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1

ALN-AS1Investigational RNAi Therapeutic for the Treatment of

Acute Hepatic Porphyrias

Tuesday, September 13, 2016

2

Agenda

Welcome

• Josh Brodsky, Associate Director, Investor Relations & Corporate Communications

Introduction

• John Maraganore, Ph.D., Chief Executive Officer

Overview of the Acute Porphyrias

• Herbert L. Bonkovsky, M.D., Professor of Medicine, Wake Forest University

School of Medicine

AIP Patient Perspective

• Ariel Lager, patient living with Acute Intermittent Porphyria

Q&A Session

• With Dr. Bonkovsky and Ms. Lager

ALN-AS1 Program

• Bill Querbes, Ph.D., Associate Director, Research

Q&A Session

3

Reminders

Event will run for approximately 75 minutes

Q&A Sessions at end of presentation

• Submit questions at bottom of webcast screen

• Questions may be submitted at any time

Replay, slides and audio available at www.alnylam.com/roundtables

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

Welcome


Introduction




School of Medicine



Q&A Session


ALN-AS1 Program


Q&A Session

6

RNAi TherapeuticsNew Class of Innovative Medicines

Harness natural pathway

Catalytic mechanism

Silence any gene in genome

Upstream of today’s medicines

Clinically proven approach

7

Alnylam Strategic Therapeutic Areas (STArs)

Investigational pipeline focused in 3 STArs

Genetic Medicines

Cardio-Metabolic Diseases

Hepatic Infectious Diseases

RNAi therapeutics for rare diseases

RNAi therapeutics for dyslipidemia, NASH,

type 2 diabetes, hypertension, and other

major diseases

RNAi therapeutics for major liver infections

beginning with hepatitis B & D

8

Alnylam Development Pipeline

9

Alnylam Development Pipeline

10

Agenda

Welcome


Introduction




School of Medicine



Q&A Session


ALN-AS1 Program


Q&A Session

Copyright H Bonkovsky 11

Acute Porphyria 101

Herbert L. Bonkovsky, M.D.Professor of Medicine & Molecular Medicine and

Translational Science,Chief of Hepatology & Metabolic Disorders

Wake Forest Univ School of MedicineWinston-Salem, NC

Prof of MedicineUniv of CT Health Center, Farmington

and Univ of NC, Chapel [email protected]

Porphyrias- Definition

• Disorders of normal porphyrin and heme synthesis

• Mostly inherited—but with effects of drugs, nutrition, alcohol, other genetic variation

• Major clinical features: acute neurovisceral attacks or cutaneous photosensitivity

• Symptoms due to effects of ALA or porphyrins

• Most common are AIP, PCT, EPP12

Diseases Associated with Gene Mutations and/or

Deficiencies in Enzymes in the Heme Biosynthesis Pathway

13


Classification of PorphyriasAccording to major site of overproduction

• Hepatic porphyrias– Acute or inducible porphyrias – ALADP, AIP, HCP, VP

– Chronic hepatic porphyrias – PCT, HEP

• Erythropoietic porphyrias– Congenital erythropoietic porphyria - CEP

– Erythropoietic protoporphyria - EPP


Classification of PorphyriasAccording to major clinical features

• Acute Porphyrias– Acute or inducible porphyrias – ALADP, AIP, HCP, VP– Major features: attacks of neurovisceral pain, dysfct

• Cutaneous porphyrias– Porphyria cutanea tarda—most common—blisters,

vesicles, chronic lesions slow to heal– Congenital erythropoietic porphyria – severe

blisters; early onset– Erythropoietic protoporphyria – acute burning,

itching, pain—no blisters, vesicles

16

Metabolic Defects and Patterns of

Precursor Excretion in the Acute Porphyrias


Selected Features of the 4 Acute Porphyrias, Genes, Enzymes

Type Inherita

nce

Defic

Enz

Subcell

locatn

Enz

Activity

[% Nl]

Known

mutns

[n]

Gene

locus

OMIM #

AIP Autos

domin

PBGD

[HMBS]

Cytosol ~50 ~300 11q23.3 +17600

HCP Autos

domin

Coprog

oxidase

Mito ~50 ~50 3q12 +121300

VP Autos

domin

Protog

oxidase

Mito ~50 ~130 1q22 #176200

ALA-D

defic

Autos

recess

ALA-D

[PBG

Synth]

Cytosol ~5 ~8 9q34 +125270


Acute Intermittent PorphyriaEstimated Prevalence of Disease

• Depends upon country and region: founder effects

– Sweden 8-10/100,000

– Finland 2-3 /100,000

– UK & W Europe 2-5/ 100,000

– USA 2-5/100,000

Prevalence of genetic defects much higher, [~65/100,000] implying incomplete penetrance


Acute PorphyriasMajor Clinical Features

• Due to dysfunction or death of neurons

• Overlapping clinical syndromes

– Acute attacks – pain crises, autonomic disease

– Peripheral sensory-motor neuropathy

– Progression to trunkal, CN, global CNS dysfunction

• Subacute or chronic pain and paresthesias

• (Seizures)


Acute PorphyriasSymptoms in Patients Needing Hospitalization


Acute PorphyriasSigns in Patients Needing Hospitalization


Acute PorphyriasPrecipitating or Aggravating Factors

• Drugs and chemicalsAlcohol HydantoinsEstrogens BarbituratesSulfonamides ProgestagensOther inducers of hepatic cytochrome(s) P-450 + ALA synthase-1

• Luteal phase of menstrual cycle• Pregnancy and post-partum period• Fasting / starvation /s/p gastric bypass• Stress / exhaustion• Infection• Surgery / anesthesia


Acute PorphyriasLaboratory Features during Attacks

• CBC, Routine liver chems usually normal• WBC may be normal, low, or high• NC/NC anemia may occur• Low serum Na, Mg common• Glucose tolerance often impaired• Serum cholesterol, LDL, & serum hormone binding

proteins often increased– TBG– Sex steroid BP’s– Corticoid BP’s

• Urine ALA, PBG, uroporphyrin increased• Blood volume often decreased


Early Diagnosis of Acute Porphyria

• Consider in all adults with unexplained symptoms, especially women 18-45 y; recurrent abdominal pain; muscle weakness; hyponatremia; dark or reddish urine

• Establish diagnosis rapidly by qual test for PBG in a single-void urine [Hoesch, Watson-Schwartz,Trace PBG kit, Thermo Scientific—no longer available—unmet need]


Effect of Light and Air on Urine of

Some Patients with Biochemically Active AIP

Urine just passed Urine left on window sill 18 h


Pos Hoesch Test—Qual Test for PBG

1= Ehrlich’s reagent 2--1 + drops of urine 2—after mixing


Acute PorphyriasManagement of Acute Attacks

• Primum nil nocere: 1st do no harm– Avoid offending drugs, chemicals.

• Maintain nutrition, fluids

– Watch for hypo-natremia, -magnesemia & treat as necessary

– At least 300 g/d dextrose or similar

• Close watch for CNS involvement

– Progressive weakness

• For pain - meperidine, morphine, methadone +thorazine

• For hypertension – propranolol; lisinopril

Effect of IV Heme in first patient with AIP treated with heme

Bonkovsky et al. PNAS 1971:68:2725-2729

Rapid Down-Regulation of Plasma

ALA and PBG by IV Heme

Heme

0

50

100

150

0 2 4 6 16 18 20 22

DAYS

AL

A (

µg

/dl)

0

200

400

600

PB

G (

µg

/dl)

ALA (µg/dl)

PBG (µg/dl)

Heme

Heme

29


Acute PorphyriasHeme Therapy

• Adverse effects

– Obliterative thrombophlebitis

– Lowering of platelet count

– Inactivation of soluble clotting factors

• Adverse effects minimized by heme-albumin

• Some patients require weekly prophylactic infusions

• Secondary iron overload; headaches; myalgias; tachyphylaxis are problems

• Unmet need—alternative, additional therapies—RNAi has shown great promise

Am J Gastroent 1991; 86:1050Ann Int Med 2005; 142:439

Ann Int Med 2006; 144:537


Acute PorphyriasProphylaxis – Prevention of Attacks

• Avoid porphyrogenic drugs, chemicalsAlcoholic beverages BarbituratesEstrogens HydantoinsSulfa drugs ProgestagensOral contraceptives CYP inducers

• Avoid prolonged fasting, low carbohydrate or protein intake.

• Prompt, appropriate treatment of intercurrent illness.

• LHRH analogues – for women with frequent cyclical attacks related to menstrual cycle.

• Periodic infusions of heme—weekly, monthly, etc


AIP Increases Risk of Cirrhosis and Hepatocellular CarcinomaMarkedly Increased Risk of Development of HCC in Acute

PorphyriasData from France, 7 yr follow-up

Screen all patients with AIP over 40 y for cirrhosis & HCCNEJM 1998; 338:1853

Variable Men Women Total

No. of patients 303 347 650

No. of patient – years 1963 2246 4208

HCC

No. of cases (95% CI) 3 (0.6-8.8) 4 (1.1-10.2) 7 (2.8-14.4)

Crude Incidence Rate 1.5% 1.8% 1.7%

Expected No. of Cases 0.16 0.04 0.20

Odds Ratio (95%) CI 19 (4-55) 110 (30-281) 36 (14-74)

Soonawalla et al., Lancet 363: 705-706, 2004

19-year-old woman with

recurrent acute neurologic

attacks had an orthotopic liver

transplant.

Pre-LT:

37 Attacks over 29 Mos

Post-LT:

None for > 8 Years

PBG/Creatinine

Hr after Liver Transplant

µm

ol/

mm

ol

Cre

ati

nin

e

Urinary Excretion of ALA &

PBG after Liver Transplant

ALA/Creatinine

33

Liver Transplant as a Cure for AcuteIntermittent Porphyria

Copyright H Bonkovsky

Liver Transplantation for Acute Porphyria

• Performed mainly in Europe

• 10 cases in UK, 2000-2010. 5 with severe neurol features. None with cirrhosis or HCC. 7/10 had mod-severe hepatic siderosis due to chronic heme Rx

• All had complete clin and biochemresolution

• Rate of devel of hepatic artery thrombosis was high—4/10 [40%] vs ~ 3%

Liver Transpl 2011: 18:195

34

Summary

• Acute hepatic porphyrias—worldwide, panethnicproblem

• Low penetrance, but often devastating for the minority of patients, mostly women, with recurrent and severe attacks

• Induction of hepatic ALAS1 is key feature in pathogenesis

• RNAi therapeutic targeting of ALAS1 has been demonstrated

• New therapy—especially self-administration early in attacks or better prophylactic option for patients with recurrent attacks—major unmet needs

35

R. Desnick, PhD, MD Mount Sinai School of Medicine, NYC, NY

212-659-8779; [email protected]

K. Anderson, MD U of Texas Medical Branch, Galveston

409-772-4661;[email protected]

M. Bissell, MD U of California, San Francisco (UCSF)


J. Bloomer, MD U. of Alabama, Birmingham (UAB)


H. Bonkovsky, MD Wake Forest Univ, Winston-Salem, NC


J. Phillips, PhD U. of Utah, Salt Lake City


D. Lyon Howe American Porphyria Foundation

866-APF-3635. http://www.porphyriafoundation.com

http://rarediseasesnetwork.epi.usf.edu/porphyrias/

36

Porphyrias Consortium—PI’sAnderson Desnick Bonkovsky

Phillips Bissell Bloomer

39

Agenda

Welcome


Introduction




School of Medicine



Q&A Session


ALN-AS1 Program


Q&A Session

Living with AIP:

Patient Perspective Ariel Lager

September 13, 2016

40

AIP is a struggle: moment-to-moment and long-term

• About me

• My diagnosis

• After surgery

• Searching for answers

• Connecting with the APF

• Coming to terms

• Treatments

• Symptom management

• Hospitalization

• Limitations of current treatment options/gene therapy

• Managing my care (beyond attacks)

• Daily (chronic symptoms)

• Weekly (infusions)

• Monthly (hormone suppression)

• Yearly (liver scans, port maintenance and repair)

• Long-term health implications

41

• Attacks

• Life-threatening

• Debilitating

• Frightening

• Long-term Damage

• Nerve-damage

• Hormonal (bone density, cardiac risk)

• Weight fluctuation

• Pain/pain medication

• Systemic (iron, inflammation)

• Quality of Life

• Lost work

• Impact to family

• Unpredictability

• If I was healthy…

AIP is a struggle: moment-to-moment and long-term 42

43

Agenda

Welcome


Introduction




School of Medicine



Q&A Session


ALN-AS1 Program


Q&A Session

44

Agenda

Welcome


Introduction




School of Medicine



Q&A Session


ALN-AS1 Program


Q&A Session

45

ALN-AS1 Therapeutic Hypothesis

Brennan et al. Nature 1979, Hermes-Lima et al. Biochem Biophys Acta 1991, Dar et al., Hepatobiliary Pancreat Dis

Int.; 9:93-6 (2010), Dowman et al., Ann Intern Med; 154:571-2 (2011)

Targeting Liver ALAS1 to Lower Heme Intermediate Production

ALN-AS1

Targeting ALA Synthetase (ALAS1)

• ALAS1 is upregulated in patients due to

various attack triggers (e.g. drugs, fasting,

hormones) causing accumulation of ALA and

PBG upstream of enzyme defect

• ALN-AS1 utilizes GalNAc conjugate

technology with ESC chemistry

• Goal is to reduce ALAS1 levels and prevent

build up of toxic intermediates

• Potential to treat all acute hepatic porphyrias

including AIP, VP and HCP

Triggers

46

RNAi Therapeutic Targeting ALAS1Potential Use for Prophylaxis and Acute Treatment

ALAS1

mRNA

ALN-AS1Acute Attack Setting (Treatment)

Rapid

Suppression

Release of pathway

bottleneck

Quick reduction in

ALA/PBG

Rapid improvement in

clinical symptoms

Days Days

Months

ALAS1

mRNA

Months

ALN-AS1

Recurrent Attack Setting (Prophylaxis)

Blunted

Up-regulation

Mild chronic prophylactic

suppression will blunt

recurrent ALAS1

upregulation

Reduction in attacks,

heme use, and

hospitalizations

47

Importance of Liver ALAS1 and ALA/PBG in

Driving AHP Attacks

Evidence

• ALA/PBG are elevated during attack and

decrease to baseline with heme concurrent

with symptomatic improvement1

◦ Heme downregulates ALAS1 through feedback

• Liver and domino transplant2,3

◦ Elevated ALA/PBG and attacks disappear in AIP

patients and are induced in recipients of AIP

livers

• Rare HCC tumors that cause increased

ALA/PBG and AIP like symptoms4

◦ Cured by hepatoma excision

• Lead poisoning induces ALA increase and AIP

like symptoms by inhibiting second step in

pathway (ALAD)5

1Sardh et al. E J of Int Med; 20:201-7 (2009)2Dar et al., Hepatobiliary Pancreat Dis Int.; 9:93-6 (2010)3Dowman et al., Ann Intern Med; 154:571-2 (2011)4Ochiai et al. Brit J Derm; 136:129-131 (1997)5Friedman et al. NEJM; 370:1542-50 (2014)

Ref. 1

Ref. 3

48

ALN-AS1 Phase 1 Study: AIP patient populations

Asymptomatic High Excreters (ASHE)

• Persistently elevated ALA/PBG

• More clinically relevant than healthy volunteers

• Ability to measure key biomarkers

• Medically stable patient population for initial safety evaluation (studied in

prior enzyme replacement trial)

Recurrent attack patients

• Highest unmet medical need

• Evaluate safety and dose regimen in small subset of patients

Sardh et al. Clin Pharmacokinet;46(4):335-49.

49

ALN-AS1 Phase 1 Study: Design and Objectives

Parts A and B (SAD/MAD) in ASHE patients

Study Design• Randomized, single-blind, placebo-controlled single and multiple ascending dose study in ASHE patients Primary Objective• Safety and tolerability of ALN-AS1Secondary Objectives• Characterize ALN-AS1 pharmacokinetics (PK) and pharmacodynamics (PD), i.e. ALA and PBG loweringExploratory Objectives• Characterize circulating ALAS1 mRNA from the liver in urine and serum using a circulating RNA detection

(cERD) assay

Study Design

• Placebo-controlled multiple dose study in recurrent attacks patients

Primary Objective

• Safety and tolerability of ALN-AS1

Secondary Objectives

• Characterize ALN-AS1 PK and PD

Exploratory Objectives

• Clinical activity of ALN-AS1 on attack characteristics and treatment, and patient quality of life

• Characterize circulating ALAS1 mRNA from the liver in urine and serum

Part C (MD) in recurrent attack patients

50

*Attack definition: intense abdominal or back pain requiring hospitalization, heme use or treatment consisting of increased carbohydrate

intake or pain medication

ALN-AS1 Phase 1 Study: Key Eligibility Criteria

Part A and B Inclusion

• Male or female, ages 18-65 years

• Acute intermittent porphyria (AIP), with genetic diagnosis of HMBS mutation

• Urine PBG > 4 mmol/mol creatinine at screening

Part A and B Exclusion

• Attack* within 6 months of screening

• Heme use in past 6 months

• Subjects with new prescription medication regimen within 3 months of screen

Part C Only Inclusion

• Experienced at least 2 porphyria attacks in past 6 months or on heme prophylaxis to

prevent attacks

• If on heme prophylaxis, willing to stop during study

51

ALN-AS1 Phase 1 Study Progress

0.10 mg/kg x 1 SC, N=4

Part A: Single-Ascending Dose (SAD) │ Randomized 3:1, Single-blind, Placebo-controlled in ASHE

0.035 mg/kg x 1 SC, N=4

0.35 mg/kg x 1 SC, N=4

1.0 mg/kg x 1 SC, N=4

Run-in Observation

(1 to 6 months)

Part C: Multiple-Dose (MD) │ Randomized 3:1, Double-blind, Placebo-controlled in AIP patients with recurrent attacks

Cohort 3 N=4

1.0mg/kg, qMx2 SC, N=4

Part B: Multiple-Ascending Dose (MAD) │ Randomized 3:1, Single blind, Placebo-controlled in ASHE

0.35 mg/kg, qMx2 SC, N=4

*The 0.035 mg/kg SAD cohort was dosed after the

0.10 and 0.35 mg/kg cohorts

Cohort 1 N=4

Cohort 2 N=4

2.5 mg/kg x 1 SC, N=4

ongoing

52

ALN-AS1 Phase 1 Study Part A and Part B Demographics and Baseline Disease Characteristics

Part A and B

Characteristic Result

Number of Patients N=23* (ALN-AS1:Placebo=21:7)

Median Age (range) 47 years (30-64)

Gender 18 Females, 5 Males

Race n 22 White/Caucasian

1 Asian

Genotype (n) 8 different mutations identified**:• HMBS_593G>A (13)

• HMBS_87+1G>A (4)

• HMBS_499-1G>A (1)

• HMBS_517C>T (1)

• HMBS_647G>A (1)

• HMBS_847_848delTG (1)

• 673C>T variant exon 11(1)

• Exon 3 shift IVS3+1G>T(1)

Mean baseline ALA (range) 11.0 mmol/mol Cr (2.9-24.6) ^

Mean baseline PBG (range) 22.0 mmol/mol Cr (4.5-50.5) ^

^Upper Limit of Normal: ALA <3.9 or 3.8 mmol/mol Cr; PBG < 1.6 or 1.5

mmol/mol Cr depending on site

Biorad assay performed at Porphyria Centers in Sweden and UK

*5 subjects had >1 treatment assignment: 2 subjects repeated Part A; 3 subjects enrolled in Part A and Part B

** 3 mutations added to database post data cut and W198X collapsed into HMBS_593G>A

Data in database as of 28 Jun 2016

Sardh et al., SSIEM, September 2016

53

Part A (SAD) and Part B (MAD) Safety and Tolerability

ALN-AS1 was generally well-tolerated in Parts A and B of Study ALN-AS1-001

No drug-related SAEs or discontinuations due to AEs• Two SAD subjects (0.035 and 0.10 mg/kg dose groups) were hospitalized for SAE of “abdominal pain”. Both

events were assessed as unlikely related to ALN-AS1 by the investigators

• One MAD* subject (1 mg/kg dose group) experienced a miscarriage 7 weeks post-conception (90 days post-ALN-AS1) during the extended follow-up period which was assessed as unlikely related by the investigator

SAD: Total of 49 AEs reported (10 AEs in 5 PBO subjects; 39 AEs in 11 ALN-AS1 subjects)• All AEs were mild or moderate in severity with the exception of one severe AE of abdominal pain (same subject

noted above with SAE at 0.10 mg/kg dose).

• AEs reported in 2 subjects were abdominal pain, diarrhea, and hypoesthesia

• 8 related or possibly related AEs were reported in 5 subjects ◦ Diarrhea, dyspepsia, hematochezia, hypoesthesia, injection site erythema, injection site pain, decreased GFR and elevated Cr

• Injection site reactions (erythema and pain) were seen in 2 subjects–both mild and transient

MAD: Total of 29 AEs reported (4 AEs in 1 PBO subject; 25 AEs in 6 ALN-AS1 subjects)• All reported AEs were mild or moderate in severity

• AEs reported in 2 subjects were nasopharyngitis and rash

• 8 related or possibly related AEs were reported in 3 subjects◦ Pruritus only (1 subject), rash only (1 subject) and pruritus and rash (1 subject)

• No injection site reactions were reported

No clinically significant changes in vital signs, EKG, clinical laboratory or physical examination

ALN-AS1 Phase 1 Study Interim Results

*All safety data in database as of 28 Jun 2016 with the exception of the MAD SAE which was as of 03 Sept 2016


54

Circulating Extracellular RNA Detection (cERD) Method for Circulating ALAS1 mRNA Detection

Monitoring RNAi Activity in Liver mRNA or 5’RACE product in tissue

Circulating secreted protein target

Detection of Circulating ALAS1 mRNA Exosomes are shed into bodily fluids from many

different cell types and contain mRNA and miRNAderived from tissue of origin

Exosomes can be used to monitor ALAS1 mRNA after ALN-AS1 dosing in serum/urine without a biopsy

0

20

40

60

80

100

120

PBS 1.25 2.5 5.0

ALAS-GalNAc

(mg/kg)N

orm

ali

ze

d

AL

AS

-1

by cERD

by liver biopsy

AS1 Transcript

QDx5, EOD, d15 (not DC)

Sehgal et al. RNA 2012, Chan et al. MTNA 2015

55

ALN-AS1 Phase 1 Study Interim ResultsSAD Pharmacodynamic Data: Serum ALAS1 mRNA by cERD

ALAS1 mRNA induced approximately 3-fold in ASHE compared to normal healthy volunteers

Rapid, dose-dependent, and durable ALAS1 mRNA lowering after single dose

• 64 ± 1% mean (SEM) maximal reduction in 2.5 mg/kg dose group

• Remaining ALAS1 mRNA levels after highest dose similar to levels in normal healthy individuals

P<0.0001

Me

an

[+

/-S

EM

] A

LA

S1

mR

NA

Lo

we

rin

g

Re

lati

ve

to

Ba

se

lin

e (

%)

80

70

60

50

40

30

20

10

0

-10

-20

-30

Days since first dose

0 5 10 15 20 25 30 35 40 45

90

100

Normal healthy individualSAD Placebo (N=5) 0.035 mg/kg ALN-AS1 (N=3) 0.10 mg/kg ALN-AS1 (N=3)

0.35 mg/kg ALN-AS1 (N=3) 1.0 mg/kg ALN-AS1 (N=3) 2.5 mg/kg ALN-AS1 (N=3)



56

ALN-AS1 Phase 1 Study Interim ResultsSAD Pharmacodynamic Data: Urinary ALA and PBG

Rapid, dose-dependent, and durable ALA and PBG lowering after single dose • Mean (SEM) maximal reduction in 2.5 mg/kg group: 86± 2% (ALA) and 95± 0.4% (PBG)

• Prolonged ALA and PBG lowering with single dose supporting monthly or quarterly dosing

• Normalization of absolute ALA/PBG levels achieved at higher doses

Excluding subject 201-0002, Day 0: 0-6 hour ALA measurement

Month

ALA

10

Me

an

[+

/-S

EM

] A

LA

Lo

we

rin

g

Re

lati

ve

to

Ba

se

lin

e (

%)

100

80

60

40

20

0

-20

-40

0 1 2 3 4 5 6 7 8 9

Dose

(mg/kg)

ALA

Placebo 0/5

0.035 1/3

0.10 3/3

0.35 2/3

1.0 3/3

2.5 3/3

ALA Assay URL: < 3.9 or 3.8 mmol/mol Cr at sites 101 or 201

PBG Assay URL: < 1.6 or 1.5 mmol/mol Cr at sites 101 or 201

SAD Placebo (N=5)0.035 mg/kg ALN-AS1 (N=3)0.10 mg/kg ALN-AS1 (N=3)

0.35 mg/kg ALN-AS1 (N=3)

1.0 mg/kg ALN-AS1 (N=3)2.5 mg/kg ALN-AS1 (N=3)



PBG

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Me

an

[+

/-S

EM

] P

BG

Lo

we

rin

g

Re

lati

ve

to

Ba

se

lin

e (

%)

100

80

60

40

20

-20

-40

-60

Month

0 1 2 3 4 5 6 7 8 9 10

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

0

Dose

(mg/kg)

PBG

Placebo 0/5

0.035 0/3

0.10 1/3

0.35 0/3

1.0 1/3

2.5 2/3

57


SAD: Changes in Serum ALAS1 mRNA and Urinary ALA/PBG Highly

Correlated

R2 = 0.79,

p<0.001

ALAS1 mRNA vs ALA

ALAS1 mRNA Lowering

Relative to Baseline (%)

SAD Placebo

0.035 mg/kg ALN-AS1

0.10 mg/kg ALN-AS1

0.35 mg/kg ALN-AS1

1.0 mg/kg ALN-AS1

2.5 mg/kg ALN-AS1

Regression Line

Uri

na

ry A

LA

Lo

we

rin

g

Re

lati

ve

to

Ba

se

lin

e (

%)

100

90

80

70

60

50

40

30

20

10

0

-10

-20

-30

-40

-50

-60

R2 = 0.87,

p<0.001

ALAS1 mRNA vs PBG

ALAS1 mRNA Lowering

Relative to Baseline (%)

70 60 50 40 30 20 10 0 -10 -20 -30 -40

Uri

na

ry P

BG

Lo

we

rin

g

Re

lati

ve

to

Ba

se

lin

e (

%)

100

90

80

70

60

50

40

30

20

10

0

-10

-20

-30

-40

-50

SAD Placebo

0.035 mg/kg ALN-AS1

0.10 mg/kg ALN-AS1

0.35 mg/kg ALN-AS1

1.0 mg/kg ALN-AS1

2.5 mg/kg ALN-AS1

Regression Line

100 90 8070 60 50 40 30 20 10 0 -10 -20 -30 -40100 90 80



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Rapid, dose-dependent, and durable ALAS1 mRNA lowering• 54 ± 2% mean (SEM) maximal reduction relative to baseline in 1.0 mg/kg dose group

• ALAS1 mRNA reduction seen with 2 doses similar to single dose

Normal healthy volunteer

Me

an

[+

/-S

EM

] A

LA

S1

mR

NA

Lo

we

rin

g

Re

lati

ve

to

Ba

se

lin

e (

%)

80

70

60

50

40

30

20

10

0

-10

-20

-30

-40

-50

Days since first dose

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70

Dose Group MAD Placebo (N=2) 0.35 mg/kg ALN-AS1 (N=3) 1.0 mg/kg ALN-AS1 (N=3)

MAD Pharmacodynamic Data: Serum ALAS1 mRNA by cERD



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ALA

Rapid, dose-dependent, and durable ALA and PBG lowering after multiple doses• Mean (SEM) maximal reduction in 1 mg/kg group: 84 ± 2% (ALA) and 89 ± 5% (PBG)

• Multiple doses without additive effect in either dose group

• Normalization of absolute ALA/PBG levels achieved at higher doses

PBG

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Me

an

[+

/-S

EM

] A

LA

Lo

we

rin

g

Re

lati

ve

to

Ba

se

lin

e (

%)

100

80

60

40

20

0

-20

-40

-60

Months

0 1 2 3 4 5 6 7 8 9 10

Months

Me

an

[+

/-S

EM

] P

BG

Lo

we

rin

g

Re

lati

ve

to

Ba

se

lin

e (

%)

100

80

60

40

20

0

-20

-40

-60

0 1 2 3 4 5 6 7 8 9 10

MAD Placebo (N=2)



MAD Placebo (N=2)



Dose

(mg/kg)

ALA

Placebo 1 /2

0.35 1/3

1.0 3/3

Dose

(mg/kg)

PBG

Placebo 0/2

0.35 0/2

1.0 2/3

ALA Assay URL: < 3.9 or 3.8 mmol/mol Cr at sites 101 or 201

PBG Assay URL: < 1.6 or 1.5 mmol/mol Cr at sites 101 or 201

ALN-AS1 Phase 1 Study Interim ResultsMAD Pharmacodynamic Data: Urinary ALA and PBG



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ALN-AS1 Phase 1 Study Interim Results Summary

ALN-AS1 generally well tolerated with single or multiple (2) doses

• SAEs deemed unlikely related to study drug and no discontinuations due to AEs

• No dose-dependent AEs or clinically significant changes in vital signs, EKG, clinical laboratory or

physical examination

Non-invasive cERD assay to quantify liver ALAS1 mRNA expression demonstrated

• ASHE have 3-fold ALAS1 mRNA induction compared to normal healthy individuals

• Rapid, dose-dependent, and durable ALAS1 mRNA lowering with single and multiple doses of ALN-

AS1; highly correlated with changes in ALA and PBG

◦ 64% with a single 2.5 mg/kg dose and 54% with multiple 1.0 mg/kg doses

Rapid, dose-dependent, and durable lowering of urinary ALA and PBG with single and multiple

doses of ALN-AS1

• 86% and 95%, respectively, with a single 2.5 mg/kg dose

• 84% and 89%, respectively with multiple 1.0 mg/kg doses

Next Steps

• Part A/B, (SAD/MAD) continue to monitor ALA, PBG and ALAS1 recovery

• Part C, MD portion in recurrent attack patients ongoing in Sweden, UK and US

◦ Plan to report initial porphyria biomarker data from Part C in late 2016

◦ Potential clinical efficacy data on frequency and severity of recurrent attacks expected in 2017

• Plan to initiate Phase 3 trial in 2017



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Study Design Overview

Design

• Observational, prospective natural

history study

Key Eligibility Criteria

• Males or Females ≥ 18 years old

• Diagnosis of AHP including AIP, VP, or

HCP by specialist

• Recurrent attacks

◦ 3+ attacks* within 12 months of screen

if not on heme prophylaxis

◦ Using heme or GnRH analogs

prophylactically

Notify Clinic if Attack and Complete:

• Attack Inventory Form

• Blood/urine samples

Study Schedule

6 months(option to extend to 1 year)

Screening Visit Telephone calls (Q 2 mos) Final Visit

• Questionnaires


• Questionnaires


• Questionnaires


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Objectives and Status

Key Objectives

• Characterizing signs and symptoms of attacks

• Determining attack rates and treatment practices

• Obtaining medical history and medication usage details

• Exploration of Biomarkers

• Capture Quality of life (QoL) data

• Understanding healthcare utilization

Final Population

• Completed enrollment with112 AHP patients

◦ 44% US, 56% EU

Next Steps

• Presentation of 6 month data from all patients to be presented in Q4

◦ AASLD in Boston, Nov 11-15

• Data will help inform design of the pivotal study in 2017

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Agenda

Welcome


Introduction




School of Medicine



Q&A Session


ALN-AS1 Program


Q&A Session

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Upcoming RNAi Roundtables

ALN-GO1 for the treatment of Primary Hyperoxaluria Type 1 (PH1)

Tuesday, September 27, 10:00 a.m. – 11:00 a.m. ET

• Barry Greene, President and Chief Operating Officer

• David Erbe, Ph.D., Director, Research

• Guest Speaker: Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatric

Nephrologist and Clinical Lead, Birmingham Children’s Hospital NHS Trust

• Guest Speaker: Jennifer Lawrence, M.D. (mother of George Tidmore, a PH1 patient)

ALN-HBV for the treatment of Hepatitis B Virus (HBV) Infection

Tuesday, October 11, 9:00 a.m. – 10:00 a.m. ET

• Barry Greene, President and Chief Operating Officer

• Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence

• Guest Speaker: Heiner Wedemeyer, M.D., Managing Senior Physician and Assistant Professor in the

Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School

For more information, please visit www.alnylam.com/roundtables

65

Thank youwww.alnylam.com

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