Alnylam Forward Looking Statements

Transcription

1 1

2 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 There are a number of important factors that could cause actual results to differ materially from the results anticipated by these forwardlooking 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. 2

3 3

4 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 4

5 Key Features of Alnylam Investigational RNAi Therapeutics Potential Attributes for Differentiation and Value MAXIMUM KNOCKDOWN (KD) EFFICACY Up to 99% CLAMPED PHARMACODYNAMICS (PD) NOT UNDRUGGABLE TARGETS ROOM TEMP As few as 2 DURABILITY VS. 26 doses per year or more doses per year SUBCUTANEOUS (SC) ROUTE 5

6 Alnylam Reproducible and Modular Platform Strategic Framework for Innovative Medicines 1 Genetically validated, liverexpressed target gene High unmet need disease Opportunity for highly competitive profile Delivery with GalNAc conjugate platform 2 Biomarker for POC in Phase 1 Blood or urine based Informative disease correlation Establish dose/regimen for late-stage development 3 Definable path to approval and market Clinical development plans with established endpoints Demonstrable value for payers 6

7 7 In Focus

8 Clinical Development Pipeline Patisiran Fitusiran Hereditary ATTR Amyloidosis Hemophilia and Rare Bleeding Disorders HUMAN POC* EARLY STAGE (IND Filed-Phase 2) Inclisiran Hypercholesterolemia LATE STAGE (Phase 2-Phase 3) COMMERCIAL COMMERCIAL RIGHTS North America, Western Europe 50% North America, Western Europe Milestones & Royalties Givosiran Acute Hepatic Porphyrias Global ALN-CC5 Complement-Mediated Diseases Global ALN-GO1 Primary Hyperoxaluria Type 1 ALN-TTRsc02 ATTR Amyloidosis Subject to partner option rights Subject to partner option rights ALN-HBV Hepatitis B Virus Infection Global 8 *Demonstrated target gene knockdown and/or additional evidence of activity in clinical studies

9 Alnylam 2017 Pipeline Goals *Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4 PATISIRAN (hattr Amyloidosis) Phase 2 OLE data APOLLO Phase 3 top-line APOLLO Phase 3 results NDA/MAA filing 2017* Early Mid Late FITUSIRAN (Hemophilia and RBD) GIVOSIRAN (Acute Hepatic Porphyrias) INCLISIRAN (Hypercholesterolemia) ADDITIONAL CLINICAL PROGRAMS Phase 2 OLE data ATLAS Phase 3 program start Phase 1, Part C data Phase 3 study start ORION-1 Phase 2 data HoFH Phase 3 study start ASCVD Phase 3 study start Continue to advance early/mid-stage pipeline; Present clinical data 9

10 Christina Living with hattr Amyloidosis Her Story Early 40s Lives in US Mother of 4, wife of active duty Marine Extensive family history of hattr Initial symptoms of carpal tunnel Symptoms progressing faster, with neuropathy in legs and arms GI symptoms with interchanging diarrhea and constipation, and incontinence Unintentional weight loss of >20lbs in last 6 months Extreme fatigue with need to take 3 naps a day just to function Challenges with working full time to help contribute to family finances Worst part is guilt of knowing that I passed this devastating disease to my children 10

11 Alexis Living with Hemophilia A with Inhibitors His Story Mid-40s Born and raised in Peru No access to factor, so took cryoprecipitate; stopped after his hematologist said he had developed an inhibitor when he was 11 years old Bled in every joint Spent large parts of childhood hospitalized Stayed at home for weeks or months Moved to US in 2012, now has access to treatments 4-5 bleeds per month Joint damage, uses crutch to walk Can only manage sedentary job 11

12 Ariel Living with Acute Intermittent Porphyria Her Story Late 30s Lives in US Disease symptoms triggered by surgical procedure Recurrent bouts of severe abdominal pain, and vomiting for weeks at a time Cyclical episodes of neuropathic symptoms with pain and loss of sensation, severe high blood pressure, tachycardia, and psychotic episodes Residual symptoms between attacks Many hospitalizations after onset, managed with medically induced menopause and weekly IV hemin, but still has attacks 12

13 Alnylam 2020 In Focus R&D Day Agenda and Speakers Time Topic Presenter 8:20 8:40 Platform and Portfolio Update Akshay Vaishnaw hattr Amyloidosis & Patisiran 8:40 9:00 Hereditary ATTR Amyloidosis Ole Suhr 9:00 9:20 Patisiran Akshay Vaishnaw 9:20 9:35 Q&A Session #1: Pipeline and Patisiran 9:35 9:50 15 minute break Hemophilia & Fitusiran 9:50 10:10 Hemophilia John Pasi 10:10 10:30 Fitusiran Akin Akinc Acute Hepatic Porphyria & Givosiran 10:30 10:50 Acute Hepatic Pophyria Robert Desnick 10:50 11:10 Givosiran Pushkal Garg 11:10 11:25 Q&A Session #2: Fitusiran and Givosiran Transition to Commercialization 11:25 11:45 Alnylam 2020 In Focus: Preparing for Commercial Success Barry Greene 11:45 11:50 Closing Statements John Maraganore 13

14 14

15 Mean (SEM) % C5 Knockdown Mean (SEM) % ALA Knockdown Mean (SEM) % AT Knockdown Mean (SEM) % PCSK9 Knockdown Multiple Human POCs Demonstrate Reproducible and Modular Nature of Platform Fitusiran 225 mcg/kg 450 mcg/kg 900 mcg/kg 1800 mcg/kg 80 mg Inclisiran Placebo 25 mg 100 mg 300 mg 500 mg 800 mg Time (Days) Time (Months) ALN-CC Givosiran Placebo mg/kg 0.1 mg/kg 0.35 mg/kg 1.0 mg/kg 2.5 mg/kg mg 200 mg 400 mg 600 mg 900 mg Placebo Time (Days) Time (Months)

16 Clinical Development Pipeline Patisiran Fitusiran Hereditary ATTR Amyloidosis Hemophilia and Rare Bleeding Disorders HUMAN POC* EARLY STAGE (IND Filed-Phase 2) Inclisiran Hypercholesterolemia LATE STAGE (Phase 2-Phase 3) COMMERCIAL COMMERCIAL RIGHTS North America, Western Europe 50% North America, Western Europe Milestones & Royalties Givosiran Acute Hepatic Porphyrias Global ALN-CC5 Complement-Mediated Diseases Global ALN-GO1 Primary Hyperoxaluria Type 1 ALN-TTRsc02 ATTR Amyloidosis Subject to partner option rights Subject to partner option rights ALN-HBV Hepatitis B Virus Infection Global 16 *Demonstrated target gene knockdown and/or additional evidence of activity in clinical studies

17 Discontinuation of Revusiran Development Safety Findings as of November 2, 2016 Following reports of peripheral neuropathy and elevated blood lactate levels in Phase 2 OLE, Alnylam conferred with independent experts and requested Phase 3 ENDEAVOUR DMC meeting ENDEAVOUR DMC met October 4, 2016 to review safety and assess overall benefit-risk profile of revusiran Based on lack of favorable benefit-risk and imbalance of mortality in ENDEAVOUR, decision made to discontinue ongoing studies and development of revusiran APOLLO DMC met October 7, 2016 at Alnylam s request and recommended continuing the Phase 3 study of patisiran without modification Alnylam continues to conduct comprehensive evaluation of ENDEAVOUR Phase 3 data Update provided during Q3 16 earnings call on November 2, 2016 Reported 17 deaths in revusiran arm, 2 deaths in placebo arm 17

18 Survival Probability Survival Probability Natural History of hattr with Cardiomyopathy Complex disorder with high unmet need Significant morbidity and mortality Fatal within 2.5 to 5 years of diagnosis Cardiomyopathy Peripheral neuropathy, seen in wide range of mutations, including V122I and also in wtattr 1.0 Product-Limit Survival Estimates (with number of subjects at risk) + Censored 0.8 Survival Probabilty NAC Columbia Pooled 18 NAC Pooled Months *presented at EC ATTR, November

19 Potential Hypotheses Being Studied Based on Current Knowledge Non-drug related Randomization imbalance Advanced stage and fast disease progression Drug-related Frequent high doses of STC conjugate Potential toxicity from parent drug or metabolite(s) DDI of con-meds On-target toxicity secondary to cardiac TTR clearance Increased sensitivity to drugrelated effects in disease state Underlying disease(s) DDI of con-meds 19

20 Revusiran 500mg qw Patisiran 0.3 mg/kg q3w Fitusiran 80mg qm Givosiran 5.0mg/kg q3m Givosiran 2.5mg/kg qm ALN-PCSsc 300mg q6m Inclisiran 300mg q3m ALN-CC5 600mg q3m ALN-TTRsc02 50mg q3m Grams of Drug Exposure Levels with Revusiran Significantly Higher than other GalNAc Conjugate Programs 30 Annualized Exposure Levels Exposure Year Equivalents Relative to Revusiran STC-GalNAc Conjugate Program Years 25 ESC-GalNAc Conjugate LNP Revusiran 500mg qw Patisiran 0.3mg/kg q3w Fitusiran 80mg qm Givosiran 5.0mg/kg q3m Givosiran 2.5mg/kg qm Inclisiran 300mg q6m 48 Inclisiran 300mg q3m 24 5 ALN-CC5 600mg q3m 12 0 ALN-TTRsc02 50mg q3m

21 ALN-TTRsc02 Opportunity Potential for Best-in-Class Profile Revusiran/IONIS-TTR Rx ALN-TTRsc02 52 DOSES PER YEAR 4 DOSES PER YEAR ANTICIPATED 21

22 ALN-TTRsc02 Phase 1 Preliminary Study Results Single Ascending Dose Study in Healthy Volunteers 1.4 Potent, Dose-Dependent, Highly Durable TTR Knockdown 1.4 Mean [+/- SEM] TTR Relative to Baseline Days since first dose Cohort Placebo (N=12) TTRSC02 (5mg) (N=6) TTRSC02 (25mg) (N=6) TTRSC02 (50mg) (N=6) TTRSC02 (100mg) (N=6) TTRSC02 (200mg) (N=6) TTRSC02 (300mg) (N=6) 22 As of data cutoff on 19Oct2016 Max TTR knockdown of 98.4% with mean max of 97.1 ± 0.5% Most potent Alnylam investigational RNAi therapeutic to date

23 ALN-TTRsc02 Phase 1 Preliminary Study Results SAD Safety and Tolerability ALN-TTRsc02 appears generally well tolerated in healthy volunteers No SAEs and no discontinuations due to AEs All AEs mild or moderate in severity 9 AEs in 5 subjects considered possibly related to treatment; all mild Events included injection site erythema, injection site pain, pruritus, cough, nausea, fatigue and abdominal pain ISRs reported in 2 subjects symptoms mild and transient No clinically significant changes in physical exams or clinical laboratory parameters (e.g., LFTs) 23 As of data cutoff on 26Oct2016

24 Hypercholesterolemia DESCRIPTION Highly prevalent disease caused by elevated levels of LDL-C that increase risk of atherosclerotic cardiovascular disease (ASCVD) PATIENT POPULATION* 31 million in U.S. have LDL-C levels >240 mg/dl About 50% of patients discontinue statin therapy within one year, and adherence decreases with time Genetically defined patient subgroups: Heterozygous FH Homozygous FH 24 * Mozaffarian et al., Circulation, 2015

25 Efficacy of One Dose of Inclisiran up to Day 90 Significant, Durable PCSK9 and LDL-C Lowering 25 Inclisiran also known as ALN-PCSsc and PCSK9si Preliminary Phase 2 study results; Ray et al., AHA, November 2016 The Medicines Company is leading and funding development of inclisiran from Phase 2 onward and will commercialize the program, if successful

26 Safety of Inclisiran to Day 90 Treatment Emergent Adverse Events (TEAE) Total=497 Inclisiran Day 1-90 Placebo Pooled 100 mg 200 mg 300 mg 500 mg (14%) N=127 N=370 N=61 N=122 N=122 N=65 Any TEAE 69 (54%) 198 (54%) 38 (62%) 64 (52%) 68 (56%) 28 (43%) Serious 5 (4%) 22 (6%) 8 (13%) 6 (5%) 6 (5%) 2 (3%) Severe 5 (4%) 12 (3%) 3 (5%) 3 (2%) 4 (3%) 2 (3%) Related 24 (19%) 67 (18%) 11 (18%) 20 (16%) 27 (22%) 9 Death 0 (0%) 1 (0.3%) 0 (0%) 0 (0%) 0 (0%) 1 (1.5%) Most common TEAEs (>2%) were myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhea, dizziness (similar incidence to placebo) 26 Inclisiran also known as ALN-PCSsc and PCSK9si Preliminary Phase 2 study results; Ray et al., AHA, November 2016 The Medicines Company is leading and funding development of inclisiran from Phase 2 onward and will commercialize the program, if successful

27 Safety of Inclisiran to Day 90 Liver and Muscle TEAE 1 Total=497 Inclisiran Day 1-90 Placebo Pooled 100 mg 200 mg 300 mg 500 mg N=127 N=370 N=61 N=122 N=122 N=65 ALT >3x ULN 0 1 (0.3%) (0.8%) 0 AST >3x ULN 0 1 (0.3%) (0.8%) 0 ALP >2x ULN 0 3 (0.8%) 1 (1.6%) 0 2 (1.6%) 2 0 Bilirubin >2x ULN CK >5x ULN 0 2 (0.6%) 0 1 (0.8%) 4 1 (0.8%) 0 Myalgia 6 (4.7%) 21 (5.7%) 5 (8.2%) 7 (5.7%) 8 (6.6%) 1 (1.5%) 1: Crossing above threshold for significance at any time after randomization regardless of baseline 2: One patient above ULN at baseline 3: No patient met the criteria for Hy s law 4: Patient >3x ULN at baseline 27 Inclisiran also known as ALN-PCSsc and PCSK9si Preliminary Phase 2 study results; Ray et al., AHA, November 2016 The Medicines Company is leading and funding development of inclisiran from Phase 2 onward and will commercialize the program, if successful

28 Safety of Inclisiran to Day 90 First Injection TEAE 1,2 Total=497 Inclisiran Placebo Pooled 100 mg 200 mg 300 mg 500 mg AE terms N=127 N=370 N=61 N=122 N=122 N=65 Injection site erythema 0 4 (1.1%) 0 2 (1.6%) 1 (0.8%) 1 (1.5%) Injection site pruritus 0 1 (0.3%) (0.8%) 0 Injection site rash Injection site reaction 0 7 (1.9%) 1 (1.6%) 1 (0.8%) 3 (2.5%) 2 (3.1%) Total (observed any time) 0 12 (3.2%) 1 (1.6%) 3 (2.5%) 5 (4.1%) 3 (4.6%) Total (observed >4 hours) 0 9 (2.4%) 1 (1.6%) 3 (2.5%) 4 (3.3%) 1 (1.5%) 1: Number of patients with adverse event classified by preferred term each patient is counted only once 2: Pre-defined histaminic/allergic type adverse events 28 Inclisiran also known as ALN-PCSsc and PCSK9si Preliminary Phase 2 study results; Ray et al., AHA, November 2016 The Medicines Company is leading and funding development of inclisiran from Phase 2 onward and will commercialize the program, if successful

29 Cumulative Human Experience to Date in Alnylam Investigational RNAi Therapeutic Programs* Number of Programs Number of Clinical Studies Total Patients or Volunteers Dosed Greatest Duration of Exposure >10 >20 >1000 ~36 months *As of November 2016 includes patients dosed in ongoing Phase 3 studies 29

30 ALT Elevations in Clinical Programs Data Transfer as of November 2016 LNP-siRNA Study Study Population Subjects Treated Max Duration Treatment ALT >3x ULN Patisiran Phase 1 NHV 22 Single dose 0 Patisiran Phase 2 hattr polyneuropathy 29 Up to 4 wks 0 Patisiran Phase 2 OLE hattr polyneuropathy 27^ Up to 25mos 1 GalNAc-siRNA Study Study Population Subjects Treated Max Duration Treatment ALT >3x ULN Revusiran Phase 1 NHV 66 6 wks 1 Revusiran Phase 2 ATTR cardiomyopathy 26 6 wks 1 Revusiran Phase 2 OLE ATTR cardiomyopathy 25^ Up to 18 mos 0 Fitusiran Phase 1, Part A NHV 3 Single dose 0 Fitusiran Phase 1, Parts B & C Severe and moderate HA and HB w/o inhibitor 25 Up to 3 mos 1 Fitusiran Phase 1 D HA and HB w/ inhibitor 16 Up to 3 mos 3 Fitusiran Phase 2 (OLE) HA and HB w/ and w/o inhibitor 23^ Up to 14 mos 3 ALN-CC5 Phase 1, Parts A & B NHV 33 Up to 3 wks 0 ALN-CC5 Phase 1, Part C PNH 6 Up to 6 mos 1 Inclisiran Phase 1 NHV w/ elevated LDL-C 51 Up to 2 mos 1 Inclisiran Phase 2 High Risk CVD; elevated LDL 370 Single dose 1 Givosiran Phase 1, Parts A & B ASHE 23 Up to 2 mos 1 Givosiran Phase 1, Part C AIP 11 Up to 6 mos 1 ALN-AAT Phase 1/2, Parts A & B NHV 19 Up to 4 mos 1 ALN-GO1 Part A NHV 24 Single dose 0 30 ALT=alanine aminotransferase; ULN=upper limit of normal ^Subjects treated with drug in previous study

31 ALT Elevations in Clinical Programs Data Transfer as of November 2016 LNP-siRNA Study Study Population Subjects Treated Max Duration Treatment ALT >3x ULN Patisiran Phase 1 NHV 22 Single dose 0 Patisiran Phase 2 hattr polyneuropathy 29 Up to 4 wks 0 Patisiran Phase 2 OLE hattr polyneuropathy 27^ Up to 25mos 1 GalNAc-siRNA Study Study Population Subjects Treated Max Duration Treatment ALT >3x ULN Revusiran Phase 1 NHV 66 6 wks 1 Revusiran Phase 2 Frequency ATTR cardiomyopathy of ALT >3x 26 ULN 6 = wks 1 Revusiran Phase 2 OLE ATTR cardiomyopathy 25^ Up to 18 mos 0 Fitusiran Phase 1, Part A NHV 2.2% 3 Single dose 0 Severe and moderate Fitusiran Phase 1, Parts B & C HA and HB w/o inhibitor (16/724) 25 Up to 3 mos 1 Fitusiran Phase 1 D HA and HB w/ inhibitor 16 Up to 3 mos 3 HA and HB w/ and w/o Fitusiran Phase 2 (OLE) inhibitor 23^ Up to 14 mos 3 ALN-CC5 Phase 1, Parts A & B NHV 33 Up to 3 wks 0 ALN-CC5 Phase 1, Part C PNH 6 Up to 6 mos 1 Inclisiran Phase 1 NHV w/ elevated LDL-C 51 Up to 2 mos 1 Inclisiran Phase 2 High Risk CVD; elevated LDL 370 Single dose 1 Givosiran Phase 1, Parts A & B ASHE 23 Up to 2 mos 1 Givosiran Phase 1, Part C AIP 11 Up to 6 mos 1 ALN-AAT Phase 1/2, Parts A & B NHV 19 Up to 4 mos 1 ALN-GO1 Part A NHV 24 Single dose 0 31 ALT=alanine aminotransferase; ULN=upper limit of normal ^Subjects treated with drug in previous study

32 ISRs in GalNAc Conjugate Clinical Programs Data Transfer as of November 2016 Study Most ISRs Reported as Mild and Transient Subjects Treated Max Duration Treatment ISR N (%) Revusiran Phase wks 32 (48.5%) Revusiran Phase wks 6 (23.1%) Revusiran Phase 2 OLE 25^ Up to 18 mos 12 (48%) Fitusiran Phase 1, Part A 3 Single dose 0 Fitusiran Phase 1, Parts B, C & D 41 Up to 3 mos 14 (34%) Fitusiran Phase 2 (OLE) 23^ Up to 14 mos 5 (22%) ALN-CC5 Phase 1, Parts A & B 33 Up to 3 wks 6 (18%) ALN-CC5 Phase 1, Part C 6 Up to 6 mos 3 (50%) Inclisiran Phase 1 51 Up to 2 mos 4 (7.8%) Inclisiran Phase Single dose 12 (3.2%) Givosiran Phase 1, Parts A & B 23 Up to 2 mos 2 (8.7%) Givosiran Phase 1, Part C 11 Up to 6 mos 2 (18%) ALN-AAT Phase 1/2, Parts A & B 19 Up to 4 mos 0 ALN-GO1 Part A 24 Single dose 4 (19%) 32 ISR = injection site reaction, IS = injection site, d/c = discontinuation ^Subjects treated with drug in previous study

33 ISRs in GalNAc Conjugate Clinical Programs Data Transfer as of November 2016 Study Most ISRs Reported as Mild and Transient Subjects Treated Max Duration Treatment ISR N (%) Revusiran Phase wks 32 (48.5%) Revusiran Phase wks 6 (23.1%) Revusiran Phase 2 OLE 25^ Up to 18 mos 12 (48%) Fitusiran Phase 1, Part A 3 Single dose 0 Frequency of ISRs = Fitusiran Phase 1, Parts B, C & D 41 Up to 3 mos 14 (34%) Fitusiran Phase 2 (OLE) 23^ Up to 14 mos 5 (22%) 15.2% ALN-CC5 Phase 1, Parts A & B 33 Up to 3 wks 6 (18%) (102/673) ALN-CC5 Phase 1, Part C 6 Up to 6 mos 3 (50%) Inclisiran Phase 1 51 Up to 2 mos 4 (7.8%) Inclisiran Phase Single dose 12 (3.2%) Givosiran Phase 1, Parts A & B 23 Up to 2 mos 2 (8.7%) Givosiran Phase 1, Part C 11 Up to 6 mos 2 (18%) ALN-AAT Phase 1/2, Parts A & B 19 Up to 4 mos 0 ALN-GO1 Part A 24 Single dose 4 (19%) 33 ISR = injection site reaction, IS = injection site, d/c = discontinuation ^Subjects treated with drug in previous study

34 Summary Leading RNAi Therapeutics Platform Reproducible and modular drug discovery and development framework Differentiated product profiles Potent, durable target knockdown Extensive safety experience > 10 programs, >20 clinical studies >1000 patients/subjects dosed for up to 36 months Low incidence of generally mild, transient ISRs and ALT elevations 34

35 35 Leo Living with hattr Amyloidosis

36 Overview of Transthyretin amyloid (ATTR) amyloidosis Ole B Suhr, Professor, M.D. Department of Publich Health and Clinical Medicine Umeå University and University Hospital Umeå, Sweden.

37 Hereditary ATTR Amyloidosis (Familial amyloidosis with polyneuropathy, or FAP) Mário Corino da Costa Andrade First large report on the disease Brain 1952;75: First Swedish case. Andersson R, Kassman T. Acta Ophthalmol (Copenh) 1968; 46: Araki S et al Arch Neurol. Chic) 18:593 (picture courtesy of Ando Y)

38 In search of the protein (1980) Amyloid and amyloidosis, 1980, Pavoa Vasim, Portugal

39 1. Tawara S. et al. Biochem Biophys Res Commun 1983; 116: Saraiva MJ et al. J Lab Clin Med 1983; 102: Connors LH et al. Amyloid 2003; 10: Westermark P et al. Proc Natl Acad Sci U S A 1990; 87: Hawkins et al. Ann Med 2015;47: Transthyretin (prealbumin) 1,2 Produced by the liver (brain, eye). Hereditary forms of transthyretin amyloidosis (more than 130 mutations described) 3 Senile systemic amyloidosis 4 wild type TTR

40 Symptoms of disease» 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.

41 » Woman of African descent Case report» At the age of 33 breast cancer, operated, recurrence at the age of 36, reoperated. 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

42 Evaluation at our centre:» Positive bone scintigraphy for amyloidosis.» Wheelchair bound, advanced autonomic neuropathy» Adrenal insufficiency» Too advanced disease for Tafamidis treatment Treatment: Does not tolerate Diflunisal Heart/liver transplantation discussed, but dies after a new cardiac arrest at the age of 42 Bone-scintigraphy/CT

43 Swiecicki PL et al. Amyloid 2015;22: Sattianayagam et al. Eur Heart J 2012; 33: Benson MD et al. Am J Cardiol 2011; 108: Connors LH et al. Am Heart J 2009; 158: Kyle RA et al. Am J Med 1996; Ng B et al. Arch Intern Med 2005;165: Predominantly heart complications Predominantly nerve complications Survival estimated to between 3 and 15 years from onset of symptoms

44 Epidemiology of hattr Amyloidosis with Polyneuropathy Estimated 10-15,000 afflicted patients worldwide 1 Country ~ Number of Cases of hattr with Polyneuropathy USA Portugal Sweden Rest of EU Brazil >600 5 Japan Steady increase of new mutations in the Swedish population (10 mutations during the last 10 years); likely related to increased disease awareness

45 Suggested pathway for amyloid formation 1, and possible treatments 4 1, 2 3 TTR-tetramer B-fibrils Misfolded monomers Full length TTR 1. Halt production of circulating mutant TTR: Liver transplantation 2 2. Decrease production of circulating TTR: Gene silencing 3,4 3. Stabilise the TTR tetramer: Diflunisal, Tafamidis 5,6 4. Removal of Amyloid deposits: antibodies, Doxycycline 7,8 None of the available treatments address CNS or eye complications 1. Hammarstrom P et al. Science 2003; 299: Holmgren G et al. Clin Genet 1991; 40: Ackermann et al. Amyloid 2012;19(S1):43 4; 4. Coelho et al. N Engl J Med 2013;369: Berk et al. JAMA 2013;310: Coelho T. et al. Neurology 2012; 79: Richards DB et al. N Engl J Med 2015; 373: Cardoso I. et al. FASEB J 2006; 20:

46 Factors related to amyloid fibril formation» Concentration of amyloidogenic protein. The amyloid fibril formation process is concentration dependent 1» Mutant protein decreases stability 2» Age: Decreased efficacy of the immune system: antibody formation against misfolded protein 3 Decreased efficacy of housekeeping system for misfolded proteins 4 1. Lachmann HJ et al. N Engl J Med 2007; 356: Hammarstrom P et al. Science. 2003;299(5607): Obayashi K et al. Clin Chim Acta. 2013;419: Santos SD et al. Journal of neuropathology and experimental neurology. 2008;67(5):449-55

47 Importance of the concentration of the amyloidogenic protein: Regression of amyloid AA-amyloidosis Henning Waldenströn, Acta Chir Scandinavia VolLXIII (1928) From the department of surgical tuberculosis at St. Göran's Hospital, Stockholm, Sweden Case III 16/ hist. 1/4-25 3% Proteinuria Liver size Outline by ink

48 1. Liver transplantation for ATTR amyloidosis» Why perform liver transplantation and exchange a healthy liver? To decrease - eliminate the production of the amyloidogenic mutated transthyretin. Mutant TTR Holmgren G et al. Clin Genet 1991; 40: First liver transplanted ATTR amyloidosis patient.

49 Patient survival (%) Patient survival (%) All TTR mutations (n=2044) n= Val30Met - Early onset Val30Met - Late onset Non-Val30Met - Early onset Non-Val30Met - Late onset Years after transplantation n=170 n=109 n=81 Ericzon BG et al. Transplantation 2015; 99:

50 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: Coelho T et al.. J Neurol 2013; 260: Waddington Cruz M et al. Amyloid 2016; 23: Berk JL et al JAMA 2013; 310:

51 Lack of efficacy of current treatments? additional pathways for ATTR formation? TTR-tetramer B-fibrils Proteolytic cleavage at residues 46, 49 and 52 Misfolded monomers Full length TTR Amyloidogenic N-terminal fragment A-fibrils The majority of ATTR amyloidosis patients currently without effective treatment, a considerable unmet medical demand Kelly JW et al. Adv Protein Chem 1997; 50: Hammarstrom Pet al. Science 2003; 299: Thylen C et al. EMBO J 1993; 12: Bergstrom J et al. Lab Invest 2004; 84: Ihse E et al. Amyloid 2013; 20: Mangione PP et al. Proc Natl Acad Sci U S A 2014; 111:

52 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

53 Thank You!

54 Patisiran Akshay K. Vaishnaw Executive Vice President, R&D and Chief Medical Officer 54

55 Hereditary ATTR Amyloidosis (hattr) DESCRIPTION PATIENT POPULATION* Orphan disease caused by mutant transthyretin (TTR) amyloid deposits in nerves, heart, gastrointestinal tract, and other tissues ~50,000 worldwide Significant morbidity and fatal within 2-15 years from symptom onset hattr Amyloidosis with polyneuropathy 10,000 hattr Amyloidosis with cardiomyopathy 40, * Ando et al., Orphanet J Rare Dis, 2013; Ruberg et al., Circulation, 2012

56 Hereditary ATTR Amyloidosis with Polyneuropathy Inexorably Progressive Fatal Disease 4-5 yrs 2-3 yrs 1-2 yrs Stage 1 Stage 2: Early Stage 2: Late Stage 3 56 Photos courtesy of Yukio Ando (Japan)

57 Patisiran: Simple Approach to Treating a Complex Disease Shutting Off Production of Disease-Causing Protein Patisiran acts to knock down both mutant and wild type TTR production Production of mutant and wild type TTR Tafamidis stabilizes TTR tetramer Unstable circulating TTR tetramers tetramers reduced Organ deposition of monomers, Organ deposition of monomers, amyloid (β-pleated) fibril amyloid (β-pleated) fibril prevented, clearance promoted Liver transplantation stops mutant TTR production Neuropathy, cardiomyopathy Neuropathy, cardiomyopathy stabilization or improvement 57

58 Patisiran Phase 2 OLE Study Design Patisiran dosing: 0.30 mg/kg IV q3w OLE Dose 1 OLE Dose 2 W1 W2 W3 W1 W2 W3 OLE Dose 3 W1 W2 W3 OLE Dose OLE (out to 2 years) W1 W2 W3 W1 W2 W3 Serum TTR levels d 0, 1, 3, 7, 17, 84, 168, 182, 231, 234 mnis+7, other clinical measures d 0 (baseline) Cardiac biomarkers d 0 (baseline) Echo d 0 (baseline) Adverse events every 6 months every 3 months every 6 months 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 58 Timelines are not to scale

59 Mean (SEM) % Serum TTR Knockdown Relative to Baseline Patisiran Phase 2 OLE Preliminary Study Results* Serum TTR Knockdown 0 Post-dose Pre-dose N=24-27 at all other time points N=23 N=22 N= Months 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 59 SEM: Standard Error of the Mean *Suhr et al., ISA, July 2016; Data as of 12May2016

60 mnis+7 Patisiran Phase 2 OLE Preliminary Study Results* Change in mnis+7 Over 24 Months Months Change from Baseline to Month 24 (N=24) mnis+7 component Mean (SEM) Median (range) Total (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) 60 + Partial imputation was used to recover mnis+7 data points where components were missing at one or more replicate measurements (per patient/visit) *Suhr et al., ISA, July 2016; Data as of 12May2016

61 mnis+7 Patisiran Phase 2 OLE Preliminary Study Results* Change in mnis+7 Over 24 Months Months Change from Baseline to Month 24 (N=24) mnis+7 component Mean (SEM) Median (range) Total (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) 61 + Partial imputation was used to recover mnis+7 data points where components were missing at one or more replicate measurements (per patient/visit) *Suhr et al., ISA, July 2016; Data as of 12May2016

62 Mean ΔmNIS+7 from baseline at 24mos Mean (SEM) ΔmNIS+7 from baseline at 24mos~ Natural History Placebo (N=66) Diflunisal (N=64) Patisiran Phase 2 OLE Preliminary Study Results* Change in mnis+7 at 24 Months out of 24 patients (71%) with no change or an improvement in mnis+7 at 24 months compared to baseline (9.4) 29.6 (3.1) (2.7) Worse Better (nonlinear; N=283) 1# // Diflunisal Ph 3 Study 2+ // Patisiran Ph 2 OLE * (N=24) -6.7 (2.3) Individual ΔmNIS+7 at 24mos in Patisiran Ph 2 OLE SEM: Standard Error of the Mean ~ Assessments drawn from studies in patients with similar baseline neurologic impairment and not based on head-to-head studies 1 Adams D et al., Neurology. 85; (2015); # Predicted progression of median NIS value from Gompertz curve fit 1 2 Berk JL et al., JAMA. 310: (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) *Suhr et al., ISA, July 2016; Data as of 12May Mean ΔmNIS+7 Across hattr Studies at 24 mos ~

63 ΔmNIS+7 ΔmNIS+7 ΔmNIS+7 ΔmNIS+7 Patisiran Phase 2 OLE Preliminary Study Results* Correlation of TTR Knockdown with ΔmNIS months (N=27) months (N=27) r= -0.49, p= r= -0.55, p= Percent (%) TTR KD Percent (%) TTR KD months (N=27) months (N=24) r= -0.37, p= r= -0.31, p= Percent (%) TTR KD Percent (%) TTR KD 63 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

64 Mean (SEM) Change From Baseline Patisiran Phase 2 OLE Preliminary Study Results* Sweat Gland Nerve Fiber Density (SGNFD): Lower Limb Distal thigh sweat gland innervation in Patient N=24 N=24 Distal Thigh (meters/mm 3 ) Distal Leg (meters/mm 3 ) N=22 N=21 N=19 P = N=18 N=20 P < Months N= N=18 P = N=17 P = Baseline 50 microns 24months 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 Green: PGP 9.5 (nerve fibers) Red: CD31 (blood vessels) Blue: DAPI (nuclei) 50 microns 64 1 Chao C et al., Ann Neurol. 78: (2015) 2-sided p values from paired t-test comparing post-baseline vs baseline *Suhr et al., ISA, July 2016; Data as of 12May2016

65 Patisiran Phase 2 OLE Preliminary Study Results* Summary of Safety and Tolerability 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%) 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 65 *Suhr et al., ISA, July 2016; Data as of 12May2016

66 2:1 RANDOMIZATION APOLLO Phase 3 Study Design Enrollment Complete N=225 Patient Population hattr: any TTR mutation, Stages 1 and 2 Neurological impairment score (NIS) of Prior tetramer stabilizer use permitted Patisiran IV q3w 0.3 mg/kg OR Placebo IV q3w Primary Endpoint at 18 months mnis+7 Key Secondary Endpoints Norfolk QOL-DN NIS-weakness mbmi 10-meter walk 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 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 66 Clinicaltrials.gov # NCT

67 APOLLO Patisiran Phase 3 Study 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/m 2 x albumin [g/dl] ( ) Patients with cardiac involvement, n (%) 122 (54) Mean NT-proBNP, ng/l (range) 1461 ( ) Mean troponin, ng/ml (range) 0.1 ( ) 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 (%) (46) (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 ( ) NIS 59.3 ( ) 67 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

68 Patient Advocacy & Scientific Leadership Patient Advocacy Education Collaboration Implementation of Alnylam Assist to help improve diagnosis rates o 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 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 Initiation of Expanded Access Program (EAP) Numerous pre-clinical and clinical investigatorinitiated studies to date (IIS) 68

69 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 Month 12 Month (62% of patients) +5.9 (65% of patients) +8.0 (65% of patients) Cortese A. J Neurol Mar 16; Randomized controlled trial in 61 patients with hattr Amyloidosis NIS-LL = neuropathy impairment score-lower limb 69

70 hattr Amyloidosis Market Opportunity ~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 comorbidities V30M Early onset S77Y F33L E89L S50R Predominantly Neurologic G47A A36P F64L E89Q V30M Late onset hattr Amyloidosis Predominantly Cardiac 1. Based on Rapezzi et al. Eur Heart J 2013;34:520 8; Semigran et al. J Am Coll Cardiol 2016;68: I107V W41L H88R T60A L111M I68L V122I 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 70

71 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 71

72 Q&A Session #1 Pipeline and Patisiran 72

73 Break Presentations to resume at 9:50am 73

74 Venkat Living with Hemophilia A

75 John Pasi, MB, ChB, PhD, FRCP, FRCPath, FRCPCH Professor of Haemostasis and Thrombosis and Consultant Haematologist Barts and the London School of Medicine and Dentistry Queen Mary, University of London

76

77 Haemophilia: chronic, disabling, painful and destructive disease

78 State of Art Treatment 2016

79 Haemophilia: not just a physical problem when striving for a normal life Diagnosis and infancy Parental stress and anxiety Inhibitor risk Infusion intravenously in very young children Central venous access devices / ports Childhood Regular infusion Restriction at school Time lost from school Adolescence Peer conformity Rebellion / poor compliance Independence Adulthood Evolving health problems, particular ankle joints Impact on job prospects Continuing life long treatment burden Relationships

80 Treatment burden remains considerable 19yr old boy Long term prophylaxis, alternate days since age 3 Occasional breakthrough bleeds, always perhaps more than usual 2016 First year at University Recurrent significant left elbow spontaneous haemarthrosis Treated with increased prophylaxis Still getting recurrent bleeding and developing chronic synovitis in dominant arm Pharmacokinetic studies show very short half life, <6hrs Requires daily high dose factor infusions to reduce bleeding and treat synovitis Affecting QoL, student life, hospital visits, treatment demands A very significant treatment and disease burden to maintain health

81 Global Issues 75% of the world is without effective therapy in 2016 Present replacement therapy remains impracticable in many parts of the world In the developed world less than 50% of patients are on optimal prophylaxis regimens Considerable unmet needs remain 81

82 Therapeutic Value Evolution of Haemophilia Treatment EHL clotting factors ( ) Biosimilars Humanized Prolonged halflife (FVIII/FIX) Recombinant era Plasma-Derived Clotting Factors (1969) Recombinant Clotting Factors FVIII, FIX, FVIIa (1990s) Widespread viral contamination Improved Safety Eliminated potential for transmission of blood borne pathogens Evolution of Products

83 Strategies For Improving Clotting Factors Higher Potency Prolonged Half Life Reduced Inhibitors Resistance to Inactivation Improved Production

84 Factor levels and bleeding rates: What is needed to significantly impact bleeding? Den Uijl et al. Haemophilia. 2011;17:

85 Changing the Traditional Treatment Paradigm? Time at risk remains Factor level Time 1 IU/dL

86 Inhibitors 25-30% of children with severe haemophilia A will develop inhibitors Significant proportion will undergo immune tolerance induction 80-85% will be tolerized with ITI after one or two rounds Those that are not tolerized will have few options other than bypass therapy BPA such as apcc and rviia are problematic and less effective than FVIII concentrate Many patients with inhibitors are severely disabled and disadvantaged Although rarer, haemophilia B inhibitor development is much worse in terms of options

87 Unmet needs Current treatment is a considerable burden Current treatment leaves gaps unless closely tailored to the individual Current accepted trough levels do not eliminate all risk of bleeding Current state of art treatment remains aspirational for many in both developed and developing worlds Inhibitor patients have limited therapeutic options that are not as efficacious as standard therapy

88 Therapeutic Value Evolution of Haemophilia Treatment Investigational therapies (2015 ) Gene therapy Novel agents Recombinant era Recombinant Clotting Factors FVIII, FIX, FVIIa (1990s) EHL clotting factors ( ) Biosimilars Humanized Prolonged half-life (FVIII/FIX) Improved Safety Eliminated potential for transmission of blood borne pathogens Plasma-Derived Clotting Factors (1969) Widespread viral contamination Evolution of Products

89 Novel Treatments in Development Bispecific antibody Anti-TFPI RNA silencing Gene therapy

90 Bispecific antibodies ACE910

91 ACE910 / emicizumab Phase 1 in HV and patients with haemophilia with and without inhibitors Phase 3 in progress Inhibitor and non-inhibitor studies Recent reports of 4 thrombotic episodes in inhibitor study

92 IN VIVO EX VIVO 3. Transplantation of modified cells to original or other site Direct injection of transducing vector into tissue or into bloodstream. Cells modified in Vivo Ideal 1. Removal of tissue Less Ideal 2. Modification and transduction of cells by vector in vitro

93 Gene therapy today A crowded field Biomarin, Baxalta, Spark, Dimension, Biogen, UCL/St Jude, UniQure, Sangamo in vivo and ex vivo options Haemophilia B Spark SPK-100 Bax335 limited benefit UniQure Sangamo Haemophilia A Biomarin BMN270 Sangamo IND filing

94 Latest early / interim data from AAV studies Spark Haemophilia B, ASH 2016 Biomarin Haemophilia A, WFH 2016

95 Gene therapy for haemophilia: clinician questions Factor expression translates to efficacy What level is enough? Pre-existing AAV immunity What variation amongst serotypes and eligibility Durability? Immune response in haemophilia B ALT response Long term safety Unknown unknowns Sophistication of the healthcare economy to adapt 95

96 Treatment is good today Effective Normalises life and life options Summary Treatment burden, though, remains significant across a range of measures EHL offer an incremental improvement Disruptive therapies excite clinicians and treaters as they offer a real and wholly new potential paradigm shift in care A very exciting time to be in haemophilia care!

97 Fitusiran Akin Akinc, Ph.D. Vice President, General Manager, Fitusiran 97

98 Fitusiran Investigational RNAi Therapeutic for Treatment of Hemophilia Fitusiran (ALN-AT3) SC-administered small interfering RNA (sirna) therapeutic targeting antithrombin (AT) Non-biologic, chemically-synthesized, with targeting ligand to specifically deliver to liver site of AT synthesis Harnesses natural RNA interference (RNAi) mechanism for regulation of plasma AT levels Therapeutic hypothesis Hemophilia A and B are bleeding disorders characterized by ineffective clot formation due to insufficient thrombin generation Fitusiran is designed to lower AT, with goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding Observation of ameliorated bleeding phenotype in patients with co-inheritance of thrombophilic traits in hemophilia 1-4 Supported by pre-clinical data 5 and emerging Phase 1 clinical results 6,7 Hemophilia A FVIII Hemophilia B FIX FVIIa FX FVIIIa FIXa FXa AT FVa Prothrombin Thrombin Fibrinogen Fibrin Blood clot FVII FV 98 1 Kurnik K, et al. Haematologica. 92: (2007); 2 Ettingshausen E, et al. Thromb Haemost. 85: (2001); 3 Negrier C, et al. Blood. 81: (1993); 4 Shetty S, et al. Br J Haematol. 138: (2007); 5 Seghal A, et al. Nat Med. 21: (2015); 6 Pasi KJ, et al. Blood. 2015, 126:551; 7 Pasi KJ, et al. Haemophilia. 2016, 22(Suppl 4)

99 Fitusiran A New Approach Potentially Offering Beneficial Features Several emerging features for potential differentiation Not a biologic it is a manufactured RNAi therapeutic No reconstitution or mixing required Administered subcutaneously (SC), as opposed to intravenously (IV) Long duration of action, currently being evaluated in clinical studies with once-monthly dosing Consistent pharmacology, limiting peaks and troughs Not a factor, therefore may help avoid inhibitor formation Room temperature stability, may not require refrigerated storage Mechanism directed at addressing thrombin production defect, amenable to hemophilia A and hemophilia B, including those who have developed inhibitors and potentially other rare bleeding disorders (RBD) 99

100 Fitusiran Phase 1 and Phase 2 OLE Study Design Part A: Single-Ascending Dose (SAD) Randomized 3:1, Single-blind, Placebo-Controlled, Healthy Volunteers Part B: Multiple-Ascending Dose (MAD), Weekly dosing Open-label, Patients with Hemophilia A or B Part C: MAD, Monthly dosing Open-label, Patients with Hemophilia A or B * Part D: MAD Monthly dosing Open-label, Patients with Hemophilia A or B with Inhibitors Phase 1 Study * Phase 2 OLE Study Cohort 1: 50 mg qm x 3 SC, N=6 Cohort 2: 80 mg qm x 3 SC, N=10 Patients eligible to roll over onto Phase 2 OLE starting on Day 84 Individual patient dose adjustment may be allowed (per Safety Review Committee) 100 OLE, Open-Label Extension; qm, monthly; SC, subcutaneous *ClinicalTrials.gov Identifier: NCT ; Pasi KJ, et al. Haemophilia. 2016, 22(Suppl 4) ClinicalTrials.gov Identifier: NCT

101 Interim Fitusiran Phase 1 (Part D) Study Results* Demographics & Baseline Characteristics in Patients with Inhibitors Age, years; mean (range) Weight, kg; mean (range) Hemophilia A with Inhibitors Hemophilia B with Inhibitors Severe Moderate 50 mg N=6 32 (22-41) 73 (55-100) mg N=10 37 (21-65) 73 (52-108) Medical history of hepatitis C *Data cut-off 06Oct2016; Pasi et al., ASH, December 2016

102 Interim Fitusiran Phase 1 (Part D) Study Results* Safety/Tolerability in Patients with Inhibitors Fitusiran generally well tolerated in inhibitor patients No discontinuations due to AEs or drug-related SAEs No thromboembolic events All AEs mild or moderate in severity Non-laboratory AEs reported in 2 patients: injection site reactions (ISRs) 7/16 (44%) and cough 2/16 (13%) ISRs all mild; mostly pain and/or erythema at injection site ALT increases >3x ULN observed in 3 patients All asymptomatic, with no concurrent elevations of bilirubin >2x ULN All patients had medical history of HCV Reversible, all patients currently with ALT <3x ULN Non-clinically significant D-dimer increases observed in some patients; none associated with laboratory signs of pathological clot formation (changes in platelets, fibrinogen, and/or PT/INR) No clinically significant changes in other laboratory parameters No instances of anti-drug antibody (ADA) formation All bleed events successfully managed with bypassing agents (rfviia, apcc) As of data cut-off, 7 patients transitioned to Phase 2 OLE; fitusiran continues to be generally well tolerated 102 *Data cut-off 06Oct2016; Pasi et al., ASH, December 2016 AE, adverse events; SAE, serious adverse events Adverse event grouping based on MedDRA-coded terms, excluding bleed events

103 Mean [+/- SEM] AT Activity Relative to Baseline Interim Fitusiran Phase 1 (Part D) Study Results* AT Lowering in Patients with Inhibitors AT lowering after monthly dosing in hemophilia patients with inhibitors Cohort 1: 50 mg (N=6) Cohort 2: 80 mg (N=10) N=1 N=1 N=1 N= N= Days since first dose Onset Observation 103 *Data cut-off 06Oct2016; Pasi et al., ASH, December 2016

104 Peak Thrombin Generation (nm) Interim Fitusiran Phase 1 (Part D) Study Results* AT Lowering is Correlated with Increased Thrombin Generation Post hoc analysis of thrombin generation by AT lowering quartiles 250 Boxes denote median and interquartile range AT Lowering < 25% (N=16) AT Lowering 25-50% (N=10) AT Lowering 50-75% (N=14) Patients with Hemophilia with Inhibitors AT Lowering >= 75% (N=16) N=4 Healthy Volunteers *Data cut-off 06Oct2016; Pasi et al., ASH, December Pasi KJ, et al. Haemophilia. 2016, 22(Suppl 4),

105 ABR Interim Fitusiran Phase 1 (Part D) and OLE Study Results* Summary of Median ABRs All Inhibitor Patients Observation Period, 50 mg vs 80 mg mg 80 mg Pre-Study Onset Observation N=16 N=16 N= ABR AsBR Median ABR, Pre-study period: 31 Median ABR, Observation period: 0 Patients reporting no bleeds: 9/16 (56%) Patients report no spontaneous bleeds (AsBR = 0): 11/16 (69%) 50 mg: Median ABR = 8, median AsBR = 5 80 mg: Median ABR = 0, median AsBR = 0 Patients reporting no bleeds: 7/10 (70%) Patients report no spontaneous bleeds (AsBR = 0): 9/10 (90%) 105 *Data cut-off 06Oct2016; Pasi et al., ASH, December 2016 OLE, open-label extension; ABR, annualized bleeding rate; AsBR, annualized spontaneous bleed rate

106 Fitusiran Phase 2 OLE Study Design Patients with Hemophilia without Inhibitors Patients previously dosed in Phase 1* study eligible to roll over onto Phase 2 Open-Label Extension (OLE)^ study Phase 1, Part B (N=12) 15, 45, 75 mcg/kg qw x 3 SC Phase 1, Part C (N=18) 225, 450 mcg/kg qm x 3 SC 900, 1800 mcg/kg, 80 mg qm x 3 SC Phase 2 OLE 50 mg qm SC 80 mg qm SC Individual patient dose adjustment may be allowed (per SRC) As of data cut-off of 06Oct2016, 16 patients from Phase 1, Parts B & C have transitioned to Phase 2 OLE Days between doses in Phase 1 and Phase 2 OLE ranged from 30 (no interruption in dosing) to OLE, open-label extension; qw, weekly; qm, monthly; SC, subcutaneous *ClinicalTrials.gov Identifier:NCT ; Pasi KJ, et al. Haemophilia. 2016, 22(Suppl 4) ^ClinicalTrials.gov Identifier: NCT patients participating in Part C previously participated in Part B

107 Interim Fitusiran Phase 2 OLE Study Results* Demographics/Baseline Characteristics in Patients without Inhibitors Age, years; mean (range) Weight, kg; mean (range) Hemophilia A Hemophilia B Severe Moderate 50 mg N=8 35 (19-61) 80 (65-94) mg N=8 41 (24-58) 74 (58-80) Medical history of hepatitis C *Data cut-off 06Oct2016; Ragni et al., ASH, December 2016

108 Interim Fitusiran Phase 2 OLE Study Results* Safety/Tolerability in Patients without Inhibitors Fitusiran generally well tolerated with up to 14 months continuous administration at mg qm No discontinuations due to AEs or drug-related SAEs No thromboembolic events All AEs mild or moderate in severity Non-laboratory AEs reported in 2 patients: 4/16 (25%) injection site reactions (ISRs) and vomiting 2/16 (13%) ISRs all mild; mostly pain and/or erythema at injection site ALT increases >3x ULN were observed in 3 patients All asymptomatic, with no concurrent elevations of bilirubin >2x ULN All patients had medical history of HCV With currently available follow-up, 2 patients with declining ALT through continued dosing No laboratory evidence of pathologic clot formation (changes in D-dimer, platelet count, fibrinogen, and/or PT/INR) No clinically significant changes in other laboratory parameters No instances of anti-drug antibody (ADA) formation All bleed events successfully managed with replacement factor Safety profile generally consistent with observations in Phase 1 study *Data cut-off 06Oct2016; Ragni et al., ASH, December 2016 AE, adverse events; SAE, serious adverse events Adverse event grouping based on MedDRA-coded terms, excluding bleed events 1. Pasi KJ, et al. Haemophilia. 2016, 22(Suppl 4)

109 AT Activity (%, relative to baseline) (mean ± SEM) Peak Thrombin (nm) Interim Fitusiran Phase 2 OLE Study Results* AT Level and Thrombin Generation in Patients without Inhibitors AT Levels Thrombin Generation HV Range HV Median % 19% mg 80 mg 0 ' 50 mg ' 80 mg 109 *Data cut-off 06Oct2016;Ragni et al., ASH, December 2016 OLE, open-label extension; AT, antithrombin; SEM, standard error of the mean; HV, Healthy Volunteer Based on last available measurement; Healthy volunteers with AT lowering <25% (Pasi KJ, et al. Haemophilia. 2016, 22(Suppl 4))

110 ABR Interim Fitusiran Phase 2 OLE Study Results* Summary of Median ABRs in Patients without Inhibitors PPx Pre-Study OD Observation N=10 N=6 N=16 Median ABR, Observation period = 1 Patients reporting no bleeds: 8/16 (50%) Patients reporting no spontaneous bleeds (AsBR = 0): 11/16 (69%) Median duration in observation period = 170 days (5.7 months) 110 *Data cut-off 06Oct2016; Ragni et al., ASH, December 2016 PPx, prophylaxis; OD, on demand; ABR, annualized bleeding rate; AsBR, annualized spontaneous bleeding rate

111 Interim Fitusiran Phase 1 and Phase 2 OLE Study Results* Summary and Next Steps Fitusiran generally well tolerated in hemophilia A and B patients with and without inhibitors Continued evidence of clinical activity Median ABR = 0 for all inhibitor patients 9/16 (56%) patients bleed-free and 11/16 (69%) patients experiencing zero spontaneous bleeds Median ABR = 1 and median AsBR = 0 for non-inhibitor patients 8/16 (50%) patients bleed-free and 11/16 (69%) patients experiencing zero spontaneous bleeds Dosing of patients continues in Phase 2 OLE study As of October 6 data cut-off, 23 (16 non-inhibitor and 7 inhibitor) patients are now enrolled in the Phase 2 OLE study Up to 14 months of continuous dosing 111 *Data cut-off 06Oct2016; Ragni et al., ASH, December 2016

112 2:1 2:1 Preliminary Fitusiran Phase 3 Program* Plan to Initiate in Early 2017 Adults and adolescents with hemophilia A or B with inhibitors On-demand N~50 Fitusiran OR OD BPA Endpoints: ABR Bypassing agent (BPA) consumption Quality of life Safety Adults and adolescents with hemophilia A or B without inhibitors On-demand N~100 Fitusiran OR OD Factor Endpoints: ABR Factor VIII or IX consumption Quality of life Safety Adults and adolescents with hemophilia A or B with or without inhibitors Prophylaxis N~100 PPX Factor/BPA Fitusiran Endpoints: ABR Factor/BPA consumption Quality of life Safety 112 *Preliminary plans subject to further diligence and health authority feedback; Patients in ATLAS studies will be allowed to roll over into open-label extension

113 Patient Advocacy & Scientific Leadership Patient Advocacy Education Collaboration Dialogue with patient advisors Multiple patient advisory boards in 2016 Presence at national, regional, and local patient advocacy meetings 7 primary abstracts and publications since 2015 at key scientific meetings in US, EU, Asia o Data presentations at WFH, APSTH, and ASH conferences in 2016 Attendance at >10 congresses and >300 peer engagements in 2016 Education initiatives through Industry Symposia and Technical Sessions at international meetings and congresses Multiple pre-clinical and clinical investigatorinitiated studies 113

114 Hemophilia Market Landscape Mature ~$10B market Highly competitive, with numerous marketed products Patients well-informed of treatment options Product information is driven through peer networks, HCPs, chapters, and manufacturers Switching opportunistic patients switch when they perceive benefit Extended half-life rfviii ~20% of prophylaxis patients in US have switched* Extended half-life rfix ~40% of prophylaxis patients in US have switched* Additional extended half-life products continue to enter market; novel non-factor agents on horizon 114 *EHL manufacturer annual reports filed on Form 10-K with Securities and Exchange Commission

115 Hemophilia Market Opportunity Diagnosed patient population* 200,000 worldwide Fitusiran has potential to address important unmet needs Improved prophylaxis in inhibitor patients More consistent hemostasis throughout dosing interval Reduced treatment burden ~4,000 with inhibitors Avoidance of inhibitor formation Initial opportunity in hemophilia A and B, with and without inhibitors Expansion possible in other rare bleeding disorders (RBDs) Significant opportunity for global expansion Up to 75% of world hemophilia population remains inadequately treated Opportunity to expand use of prophylactic therapy 115 *World Federation of Hemophilia, Report on the Annual Global Survey 2014 (October 2015); World Federation of Hemophilia, Report on the Annual Global Survey 2015 (October 2016)

116 Fitusiran Program Summary & Next Steps Fitusiran is a promising investigational approach for treatment of hemophilia and rare bleeding disorders Differentiated approach with potential to address significant unmet need Positive data from ongoing Phase 1 and Phase 2 OLE studies Generally well tolerated in hemophilia A and B patients with and without inhibitors Clinical activity results support further advancement Median ABR and AsBR of zero in inhibitor patients in Phase 1 Median ABR of one, median AsBR of zero in non-inhibitor patients in Phase 2 OLE Alliance with Sanofi Genzyme Co-development, co-commercialization in US, Canada, and Western Europe Plan to initiate ATLAS Phase 3 program in early

117 117 Rose Living with Acute Intermittent Porphyria

118 CLINICAL OVERVIEW OF THE ACUTE HEPATIC PORPHYRIAS (AHPs) Inborn Errors of Heme Biosynthesis Robert J. Desnick, Ph.D., M.D. Dean for Genetic & Genomic Medicine Professor & Chair Emeritus Department of Genetics & Genomic Sciences Icahn School of Medicine at Mount Sinai, New York, NY

119 ACUTE HEPATIC PORPHYRIAS (AHPs) OUTLINE Brief Review: Heme Biosynthesis & Regulation The Acute Hepatic Porphyrias (AHPs): Prevalence Acute and Chronic Manifestations Pathogenesis of Acute Attacks Current Therapies: Heme Replacement Orthotopic Liver Transplantation

120 Mitochondria HEME BIOSYNTHETIC PATHWAY SUCCINYL COA GLYCINE COŌ CH CH 2 CoAS C O H H C NH 2 COO ALA-SYNTHASE (ALAS) B 6 CoASH CO 2 COO CH 2 CH 2 C=O H C NH H AMINOLEVULINIC ACID (ALA) ALA - DEHYDRATASE H 2 O NH 2 CH 2 HMB-SYNTHASE COŌ COO CH 2 CH 2 CH 2 N H H PORPHOBILINOGEN (PBG) 4 NH 3 Cytoplasm Vi CH3 Pr Ac CH3 CH3 N N Fe N N Vi CH3 Ac HO Pr N H H N N H H N Pr Ac Pr 2 H+ Fe ++ Pr HEME FERROCHELATASE URO-SYNTHASE Ac Pr HYDROXYMETHYLBILANE H 2 O Vi CH3 Pr Ac CH3 N H N Vi Ac N H N H Pr CH3 N H N CH Ac H N H N Ac Pr PROTOPORPHYRIN IX 6H URO - PROTO-OXIDASE DECARBOXYLASE Vi Pr CH Pr UROPORPHYRINOGEN III Pr Pr 4 H 4 CO 2 CH3 CH3 CH3 N H N H H H N N Pr Pr Vi CH PROTOPORPHYRINOGEN IX 2CO 2 2 H COPRO-OXIDASE CH3 CH3 N H N H H H N N Pr Pr Pr CH3 COPROPORPHYRINOGEN III

121 HEME BIOSYNTHETIC PATHWAY - LIVER Mitochondria SUCCINYL COA GLYCINE COŌ CH CH 2 CoAS C O FEEDBACK H H C NH 2 COO ALA-SYNTHASE 1 (ALAS1) B 6 CoASH CO 2 COO CH 2 CH 2 C=O H C NH H ALA REPRESSION ALA - DEHYDRATASE H 2 O NH 2 CH 2 HMB-SYNTHASE COŌ COO CH 2 CH 2 CH 2 N H H PBG 4 NH 3 Cytoplasm Vi CH3 Pr Ac CH3 CH3 N N Fe N N Vi CH3 Ac HO Pr N H H N N H H N Pr Ac Pr 2 H+ Fe ++ Pr HEME FERROCHELATASE URO-SYNTHASE Ac Pr HYDROXYMETHYLBILANE H 2 O Vi CH3 Pr Ac CH3 N H N Vi Ac N H N H Pr CH3 N H N CH Ac H N H N Ac Pr PROTOPORPHYRIN IX 6H URO - PROTO-OXIDASE DECARBOXYLASE Vi Pr CH Pr UROPORPHYRINOGEN III Pr Pr 4 H 4 CO 2 CH3 CH3 CH3 N H N H H H N N Pr Pr Vi CH PROTOPORPHYRINOGEN IX 2CO 2 2 H COPRO-OXIDASE CH3 CH3 N H N H H H N N Pr Pr Pr CH3 COPROPORPHYRINOGEN III

122 HEME BIOSYNTHETIC PATHWAY - LIVER Mitochondria SUCCINYL COA GLYCINE COŌ CH CH 2 CoAS C O H H C NH 2 COO ALA-SYNTHASE 1 (ALAS1) B 6 CoASH CO 2 COO CH 2 CH 2 C=O H C NH H AMINOLEVULINIC ACID (ALA) ALA - DEHYDRATASE H 2 O NH 2 CH 2 HMB-SYNTHASE COŌ COO CH 2 CH 2 CH 2 N H H 4 NH 3 Cytoplasm PORPHOBILINOGEN (PBG) Vi CH3 Pr Ac CH3 CH3 N N Fe N N Vi CH3 Ac HO Pr N H H N N H H N Pr Ac Pr 2 H+ Fe ++ Pr HEME FERROCHELATASE URO-SYNTHASE Ac Pr HYDROXYMETHYLBILANE H 2 O Vi CH3 Pr Ac CH3 N H N Vi Ac N H N H Pr CH3 N H N CH Ac H N H N Ac Pr PROTOPORPHYRIN IX 6H URO - PROTO-OXIDASE DECARBOXYLASE Vi Pr CH Pr UROPORPHYRINOGEN III Pr Pr 4 H 4 CO 2 CH3 CH3 CH3 N H N H H H N N Pr Pr Vi CH PROTOPORPHYRINOGEN IX 2CO 2 2 H COPRO-OXIDASE CH3 CH3 N H N H H H N N Pr Pr Pr CH3 COPROPORPHYRINOGEN III

123 ACUTE HEPATIC PORPHYRIAS (AHPs) Porphyria Autosomal Dominant: Acute Intermittent Porphyria (AIP) HMB-Synthase Hereditary Coproporphyria (HCP) COPRO-Synthase Variegate Porphyria (VP) PROTO-Synthase Autosomal Recessive: ALA-Dehydratase Deficient Porphyria (ADP) ALA-Dehydratase Major Clinical Manifestations: Life-Threatening Acute Neurovisceral Attacks Chronic Neuropathic Pain & Progressive Neuropathy Deficient Enzyme Activity (% of Normal) 50% 50% 50% <5% Biochemical & Molecular Diagnoses: Most Patients Identified During/After an Acute Attack: Markedly Elevated Urinary/Plasma ALA/ PBG (>5-15, >20-120, resp.) Increased Liver ALAS1 mrna and Enzyme Activity (10-15) Mutation Analysis Identifies All Patients

124 ESTIMATED PREVALENCE OF AHPs Country Patients/100,000 Sweden 4-5* Finland 2-3* UK & Western Europe 2-5* United States 2-5** American Porphyria Foundation Patient Registry 6200 Registered Members, ~3,700 Acute Hepatic Patients, Most Are Biochemically/Mutation Confirmed: AIP: 2,798 HCP: 592 VP: 312 Total = 3,702 *Andersson C.,AIP in Northern Sweden, PhD Thesis, 1997; Elder et al.,j.inherit Metab Dis Epub Nov 1, 2012, **Estimated

125 MOUNT SINAI PORPHYRIA DIAGNOSTIC & TREATMENT CENTER Acute Hepatic Porphyria Patients Annual Number Diagnosed and Mutations Confirmed; 1/1/2010 to 11/30/2016 Year AIP VP HCP Total (11 Months) Total Initial Misdiagnosis is Common in Many Patients Mean Time from First Symptoms to Diagnosis is ~10 Years Prevalence likely Underestimated

126 AHPs: MANIFESTATIONS Acute Neurovisceral Attacks: Prodrome: Confusion: Brain Fog, Insomnia, Fatigue - Warning Signal Acute Attack: Excruciating Abdominal Pain, Vomiting, BP and HR Can Progress to: Muscle Weakness, Paralysis, Seizures, if Untreated Precipitating Factors that Increase ALAS1: Drugs (P450 Inducers), Alcohol Dieting, Low Caloric Intake Hormonal Changes (Menstruation), Etc. Chronic Manifestations: Between Attacks: Many Patients Have Progressive Neuropathy & Severe Neuropathic Pain Requiring Pain Medication Fatigue, Chronic Nausea, Weakness and Insomnia Difficulty Maintaining Work Activities, Live in Fear of Attack

127 PATHOGENESIS OF THE ACUTE ATTACKS IN AIP Normal Hepatic Heme-Mediated Feedback Repression Glycine + Succinyl CoA ALAS1 ALAD HMB-Synthase ALA PBG HMB HEME 50% HMB-Synthase ALAS1 ALAD ALA PBG HMB HEME Decreased Hepatic Heme-Mediated Feedback Repression Clinically Manifest AIP

128 ACUTE INTERMITTENT PORPHYRIA (AIP) Most Common Acute Hepatic Porphyria Clinical Groups Based on Frequency of Acute Attacks: Recurrent Attacks: 4 or more attacks/yr; Men & Women As Frequent as Weekly or Monthly Women with Monthly Attacks during Luteal Phase of Menstrual Cycle About 50% Have Daily Symptoms Between Attacks Sporadic Attacks: < 3 Attacks/yr; Men & Women Asymptomatic High ALA/PBG Excreters (ASHE): Previous Attack in Most Cases, with Persistently Elevated ALA and PBG At High Risk of Recurrent Attacks and May Have Disease Complications

129 ACUTE NEUROVISCERAL ATTACKS: INCIDENCE OF SYMPTOMS Symptom % of Patients Abdominal Pain 95 Vomiting 72 Constipation 70 Muscle Weakness 68 Tachycardia 62 Mental Symptoms 48 Hypertension 45 Convulsions 15 Paralysis 10

130 MANAGEMENT OF ACUTE PORPHYRIC ATTACKS Admit to Hospital or Outpatient Clinic ASAP Treatment Delay Can Result in Worsening of Symptoms, Prolonged Recovery and Life-threatening Complications Withdraw All Common Precipitants (Drugs, Alcohol, Fasting, Infection...) Use Opiates as Needed for Pain Order Hematin (Panhematin ) (Inhibits ALAS1) 3-4 mg/kg IV Daily for 4 Days or Until Symptoms Improve

131 SAFETY OF HEMIN Hematin (Panhematin ) 1 ST Orphan Drug, 1982 Approved Based on Small Open Label Studies, but in Clinical Use for >30 Years Adverse Reactions or Side Effects 1-4 : Phlebitis, Coagulopathy 1, Fever, Aching, Malaise, Migraine, Hemolysis, One Case of Circulatory Collapse 2, One Case of Transient Renal Failure After Excessive Dose 3 Tachyphylaxis Reported in Patients with Long Term Use 5 Chronic Use Requires a Port with Infection and Thrombosis Risk Chronic Use Has Been Associated with Iron Overload FDA Has Not Approved Prophylactic Use 1 Morris DL, et al. Ann Intern Med 1981;95:700-1.; 2 Khanderia U. Clin Pharm 1986;5: Dhar GJ, et al. Acta Med Scand 1978;203: ; 4 Anderson KE, et al. Am J Med. 2006; 119:801.e19-24, 5 Besur et al. Metabolites 2014; 4,

132 CASE STUDY- RECURRENT ATTACKS IN A 30 Y/O FEMALE WITH AIP 20 Attacks in a Year 32 Days of IV Hematin Hospitalization for Some Attacks, Others On Demand Breakthrough Attacks Despite Bi-weekly Heme Prophylaxis Extremely Poor Quality of Life, Multiple Days Lost from Work

133 mmol/mmol Creatinine LIVER TRANSPLANTATION IN ACUTE HEPATIC PORPHYRIA Soonawalla et al., Lancet 363: , 2004 A 19 y/o Woman with Multiple Recurrent Acute Attacks Unresponsive to Hematin Had an Orthotopic Liver Transplant Transplant Demonstrated Importance of Liver in Disease Pathogenesis ~10 Additional Patients Transplanted in Europe Domino Transplant Patients Had Increased ALA & PBG and Attacks Challenges: High Frequency of Hepatic Artery Thromboses Limited Availability of Organs High Morbidity & Mortality Pre-Tx: 37 Attacks over 29 Months Post-Tx: None for > 10 Years Urinary Excretion of ALA & PBG after Liver Transplant ALA/Creatinine PBG/Creatinine Hr after Liver Transplant

134 IDEAL NEXT GENERATION THERAPY Excellent Safety Profile Effective for Prophylaxis in Recurrent Attack Patients Decrease Number of Attacks Minimize Symptoms in Between Attacks No Evidence of Tachyphylaxis Convenient Administration: Ideally Subcutaneous or Oral Route to Avoid Portacath Potential for at Home Use Faster/Longer Lasting Effects for Acute Treatment: Minimize Multi-Day Hospitalizations

135 RATIONALE FOR TARGETING HEPATIC ALAS1 ALAS1 mrna Strongly Upregulated During Attacks Hematin Down Modulates ALAS1 Addition of Heme to Liver Cells in Culture Leads to Reduced ALAS1 mrna Liver Transplant Is Curative Domino Transplant Recipients Have Increased ALA/PBG & Have AIP Symptoms Liver Derived ALA & PBG Drive Attacks

136 CONCLUSIONS Acute Hepatic Porphyrias Are Panethnic and a Worldwide Problem Attacks Can Be Either Recurrent or Sporadic: Life-Threatening Signs and Symptoms Poor Quality of Life, Long Hospital Stays Chronic & Progressive Neuropathic Pain & Neuropathy ALAS1 Targeting in Liver Has Been Validated: Liver Transplant and Heme Infusion Therapy Unmet Need for New Therapeutic Options: Effective for Prophylaxis Better Safety Profile and Faster Onset Easier Drug Delivery Strategy

137 Givosiran (ALN-AS1) Pushkal Garg, M.D. Senior Vice President, Clinical Development 137

138 Givosiran: Investigational RNAi Therapeutic Therapeutic Hypothesis Knockdown of Liver ALAS1 Protein to Reduce ALA/PBG ALA/PBG induce porphyria symptoms ALAS1 protein Givosiran (ALN-AS1) knockdown of ALAS1 reduces ALA/PBG production and prevents attacks Givosiran (ALN-AS1) 138

139 Givosiran Phase 1 Study: Parts A and B Study Design and Objectives Part A: Single-Ascending Dose (SAD) Randomized 3:1, Single-blind, Placebo-controlled, in Asymptomatic High Excreter Patients (ASHE) 0.035* mg/kg x 1 SC, N= mg/kg x 1 SC, N= mg/kg x 1 SC, N=4 1.0 mg/kg x 1 SC, N=4 Part A and B Study Objectives: Primary: safety Secondary: PK and PD (ALA, PBG) Exploratory: ALAS1 mrna by cerd 2.5 mg/kg x 1 SC, N=4 Part B: Multiple-Ascending Dose (MAD) Randomized 3:1, Single-blind, Placebo-controlled, in ASHE Patients 0.35 mg/kg, qmx2 SC, N=4 1.0mg/kg, qmx2 SC, N=4 139 Clinicaltrials.gov: NCT *0.035 mg/kg cohort dosed after 0.10 and 0.35 mg/kg cohorts

140 Mean [+/- SEM] ALAS1 mrna Lowering Relative to Baseline (%) Givosiran Phase 1 Study Interim Results Part A 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< SAD Placebo (N=5) mg/kg Givosiran (N=3) 0.10 mg/kg Givosiran (N=3) 0.35 mg/kg Givosiran (N=3) 1.0 mg/kg Givosiran (N=3) 2.5 mg/kg Givosiran (N=3) Days since first dose Normal healthy individual 140 Data in database as of 28 Jun 2016 Sardh et al., SSIEM, September 2016

141 Mean [± SEM] Creatinine Normalized PBG Relative to Baseline Mean [± SEM] Creatinine Normalized ALA Relative to Baseline Givosiran Phase 1 Study Interim Results Part A Pharmacodynamic Data: Urinary PBG and ALA Part A (SAD): PBG Part A (SAD): ALA Month Month Parts A and B Safety Summary Givosiran was generally well tolerated No discontinuations or serious adverse events related to study drug No clinically significant changes in physical examination or laboratory tests 2 mild and transient injection site reactions SAD Placebo (N=5) mg/kg Givosiran (N=3) 0.1 mg/kg Givosiran (N=3) mg/kg Givosiran (N=3) 1.0 mg/kg Givosiran (N=3) 2.5 mg/kg Givosiran (N=3) SAD, Single-Ascending Dose; 5 subjects had >1 treatment assignment: 2 subjects repeated Part A; 3 subjects enrolled in Parts A and B; Reference ranges: ALA ULN: < 3.9 or 3.8 mmol/mol Cr at sites 101 or 201; PBG ULN: < 1.6 or 1.5 mmol/mol Cr at sites 101 or *Data transfer date: 07 Nov 2016; Sardh et al., ASH, December 2016

142 Givosiran Phase 1 Study: Part C Overview* Run-in Phase (3 months) Run-in Observation Run-in Observation D0 Givosiran Treatment Phase (6 months) D84 Cohort 1, 2.5 mg/kg q3m x 2, N=4 Cohort 2, 2.5 mg/kg qm x 4, N=4 D168 Run-in Observation Cohort 3, 5 mg/kg qm x 4, N=4 Run-in Observation Cohort 4, 5 mg/kg q3m x 2, N=4 Study Design Placebo-controlled, double-blind, randomized 3:1, multiple dose study in AIP patients with recurrent attacks Key Inclusion Criteria: o Genetic confirmation of AIP o 2 attacks in past 6 months if on-demand treatment or willing to stop hemin prophylaxis during study. One attack in run-in required for randomization. Objectives Safety and tolerability of givosiran Characterize givosiran PK and PD Exploratory Objectives Clinical activity of givosiran on attack characteristics and treatment Characterize circulating ALAS1 mrna from the liver in urine and serum 142 *Data cut-off is D168 for Cohort 1 (unblinded) and D84 for Cohort 2 (blinded) Clinicaltrials.gov: NCT

143 Interim Givosiran Phase 1 (Part C) Study Results* Demographics and Baseline Disease Activity: Cohorts 1 and 2 Demographics (N=8) Age, years; mean (range) 39.4 (21-60) Sex: Female, n (%) 7 (88) Race: White/Caucasian, n (%) 8 (100) Patient Reported Attack Number in last 12 mos; mean (range) 17.9 (0-50) Hemin prophylaxis use prior to study, n (%) 5 (62) Baseline Disease Activity (N=8) Baseline PBG, mmol/mol Cr; mean (min, max) 48.6 (12.3, 88.2) Baseline ALA, mmol/mol Cr; mean (min, max) 23 (2.6, 36.7) 143 *Data transfer date: 07 Nov 2016; Sardh et al., ASH, December 2016 ULN: ALA <3.9 or 3.8 mmol/mol Cr; PBG < 1.6 or 1.5 mmol/mol Cr depending on site

144 Interim Givosiran Phase 1 (Part C) Study Results* Safety and Tolerability in AIP Patients with Recurrent Attacks No drug-related SAEs in Cohorts 1-4 Cohorts 1 and 2 No discontinuations due to AEs During treatment period, all randomized patients (8/8) reported at least 1 nonporphyria attack AE o o o o Majority of AEs mild or moderate in severity AEs reported in 3 patients were abdominal pain, nausea, vomiting, nasopharyngitis, and headache (3 patients each) Possibly or definitely related AEs reported in 2 cases were injection site reaction and myalgia; all mild No clinically significant changes in vital signs, EKG, clinical laboratory parameters or physical examination Cohort 3 After data transfer date, one patient experienced an SAE of acute pancreatitis complicated by pulmonary embolism resulting in death o o Event assessed as unlikely related to givosiran or placebo by investigator due to presence of gallbladder sludge Safety Review Committee in agreement with assessment 144 *Data transfer date: 07 Nov 2016; Sardh et al., ASH, December 2016

145 Interim Givosiran Phase 1 (Part C) Study Results* Clinical Activity Data: Cohort 1, Placebo Patient Run-in 120 Treatment Study Day PBG ALA Heme Porphyria Attack Hospitalization mmol/mol/cr Period Weeks Attacks Attacks Annualized Max Attack-Free Interval (Days) Hemin Doses Hemin Doses Annualized Run-In Treatment *Data transfer date: 07 Nov 2016; Sardh et al., ASH, December 2016

146 Interim Givosiran Phase 1 (Part C) Study Results* Clinical Activity Data: Cohort 1, Givosiran Patient 1 Run-in Study Day Treatment PBG ALA Heme Porphyria Attack Hospitalization mmol/mol/cr Period Weeks Attacks Attacks Annualized Max Attack-Free Interval (Days) Hemin Doses Hemin Doses Annualized Run-In Treatment *Data transfer date: 07 Nov 2016; Sardh et al., ASH, December 2016

147 Interim Givosiran Phase 1 (Part C) Study Results* Clinical Activity Data: Cohort 1, Givosiran Patient 2 Run-in Study Day Treatment PBG ALA Heme Porphyria Attack Hospitalization mmol/mol/cr Period Weeks Attacks Attacks Annualized Max Attack-Free Interval (Days) Hemin Doses Hemin Doses Annualized Run-In Treatment *Data transfer date: 07 Nov 2016; Sardh et al., ASH, December 2016

148 Interim Givosiran Phase 1 (Part C) Study Results* Clinical Activity Data: Cohort 1, Givosiran Patient 3 Run-in Treatment PBG ALA Study Day Heme Porphyria Attack Hospitalization mmol/mol/cr Period Weeks Attacks Attacks Annualized Max Attack-Free Interval (Days) Hemin Doses Hemin Doses Annualized Run-In Treatment *Data transfer date: 07 Nov 2016; Sardh et al., ASH, December 2016

149 % Decrease in Annualized Attack Rate % Decrease in Annualized Hemin Doses Maximum Attack Free Interval (Ratio Relative to Run-In) Interim Givosiran Phase 1 (Part C) Study Results* Summary of Clinical Activity Data Cohorts 1 and 2 in AIP Patients Givosiran Treated Period Relative to Run-in 100 Cohort 1: Mean 74% Decrease in Annualized Attack Rate Cohort 1: Mean 75% Decrease in Annualized Hemin Doses Cohort 1: Maximum Attack Free Interval 10.5x Relative to Run-In PBO Givo- 1 Givo- 2 Givo- 3 Mean C1- Givo Mean C2 0 PBO Givo- 1 Givo- 2 Givo- 3 Mean C1- Givo Mean C2 0 PBO Givo- 1 Givo- 2 Givo- 3 Mean C1- Givo Mean C2 Cohort 1 Cohort 2 Cohort 1 Cohort 2 Cohort 1 Cohort 2 Cohort 1 is through D168, Cohort 2 through D84 of the treatment phase Cohort 2 data is aggregated (including placebo) to protect blind 149 *Data transfer date: 07 Nov 2016; Sardh et al., ASH, December 2016

150 Interim Givosiran Phase 1 (Part C) Study Results* Summary and Study Next Steps Givosiran safety and tolerability No drug-related SAEs or discontinuations due to AEs No dose-dependent AEs or clinically significant changes in vital signs, EKG, clinical laboratory parameters or physical examination Cohort 3: one unlikely related fatal SAE of acute pancreatitis complicated by a pulmonary embolism Givosiran showed robust clinical activity in AIP patients with recurrent attacks Data suggest modest lowering, and/or blunting of further increases during attacks, of ALA/PBG may be sufficient for clinical activity Cohort 1 Data in Givosiran-treated patients: 74% reduction in annualized attack rate compared to run-in 75% reduction in annualized hemin usage compared to run-in 10.5x maximum attack free interval (~82 days longer on average) compared to run-in Aggregated Cohort 2 Blinded Data: Supportive data demonstrating reduction in attack rate and hemin usage compared to run-in Study Next Steps Complete dosing of Cohorts 3 and 4 Ongoing open label extension study for longer term safety and clinical activity data 150 *Data transfer date: 07 Nov 2016

151 Natural History Study Results Demonstrate Severe Disease Burden Design Observational, multinational, prospective natural history study 112 patients across 13 countries Diagnosis of acute hepatic porphyria (AHP), including AIP, HCP, VP Recurrent attacks (>3+ attacks/last 12M) or using prophylactic treatment >70% Attacks requiring hemin or treatment in hospital or healthcare setting >65% Patients experience chronic symptoms between attacks 4.6 Average hospital stays per year, ranging 1-60 days Severe Disease Burden; Impact on QOL measures comparable to HAE 151

152 RANDOMIZATION Potential Phase 3 Study Design for Givosiran* Initial Focus on Prophylaxis for Recurrent AIP Patients Patient Population Biochemical and genetic diagnosis of AIP 4 attacks per yr if not on hemin prophylaxis If on hemin prophylaxis, willing to stop for study duration N = Givosiran OR Placebo Endpoints Change in annualized attack rate compared to baseline ALA, PBG and ALAS1 levels Hemin usage Hospitalization EQ-5D-5L QoL Safety and tolerability All completers eligible for givosiran treatment in Phase 3 OLE study 152 *Preliminary plans subject to further diligence and health authority feedback

153 Patient Advocacy & Scientific Leadership Patient Advocacy Education Collaboration Support of American Porphyria Foundation (APF) o Advocacy team presence at multiple APF patient events in 2016 o Patient advisory board scheduled for early 2017 to better understand patient needs Building relationships with leading European advocacy groups such as the British Porphyria Association (BPA) EXPLORE Natural History Study o Largest prospective study ever conducted in AHP Data presentations at SSIEM, AASLD, and ASH conferences in 2016 Disease awareness and education initiatives ongoing Long standing collaboration with the American Porphyria Consortium and European Porphyria Network Investigators Protect the Future initiative for porphyria physician training 153

154 Acute Hepatic Porphyria Market Landscape Major Unmet Need No approved therapy for attack prevention No significant investigational drugs in development Only available therapy (hemin) has modest efficacy and safety limitations In EXPLORE study, mean of 3.3 attacks per year on hemin prophylaxis vs. 5.1 attacks per year without Short duration of drug activity and reports of decreased effectiveness over time Side effects including nausea, vomiting, headache, phlebitis Risk of iron overload Risk of venous destruction or complications from venous port (e.g. infection, clots) 154 Bissell DM, Wang B. J Clin Transl Hepatol. 2015;3: Anderson KE, Bloomer JR, Bonkovsky HL, et al. Ann Intern Med. 2005;142: Balwani M, Desnick RJ. Blood. 2012;120: Bonkovsky HL. Am Soc Hematol Educ Program. 2005: Wahlin S, Harper P. In: Ferreira GC, Kadish KM, Smith KM, Guilard R, eds. Handbook of porphyrin science. Vol

155 Acute Hepatic Porphyria Market Opportunity AHP represents a global opportunity with potential for continuous expansion Acute intermittent porphyria (AIP) Variegate porphyria (VP) Hereditary coproporphyria (HCP) Asymptomatic high excreters (ASHE) Launch Target AIP patients with recurrent attacks Disease Expansion VP, HCP patients with recurrent attacks AIP Patient Expansion All AHP patients with sporadic attacks Life Cycle Management Acute attacks; ASHE subjects 155

156 Commercial Opportunity - High Unmet Need Supported by Close Analogue: HAE Acute Hepatic Porphyria could be a significant growth market AHP has many similarities to Hereditary angioedema (HAE) prior to the advent of effective prophylactic treatments Underdiagnosed rare disease with low consensus prevalence HAE: 2:100,000 AHP: 2-5:100,000 (AIP only) Acute, life-threatening episodes requiring urgent medical attention Suboptimal on-demand therapies Prophylaxis primary endpoint of reduction in attack frequency High burden on the healthcare system and patient QoL 800 M 400 M 0 M Cinryze Global Sales Cinryze Launch Date: October 2008 WAC Price: >$500K pppy 156

157 Givosiran Program Summary & Next Steps Phase 1 data providing initial evidence of clinical activity in AIP patients experiencing recurrent attacks 74% decrease in annualized attack rate, 75% decrease in annualized hemin doses, >10X increase in maximum attack free interval in Part C cohort 1 Attractive global commercial opportunity Substantial unmet need and potential for continuous expansion Next Steps Additional Phase 1 data planned for mid-2017, likely at ICPP in June 2016 Rapid acceleration to Phase 3 Plan to engage in regulatory discussions to align on pivotal study design for late 2017 start 157

158 Q&A Session #2 Fitusiran and Givosiran 158

159 159

160 Alnylam s Commercial Transition Commercial Leaders Commercial Excellence Patient Solutions Payer Relationships Physician Education Quality & Compliance Medically Focused Transparency Innovation Patient Focus Scientific Excellence RNAi Pioneers Thousands of Data Presentations Hundreds of Papers Integrity R&D Leaders 160

161 R&D Strategy Enables Definable Path to Approval and Market with a Steady Stream of New Products 1 Genetically validated, liverexpressed target gene High unmet need disease Opportunity for highly competitive profile Delivery with GalNAc conjugate platform 2 Biomarker for POC in Phase 1 Blood or urine based Informative disease correlation Establish dose/regimen for late-stage development 3 Definable path to approval and market Clinical development plans with established endpoints Demonstrable value for payers 161

162 Alnylam 2020 In Focus Planned Rapid Launch Succession Givosiran ~2020 Fitusiran ~2019 Patisiran ~

163 Patisiran In Development for the Treatment of hattr Amyloidosis ~PLANNED LAUNCH DATE 2018 MARKET SIZE WORLDWIDE 20-50k (mixed phenotype with polyneuropathy) PATIENT ADVOCACY PRODUCT RIGHTS North America, Western Europe KEY CALL POINTS Amyloid Centers Amyloidosis Specialists (including neurologists, cardiologists) Hematologists 163

164 Fitusiran In Development for the Treatment of Hemophilia and RBD ~PLANNED LAUNCH DATE 2019 MARKET SIZE WORLDWIDE 200k non-inhibitor patients 80% Hem A, 20% Hem B PATIENT ADVOCACY NHF ~4,000 inhibitor patients ~3,000 severe RBD patients WFH KEY CALL POINTS PRODUCT RIGHTS 50% North America, Western Europe Hemophilia Treatment Centers Hematologists 164

165 Givosiran In Development for the Treatment of Acute Hepatic Pophyria ~PLANNED LAUNCH DATE 2020 MARKET SIZE WORLDWIDE 2-5:100k (AIP) PATIENT ADVOCACY ~1,000 patients with recurrent attacks in US/EU PRODUCT RIGHTS Global KEY CALL POINTS Porphyria Network Neurologists Hematologists Emergency Medicine Pain Medicine 165

166 Succeeding in Rare Disease Requires a Specific Road Map Engagement and Advocacy Educate Retain Diagnose/ Expand RNAi Therapeutics Success Support and Solutions Access Best or First-in-Class Product Profiles 166

167 Key Commercial Objectives for Prepare for planned patisiran launch Lay foundation for planned fitusiran and givosiran launches Givosiran ~2020 Fitusiran ~2019 Patisiran ~ Build commercial capabilities to address evolving environment Keep patients in the center of what we do Best talent in place Extend Alnylam culture of science, passion, excellence, and urgency into commercial Integrated Access, Medical, Patient Services, Account Management Capabilities to execute Global planning, execution and performance management 3 Provide excellent commercial support to pipeline Pipeline support New product planning Broaden our commercial lens 167

168 Alnylam Expansion in North America & Western Europe Growth of Commercial Organization and European Presence Cambridge, MA Maidenhead, UK Zug, Switzerland TODAY European headquarters in Zug, Switzerland Development hub in Maidenhead, UK Build-out of Commercial Organization and Medical Affairs teams across North America and Western Europe underway 168

169 Alnylam Global Expansion Growth of Commercial Organization and ROW Presence TOMORROW Alnylam prepares for planned global launches (e.g., givosiran, ALN-CC5) ROW expansion plans in development 169

170 Medical, Access, and Patient Services are Foundation of Country-Level Launch Medical Critical country-level external activities * Engage and collaborate with key stakeholders Educate on disease and data Access Improve diagnosis and treatment pathway Provide early access to patients in need Account Management Patient Services Lay foundation for local access: evidence, burden of disease, value dossiers, performance based agreements Resolve administration hurdles Develop patient solutions/services 170 *in line with local legal and compliance requirements

171 Supply Chain Map Ensuring Consistent Drug Supply to Meet Commercialization Goals Alnylam Alewife Manufacturing Facility Fully operational and ready for patisiran launch Alnylam Norton DS Manufacturing Facility Expect to be commercially operational in

172 Commercial Readiness Summary Enable multiple planned product launches Recognize exciting market opportunities with global expansion Ensure launch readiness Prepare and manage product supply 172 Achieve Alnylam 2020 and Beyond

173 173

174 Alnylam 2017 Pipeline Goals *Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4 PATISIRAN (hattr Amyloidosis) Phase 2 OLE data APOLLO Phase 3 top-line APOLLO Phase 3 results NDA/MAA filing 2017* Early Mid Late FITUSIRAN (Hemophilia and RBD) GIVOSIRAN (Acute Hepatic Porphyrias) INCLISIRAN (Hypercholesterolemia) ADDITIONAL CLINICAL PROGRAMS Phase 2 OLE data ATLAS Phase 3 program start Phase 1, Part C data Phase 3 study start ORION-1 Phase 2 data HoFH Phase 3 study start ASCVD Phase 3 study start Continue to advance early/mid-stage pipeline; Present clinical data 174

175 175 In Focus

176 Focus on PATIENTS Why we do what we do Alexis Living with Hemophilia A Christina Living with hattr Amyloidosis Ariel Living with Acute Intermittent Porphyria 176

177 177 Thank you for coming!