidis stabilizes

TTR tetramer

24

Patisiran Phase 2 OLE Study Design

Timelines are not to scale

hATTR-PN 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

25

Patisiran Phase 2 OLE Preliminary Study Results*Serum TTR Knockdown

• Mean serum pre-dose TTR knockdown of approximately 80%

• Mean serum TTR knockdown at 24 months of 84%

• Mean maximal serum post-dose TTR knockdown of 93%

• Maximal individual patient post-dose knockdown of 97%

• Similar TTR knockdown in patients on patisiran alone or on patisiran + TTR tetramer stabilizers

SEM: Standard Error of the Mean

*Suhr et al., ISA, July 2016; Data as of 12May2016

Me

an

(S

EM

) %

Se

rum

TT

R K

no

ck

do

wn

Rela

tive

to

Bas

eli

ne

100

80

60

40

20

0

Months0 2 4 6 8 10 12 14 16 18 20 22 24 26

Post-dose

Pre-dose

N=24-27 at all other time pointsN=21

N=22

N=23

26

Patisiran Phase 2 OLE Preliminary Study Results*Change in mNIS+7 Over 24 Months


mN

IS+

7

0

25

50

75

100

125

150

Months

0 6 12 18 24

mNIS+7 component

Change from Baseline to Month 24 (N=24)

Mean (SEM) Median (range)

Total+ -6.7 (2.3) -6.8 (-34.6, 15.4)

NIS-weakness 1.38 (1.5) 0 (-13.5, 24.4)

NIS-reflexes -0.1 (0.5) 0 (-6.0, 7.0)

QST -7.7 (2.2) -6.0 (-40.0, 16.0)

NCS Σ5 -0.2 (0.2) -0.3 (-2.0, 2.5)

Postural BP -0.1 (0.1) 0 (-1.0, 0.5)

+Partial imputation was used to recover mNIS+7 data points where components were missing at one or more

replicate measurements (per patient/visit)

27

Patisiran Phase 2 OLE Preliminary Study Results*Change in mNIS+7 Over 24 Months


mN

IS+

7

0

25

50

75

100

125

150

Months

0 6 12 18 24

mNIS+7 component

Change from Baseline to Month 24 (N=24)

Mean (SEM) Median (range)

Total+ -6.7 (2.3) -6.8 (-34.6, 15.4)

NIS-weakness 1.38 (1.5) 0 (-13.5, 24.4)

NIS-reflexes -0.1 (0.5) 0 (-6.0, 7.0)

QST -7.7 (2.2) -6.0 (-40.0, 16.0)

NCS Σ5 -0.2 (0.2) -0.3 (-2.0, 2.5)

Postural BP -0.1 (0.1) 0 (-1.0, 0.5)

+Partial imputation was used to recover mNIS+7 data points where components were missing at one or more

replicate measurements (per patient/visit)

28

Me

an

Δm

NIS

+7

fro

m b

as

eli

ne

at

24

mo

s

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

Patisiran Phase 2 OLE Preliminary Study Results*

SEM: Standard Error of the Mean

~ Assessments drawn from studies in patients with similar baseline neurologic impairment and not based on head-to-head studies1Adams D et al., Neurology. 85;675-682 (2015); #Predicted progression of median NIS value from Gompertz curve fit1

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


Change in mNIS+7 at 24 Months

17 out of 24 patients (71%) with no change or an improvement in

mNIS+7 at 24 months compared to baseline

Individual ΔmNIS+7 at 24mos in Patisiran Ph 2 OLE

Me

an

(S

EM

) Δ

mN

IS+

7 f

rom

ba

se

lin

e a

t 2

4m

os

~-35

-30

-25

-20

-15

-10

-5

0

5

10

15

Natu

ral H

isto

ry

(no

nli

ne

ar;

N=

28

3)1

#

Diflunisal

Ph 3 Study2+

//

Pla

ce

bo

(N=

66

)

Dif

lun

isa

l

(N=

64

)

//

Mean ΔmNIS+7 Across

hATTR Studies at 24 mos~

25.8

(9.4)

29.6

(3.1)

9.2

(2.7)

-6.7

(2.3)

20

25

30

Patisiran

Ph 2 OLE†*

(N=24)Worse

Better

29

Patisiran Phase 2 OLE Preliminary Study Results*

Note: three patients had missing D17 TTR: one was replaced by D7 and two replaced by D84.† Percent (%) TTR knockdown from baseline at Day 17 post-first dose of patisiran

*Coelho et al., ISA, July 2016; Data as of 12May2016

Correlation of TTR Knockdown with ΔmNIS+7

Percent (%) TTR KD†

Δm

NIS

+7

50 60 70 80 90 100

-30

-20

-10

0

10

20

30

40

r= -0.49 , p= 0.0099


Δm

NIS

+7

50 60 70 80 90 100

-30

-20

-10

0

10

20

30

40

r= -0.55 , p= 0.0029


Δm

NIS

+7

50 60 70 80 90 100

-30

-20

-10

0

10

20

30

40

r= -0.37 , p= 0.055


Δm

NIS

+7

50 60 70 80 90 100

-30

-20

-10

0

10

20

30

40

r= -0.31 , p= 0.15

6 months (N=27)

12 months (N=27)

18 months (N=27)

24 months (N=24)

30

Mean

(S

EM

) C

han

ge F

rom

Baselin

e

-1.0

-0.50.00.5

1.01.5

2.0

2.5

3.03.5

4.0

4.55.05.5

6.0

6.57.0

Months0 6 12 18 24

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Patisiran Phase 2 OLE Preliminary Study Results*Sweat Gland Nerve Fiber Density (SGNFD): Lower Limb

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

• Statistically significant increase in distal thigh SGNFD at 12, 18, and 24 months and

distal leg SGNFD at 24 months

• In a separate study in hATTR polyneuropathy patients with highly pathogenic A97S

mutation,1 SGNFD correlated to autonomic system involvement and disability burden

Distal thigh sweat gland innervation†

in Patient 010-0004

†Green: PGP 9.5 (nerve fibers)Red: CD31 (blood vessels)

Blue: DAPI (nuclei)

1Chao C et al., Ann Neurol. 78:272-83 (2015)‡2-sided p values from paired t-test comparing post-baseline vs baseline


Distal Leg (meters/mm3)

Distal Thigh (meters/mm3)

N=19

P = 0.0072‡

N=20

P < 0.001‡

N=21N=18

N=19

N=24

N=24

N=22

N=18

P = 0.0041‡

N=17

P = 0.0070‡

Baseline

24months

50 microns

50 microns

31

Patisiran Phase 2 OLE Preliminary Study Results*Summary of Safety and Tolerability

• 6 patients (22.2%) with 9 reports of serious adverse

events (SAEs); 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

• Majority of AEs were mild or moderate

◦ 4 patients (14.8%) had severe AEs not related to study drug

◦ Most common related AEs reported in > 3 patients were

flushing (6 patients [22.2%]) and infusion related reaction

(5 patients [18.5%]), all of which were mild

• No clinically significant changes in liver function tests,

renal function, or hematologic parameters, including

platelets

Common Adverse Events (AEs) in

≥10% of patients

AE by Preferred Term Patisiran (N=27)

Flushing 7 (25.9%)

Diarrhea 6 (22.2%)

Nasopharyngitis 6 (22.2%)

Urinary tract infection 6 (22.2%)

Vomiting 6 (22.2%)

Wound 6 (22.2%)

Infusion related reaction 5 (18.5%)

Nausea 5 (18.5%)

Insomnia 4 (14.8%)

Neuralgia 4 (14.8%)

Pyrexia 4 (14.8%)

Anemia 3 (11.1%)

Bronchitis 3 (11.1%)

Edema peripheral 3 (11.1%)

Macular degeneration 3 (11.1%)

Musculoskeletal pain 3 (11.1%)

Osteoporosis 3 (11.1%)


32

APOLLO Phase 3 Study DesignEnrollment Complete

All completers eligible for patisiran treatment on Phase 3 OLE study (APOLLO-OLE)

Enrollment completed; mid-2017 data readout, supporting 2017 NDA/MAA if positive

Clinicaltrials.gov # NCT01960348

N=225

Patient Population

• hATTR: any

TTR mutation,

Stages 1 and 2

• Neurological

impairment score

(NIS) of 5-130

• Prior tetramer

stabilizer use

permitted

2:1

RA

ND

OM

IZA

TIO

N

Patisiran IV

q3W

0.3 mg/kg

Placebo IV

q3W

Primary Endpoint at

18 months

• mNIS+7

Key Secondary

Endpoints

• Norfolk QOL-DN

• NIS-weakness

• mBMI

• 10-meter walk

OR

APOLLO DMC met October 7, 2016 at Company’s request and

recommended continuing Phase 3 study of patisiran in patients

with hATTR amyloidosis without modification

33

APOLLO Patisiran Phase 3 Study

†Represents 57 different mutations, including GLU-89-GLN (n=13); THR-60-ALA (n=13); ALA-97-SER (n=15);

SER-50-ARG (n=8); as well as numerous other mutations with <5 patients per group

*Adams et al., ISA, July 2016; Data as of 01 March 2016

Baseline Demographics

Characteristic Result

Number of patients N=225

Median age, years (range) 62 years (24-82)

Gender, n (%) males 167 (74)

Race, n (%)

Asian 51 (23)

Black/African or African American 6 (3)

White / Caucasian 162 (72)

Other/Missing 6 (3)

Previous tetramer stabilizer use, n (%) 119 (53)

mBMI, kg/m2 x albumin [g/dL] 978.7 (522.1-1530.0)

Patients with cardiac involvement, n (%) 122 (54)

Mean NT-proBNP, ng/L (range) 1461 (40-7895)

Mean troponin, ng/mL (range) 0.1 (0.1-1.0)

LV wall thickness, cm (range) 1.67 (1.3, 2.6)

Ejection fraction (range) 60.6 (31.8, 82.4)

Characteristic Result

TTR genotype, n (%)

V30M 95 (42)

nonV30M* 130 (58)

FAP Stage, n (%)

1 104 (46)

2 119 (53)

3 2 (1)

PND Score, n (%)

I 57 (25)

II 65 (29)

IIIA 63 (28)

IIIB 38 (17)

IV 2 (1)

Neuropathy Impairment Scores, mean (range)

mNIS+7 78.8 (8.0-165.0)

NIS 59.3 (6.0-141.6)

34

Patient Advocacy & Scientific Leadership

• Initiation of Expanded

Access Program (EAP)

• Numerous pre-clinical

and clinical investigator-

initiated studies to date

(IIS)

• 15 primary abstracts and

publications since 2013

• Attendance at >30

congresses and >2000

peer engagements

• Symposia and facilitation

of dialogue among

specialists to increase

awareness of disease

burden

• Implementation of

Alnylam Assist to help

improve diagnosis rateso Free third-party genetic

screening and

counseling programs

o >900 individuals tested

over past 2 years

• Invited to attend >25

patient meetings over

past 2 years

Patient Advocacy Education Collaboration

35

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

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

access (e.g., not reimbursed in UK)

◦ Some patients receiving tafamidis may experience worsening of symptoms, often within

first year of treatment

◦ Multiple studies that document

disease progression during

tafamidis treatment

• Orthotopic liver transplantation (OLT)

use declining worldwide

◦ Generally limited to younger patients

with V30M mutation

◦ Involves significant risks and may still

result in disease progression

• Few investigational therapies in

clinical development

Cortese et al. Study Results

N 61

Baseline NIS-LL 28 ± 5

Month 6 +4.5 (62% of patients)



Cortese A. J Neurol. 2016 Mar 16;

Randomized controlled trial in 61 patients with hATTR Amyloidosis

NIS-LL = neuropathy impairment score-lower limb

36

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 QOL secondary endpoints

• Ongoing support for programs to improve diagnosis rates and enable earlier intervention

~50,000 patients WW

• Some mutations

endemic to certain

regions

• Often misdiagnosed

due to heterogeneity of

disease

◦ Variable disease

penetrance, age of

onset, symptoms at

presentation, and

comorbidities1. Based on Rapezzi et al. Eur Heart J 2013;34:520–8; Semigran et al. J Am Coll Cardiol 2016;68:173–75

Predominantly Neurologic Predominantly Cardiac

hATTR Amyloidosis

V30MEarly onset

S77Y E89L

S50R

G47A

E89Q

V30MLate onset

I68L

L111M

T60A

H88RI107V V122IF33L

F64L W41L

A36P

37

Patisiran Program Summary & Next Steps

Current therapies for hATTR Amyloidosis insufficient to meet patient needs; unmet medical need remains

• Progressive sensorimotor and autonomic neuropathy, cardiomyopathy; often fatal within 10 years

• Primary treatment option is liver transplantation

• No approved therapies in US

• Published evidence of disease progression on TTR stabilizers

Phase 2 OLE continues to provide preliminary evidence of acceptable safety profile and clinical activity at 24 months

APOLLO Phase 3 Ongoing

• Phase 2 Open-Label Extension (OLE) study has completed; majority of patients rolled onto APOLLO-OLE study

• APOLLO top-line expected in mid-2017; results in late 2017

• Assuming positive outcome, NDA/MAA filings expected year-end 2017

Preparing for commercialization following approval in US, Canada, Western Europe

• Preparing for ROW commercialization with Sanofi Genzyme following ROW approvals

Documents

Living with hATTR Amyloidosis - Alnylam ATTR Amyloidosis (Familial amyloidosis with polyneuropathy, or FAP) Mário Corino da Costa Andrade1906-2005. First large report on the disease