Corporate Overview. November Alnylam Pharmaceuticals, Inc.

Transcription

1 Corporate Overview November Alnylam Pharmaceuticals, Inc.

2 Please note this is an interactive PDF Click these bubbles in order to access complete data slides Click the safety bars in order to access additional safety data 2

3 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 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. 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 Alnylam Strategic Therapeutic Areas (STArs) Investigational pipeline focused in 3 STArs Genetic Medicines RNAi therapeutics for rare diseases Cardio-Metabolic Diseases RNAi therapeutics for dyslipidemia, NASH, type 2 diabetes, hypertension, and other major diseases Hepatic Infectious Diseases RNAi therapeutics for major liver infections beginning with hepatitis B & D 7

8 Alnylam Development Pipeline 8

9 Hereditary ATTR Amyloidosis Patisiran and ALN-TTRsc02 9

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

11 RNAi Therapeutics for hattr Amyloidosis Potential for Disease Modification by Reducing Pathogenic Protein 1 Genetically validated, liverexpressed target gene Mutant Transthyretin (TTR) is disease-causing protein Potential for highly competitive profile vs. TTR stabilizers 2 Biomarker for POC in Phase 1 Serum biomarker TTR Causal in amyloid deposits in nerves (hattr-pn) and heart (hattr-cm) 3 Definable path to approval and market Streamlined clinical development plans Established Endpoints: Neurological Impairment Score (hattr-pn) 11

12 Alnylam ATTR Amyloidosis Portfolio* Committed to Continued Innovation for Patients hattr-pn IV administration patisiran Phase 2 completed Phase 2 Open-Label Extension (OLE) study ongoing Phase 3 trial ongoing; fully enrolled with top-line results expected in mid-2017 APOLLO-OLE study ongoing ALN-TTRsc02 ATTR hattr-pn, hattr-cm & wtattr ESC second generation chemistry Expect quarterly SC dose regimen Phase 1 ongoing; initial data expected in late *In October 2016, Alnylam decided to discontinue development of revusiran, which used STC first generation GalNAc chemistry and was being developed for treatment of hattr-cm

13 Patisiran Interim Phase 2 OLE Study Results* Ongoing Study in hattr-pn Patients Mean max 93% TTR KD clamped thru 24 months Mean -6.7 point change in mnis+7 at 24 months >70% patients show improvement in mnis+7 scores TTR KD correlated with improvement in mnis+7 scores Evidence for Potential Halting or Improvement of Neuropathy Progression Safety: Generally well tolerated out to 25 months 9 non-drug related SAEs in 6 patients Majority of AEs mild to moderate, including mild flushing (22.2%) and mild infusion-related reactions (18.5%) No significant lab findings, including platelets, and no drugrelated discontinuations PLANNED NEXT STEPS 36-month Phase 2 OLE data in 2017 Alnylam NA/EU; Sanofi Genzyme ROW 13 *Preliminary Phase 2 OLE results based on data in database as of May 12, 2016; Suhr, ISA, July 2016

14 2:1 RANDOMIZATION APOLLO Phase 3 Study Design Enrollment Complete N=225 Patient Population hattr-pn: 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 and MAA if positive Statistical Considerations Placebo-estimated mnis+7 progression rate of 17.8 points/year derived from natural history study of 283 hattr-pn patients 90% Power to detect as little as 37.5% difference in ΔmNIS+7 between treatment groups with 2-sided alpha=0.05 Based on original target enrollment of 200 patients 14 Clinicaltrials.gov # NCT

15 ALN-TTRsc02 Opportunity Potential for Best-in-Class Profile IONIS-TTR Rx ALN-TTRsc02 52 DOSES PER YEAR 4 DOSES PER YEAR ANTICIPATED PLANNED NEXT STEPS Phase 1 started in June 2016 Initial Data late 2016 Phase 3 start in

16 Discontinuation of Revusiran Development Safety Findings as of October 7, 2016 Following reports of peripheral neuropathy and elevated blood lactate levels in Phase 2 OLE, Company conferred with independent experts and then requested Phase 3 ENDEAVOUR DMC meeting after receiving additional reports ENDEAVOUR DMC met October 4, 2016 to review safety data in light of new information and to assess overall benefit-risk profile of revusiran in patients with hattr-cm DMC reported no conclusive evidence of drug-related peripheral neuropathy signal However, recommended suspension of dosing based on lack of favorable benefit-risk Company subsequently reviewed unblinded ENDEAVOUR data which revealed imbalance of mortality Decision to discontinue all ongoing studies and further development of revusiran APOLLO DMC met October 7, 2016 at Company s request and recommended continuing the Phase 3 study of patisiran in patients with hattr-pn without modification Company continues to conduct comprehensive evaluation of ENDEAVOUR Phase 3 data Update provided during Q3 16 earnings call on November 2, deaths in revusiran arm, 2 deaths in placebo arm Most deaths cardiovascular in nature; none attributed to study drug Further update on progress of evaluation expected at R&D Day on December 16 th No evidence of drug-related peripheral neuropathy or cardiovascular mortality signal based on current assessment of safety data from >800 subjects/patients dosed across 9 other clinical programs, with exposure of up to 34 months (as of Sep 30, 2016) 16

17 Hemophilia and Rare Bleeding Disorders Fitusiran 17

18 Hemophilia and Rare Bleeding Disorders DESCRIPTION Genetic deficiency resulting in inability to generate thrombin and to stop bleeding PATIENT POPULATION* Hemophilia A and B 178,500 worldwide Highest need is prophylaxis for inhibitor patients and to avoid inhibitor formation in all patients Global need due to frequent IV infusions, ability to manufacture, and cold chain 3,500 with inhibitors 18 * World Federation of Hemophilia, Report on the Annual Global Survey 2014 (October 2015)

19 Fitusiran for Hemophilia Potential Game-Changing SC Therapy that Restores Hemostasis 1 Genetically validated, liverexpressed target gene Antithrombin (AT) is key natural anticoagulant Undruggable with mabs or small molecules (SM) Co-inheritance of AT deficiency with hemophilia associated with milder bleeding phenotype 2 Biomarker for POC in Phase 1 Plasma biomarkers measure components in coagulation cascade: AT Thrombin Generation 3 Definable path to approval and market Two separate pivotal trials in inhibitor and on-demand patients Established Endpoint: Annualized Bleeding Rate (ABR) 19

20 Fitusiran Interim Phase 1 Study Results* Ongoing Study in Hemophilia A & B Patients, Including Inhibitors Up to 91% AT lowering Up to mean 290% increase in thrombin generation Median estimated ABR of 0 in non-inhibitor patients AT lowering, thrombin generation increases, and preliminary evidence of reduced bleeding in first inhibitor cohort DURABILITY Monthly SC fixed dose regimen Evidence for Potential Restoration of Hemostasis in Severe Hemophilia A and B Safety: Generally well tolerated No SAEs; majority of AEs mild or moderate o Mild ISRs in 11 (35%) patients One discontinuation due to AE considered severe, possibly drug-related o o o Non-cardiac chest pain; associated transient increases in LFTs, D-dimer, CRP Extensive evaluation unremarkable; VTE excluded Event resolved with symptomatic management; antacids, analgesics No thromboembolic events; no lab evidence for pathologic clot formation PLANNED NEXT STEPS Additional data at ASH in December 2016 Start Phase 3 studies in early Alnylam, Sanofi Genzyme NA/EU; Sanofi Genzyme ROW *Interim Phase 1 study results as of July 11, 2016; Pasi et al., WFH, July 2016

21 Complement-Mediated Diseases ALN-CC5 21

22 Complement-Mediated Diseases DESCRIPTION Numerous debilitating diseases caused by abnormal complement activity In PNH, manage breakthrough hemolysis and reduce burden of frequent IV infusions PATIENT POPULATIONS* - Paroxysmal noctural hemoglobinuria (PNH) - Atypical hemolytic uremic syndrome (ahus) - Neuromyelitis optica - Myasthenia gravis - and many others >5,000 Patients with PNH & ahus on eculizumab 1, initially 22 * Estimated based on Alexion s Third Quarter 2015 Financial Results 1 eculizumab, trade name Soliris, Alexion Pharmaceuticals, Inc.

23 ALN-CC5 for Complement-Mediated Diseases Potential New Approach for Optimized Therapy 1 Genetically validated, liverexpressed target gene Complement C5 is key component of terminal complement pathway; clinically validated in PNH & ahus 2 Biomarker for POC in Phase 1 Serum biomarkers: C5 Serum hemolytic activity Lactate dehydrogenase (LDH) 3 Definable path to approval and market Small pivotal study in PNH patients Established endpoints: LDH reduction Blood transfusions 23

24 ALN-CC5 Initial Phase 1/2 Study Results* Initial Results in 6 PNH Patients Up to 99% C5 KD LDH normalized for 1 month with 75% reduction in Ecu dose Disease control in Ecu inadequate responder patient experiencing breakthrough hemolysis Significant improvement of Ecu PK with >3x increase in Ecu trough levels DURABILITY Expect quarterly SC dose regimen Potential opportunity to transform PNH with reduced burden of Ecu dose and frequency and to improve disease control in Ecu inadequate responder patients Safety: Generally well tolerated No SAEs, no discontinuations due to AEs In one patient, asymptomatic, transient grade 3 elevation of LFTs observed; possibly related Mild, transient ISRs observed in 3 patients PLANNED NEXT STEPS Start PNH Phase 2 at ASH in December 2016 Start monotherapy Phase 2 studies in other indications In *Preliminary Phase 1/2 study results based on data transferred up to June 6, 2016; Hill, EHA, June 2016

25 Acute Hepatic Porphyrias ALN-AS1 25

26 Acute Hepatic Porphyrias DESCRIPTION PATIENT POPULATION* Family of ultra-rare orphan diseases causing incapacitating and potentially fatal attacks with sporadic attacks ~5,000Patients in U.S./EU with recurrent attacks ~1,000Patients in U.S./EU Symptoms include: - Severe Abdominal Pain - Peripheral and Autonomic Neuropathy - Neuropsychiatric Symptoms Predominantly female, commonly misdiagnosed 26 * ORPHANET; The Porphyria Consortium

27 ALN-AS1 for Acute Hepatic Porphyrias Potential Transformative Therapy to Prevent Debilitating Attacks 1 Genetically validated, liverexpressed target gene ALAS1 is upstream of genetic defect in acute hepatic porphyrias Liver-specific inhibition undruggable with SM Up-regulation of ALAS1 results in accumulation of toxic intermediates ALA and PBG that drive disease 2 Biomarker for POC in Phase 1 Serum and urinary biomarkers: ALA PBG 3 Definable path to approval and market Small pivotal study in recurrent attack patients Endpoints: Porphyria attack frequency and severity ALA and PBG levels 27

28 ALN-AS1 Interim Phase 1 Study Results* Ongoing Study in Asymptomatic & Symptomatic Porphyria Patients Up to 64% silencing of ALAS-1 mrna Up to 86% lowering of ALA Up to 95% lowering of PBG Durable ALA and PBG reductions, with effects lasting >10 months after single dose DURABILITY Monthly and possibly quarterly SC dose regimen Potent and Durable Lowering of Toxic Heme Synthesis Intermediates that Mediate Attacks Safety: Generally well tolerated 3 SAEs all deemed unlikely related to study drug, and no discontinuations Majority of AEs reported were mild-moderate in severity No clinically significant laboratory abnormalities related to study drug PLANNED NEXT STEPS Recurrent attack patient data at ASH in December 2016 Start Phase 3 in Alnylam retains global rights to the ALN-AS1 program *Interim Phase 1 study results as of June 28, 2016; Sardh et al., SSIEM, September 2016

29 Hypercholesterolemia Inclisiran (aka ALN-PCSsc) 29

30 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 30 * Mozaffarian et al., Circulation, 2015

31 Inclisiran* for Hypercholesterolemia First-in-Class PCSK9 Synthesis Inhibitor 1 Genetically validated, liverexpressed target gene PCSK9 protein decreases LDL-C receptor levels, resulting in elevated cholesterol in blood Potential for highly competitive profile vs. anti-pcsk9 mabs Loss-of-function mutations in PCSK9 associated with lower LDL-C and decreased CV risk 2 Biomarker for POC in Phase 1 Serum biomarkers for regulation of cholesterol levels: PCSK9 LDL-C 3 Definable path to approval and market Pivotal trial in broad population of ASCVD patients; focused FH studies Established Endpoint: LDL-C 31 * Incliisiran also known as ALN-PCSsc and PCSK9si

32 Inclisiran* Interim ORION-1 Phase 2 Study Results Study in 501 ASCVD Patients Mean 74% PCSK9 KD at Day 90 Mean 50% LDL-C lowering at Day 90 after single dose Mean 52% LDL-C lowering at Day 180 after two quarterly doses 100% of patients with LDL-C lowering at Day 180 after two doses Potential Bi- or Tri-annual SC Dosing Regimen with LDL-C Lowering Comparable to Bi-monthly mabs ** Safety: Generally well tolerated No drug-related SAEs or discontinuations One fatal MI deemed unrelated to study drug Majority of AEs mild or moderate in severity Infrequent, transient ISRs in 3.2% patients One subject with ALT >3x ULN, attributed to concomitant statins * Inclisiran also knowns as ALN-PCSsc and PCSK9si Ray et al., AHA, November 2016 PLANNED NEXT STEPS Complete Phase 2 data by YE 2016 Start Phase 3 in ** Based on reported data (Zhang et al., BMC Med., 2015); no direct head-to-head studies have been performed The Medicines Company is leading and funding development inclisiran from Phase 2 onward and will commercialize the program, if successful

33 Other Programs to Watch 33

34 Primary Hyperoxaluria Type 1 (PH1) ALN-GO1 Interim Phase 1/2 Study Results in Healthy Volunteers DESCRIPTION Genetic mutations lead to excessive oxalate production, resulting in recurrent kidney stones and extensive renal damage DRUG MECHANISM ALN-GO1 targets glycolate oxidase (GO), an enzyme upstream from the genetic defect, for potential lowering of oxalate levels DURABILITY Monthly and possibly quarterly SC dose regimen Safety: Generally well tolerated No SAEs or discontinuations due to AEs All AEs mild or moderate, with exception of one subject with transient, asymptomatic CPK elevation deemed unrelated to study drug Up to PATIENT POPULATION* 8-fold increase in plasma glycolate in healthy volunteers ~5,000 worldwide Primarily affects children Sustained through 85 days at highest dose PLANNED NEXT STEPS Oxalate lowering data in PH1 patients in Milliner et al., IPNA, September 2016 * Cochat et al., N Engl J Med, 2013

35 Hepatitis B Virus (HBV) Infection ALN-HBV DESCRIPTION Viral infection leading to cirrhosis and hepatocellular carcinoma (HCC) Pre-clinical results: up to 3.6 log 10 HBsAg reduction PATIENT POPULATION* 1/3 of global population exposed ~290M patients worldwide, 25M in U.S./EU/Japan with chronic infection DRUG MECHANISM ALN-HBV targets all four transcripts of viral genome for potential reduction of HBsAg levels and increase in seroconversion rates 35 >4 log 10 reduction in viral DNA in chronically infected chimps Phase 1/2 Initiated in July 2016 PLANNED NEXT STEPS Initial clinical data in mid-2017 * Schweitzer et al. Lancet 386: , 2015; Basnayake, S.K. and Easterbrook, P.J., J. Viral Hepatitis 23: , 2016 Sepp-Lorenzino, Liver Meeting, November 2015

36 36 Guidance and Goals

37 37 37

38 Potential Multi-Year Pipeline Progression 38

39 Potential Multi-Year Pipeline Progression >10 Clinical readouts in

40 Potential Multi-Year Pipeline Progression >5 Programs in Phase 3 in

41 Potential Multi-Year Pipeline Progression 1 st Phase 3 data readout and, if positive, NDA in

42 Alnylam 2016 Pipeline Goals* *Goals as updated in 8/16 **Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4 2016** Early Mid Late PATISIRAN (hattr-pn) REVUSIRAN (hattr-cm) ALN-TTRsc02 (ATTR Amyloidosis) FITUSIRAN (Hemophilia and RBD) ALN-CC5 (Complement-Mediated Disease) ALN-AS1 (Hepatic Porphyrias) ALN-AAT (Alpha-1 Antitrypsin Deficiency) ALN-GO1 (Primary Hyperoxaluria) New Genetic Medicine Program INCLISIRAN (Hypercholesterolemia) Complete APOLLO Phase 3 Accrual Phase 2 OLE 24 Month Data Complete ENDEAVOUR Phase 3 Accrual Phase 2 OLE 12 Month Data CTA Filing Start Phase 1 Initial Phase 1 Data Phase 1 Data Phase 1/2 OLE Data Phase 1/2 Data Phase 2 PNH Start Phase 1 Data Initial Phase 1 Data Start Phase 1 Initial Phase 1 Data CTA Filing Initial Phase 2 Data ALN-HBV (Hepatitis B Virus Infection) CTA Filing Start Phase Alnylam discontinued development of ALN-AAT and revusiran in September and October 2016, respectively

43 Select Scientific and Clinical Meetings Late 2016 Conference Date (Location) Expected Presentation(s) Inclisiran American Heart Association (AHA) Scientific Sessions November 15 (New Orleans) Inclisiran ORION-1 Phase 2 Fitusiran ALN-CC5 ALN-AS1 American Society of Hematology (ASH) Annual Meeting December 3-6 (San Diego) Fitusiran Phase 1, Parts C and D (highest and fixed dose cohorts, including inhibitor patients); Initial Fitusiran Phase 1/2 OLE; ALN-CC5 Phase 1/2 (PNH patients); ALN-AS1 Phase 1, Initial Part C data (recurrent attack patients) ALN-TTRsc02 Corporate R&D Day 2016 December 16 (New York) ALN-TTRsc02 Phase 1 43

44 Financial Summary and Guidance 2016 Q3 Financial Results Cash ~$1.2B Includes $150.0 million in restricted investments GAAP Revenues $13.7M Total GAAP Operating Expenses $120.3M Research and Development Expense $97.9M General and Administrative Expense $22.4M GAAP Net Loss of $104.1M Shares Outstanding ~85.8M 2016 Guidance Year-end cash >$1.0B Includes $150.0 million of restricted investments received from credit agreements related to build out of new drug substance manufacturing facility 44

45 45 Thank You

46 46 Backup Slides

47 Grams of drug Exposure Levels with Revusiran Significantly Higher than other GalNAc Conjugate Programs Annualized Exposure Levels Return to Previous Slide 30 STC-GalNAc conjugate ESC-GalNAc conjugates Exposure Year Equivalents Relative to Revusiran 25 Revusiran 500mg qw STC-GalNAc conjugate Fitusiran 80mg qm 20 ALN-PCSsc 300mg q3m ESC-GalNAc conjugates 15 ALN-PCSsc 300mg q6m ALN-CC5 600mg q3m 10 ALN-AS1 2.5mg/kg qm Years 0 Revusiran 500mg qw Fitusiran 80mg qm ALN-PCSsc ALN-PCSsc 300mg q3m 300mg q6m ALN-CC5 ALN-AS1 600mg q3m 2.5mg/kg qm 47

48 Return to Previous Slide 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 48 *Adams et al., ISA, June 2016; Data as of 12May2016

49 Mean (SEM) % Serum TTR Knockdown Relative to Baseline Return to Previous Slide 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 49 SEM: Standard Error of the Mean *Adams et al., ISA, June 2016; Data as of 12May2016

50 mnis+7 Return to Previous Slide 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) 50 *Data as of 12May Partial imputation was used to recover mnis+7 data points where components were missing at one or more replicate measurements (per patient/visit)

51 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) Return to Previous Slide (2.7) (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) *Adams et al., ISA, June 2016; Data as of 12May Mean ΔmNIS+7 Across hattr-pn Studies at 24 mos ~

52 ΔmNIS+7 ΔmNIS+7 ΔmNIS+7 ΔmNIS+7 Patisiran Phase 2 OLE Preliminary Study Results* Correlation of TTR Knockdown with ΔmNIS+7 Return to Previous Slide 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 52 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 *Adams et al., ISA, June 2016; Data as of 12May2016

53 Serum TTR (Fraction Pre-dose) Superior TTR Knockdown with ALN-TTRsc02 ALN-TTRsc02 Compared to Revusiran in NHP** Return to Previous Slide 1 mg/kg ALN-TTRsc02 5 mg/kg Revusiran; QD x 5, QW x QDx5, QWx4 5 mg/kg Revusiran SD 1 mg/kg ALN-TTRsc ALN-TTRsc02 Revusiran Days Cumulative eauc Dose (ug/ml*day) (mg/kg) **Data on graph does not represent a side by side study. The two NHP studies were performed independently. Revusiran ± 1559 ALN-TTRsc ± Meyers, OTS, Oct. 2015

54 Interim Fitusiran Phase 1 Study Results* Safety/Tolerability, Parts B, C, & D Return to Previous Slide No SAEs related to study drug Majority of AEs mild or moderate in severity AEs (excluding ISRs) in 10% of patients Upper respiratory tract infection (10%), arthralgia (10%) 11 (35%) patients reported drug-related ISRs, all mild Mostly pain and/or erythema at injection site One patient discontinued due to AE of non-cardiac chest pain; considered severe and possibly related Associated with transient elevations of ALT (10x ULN), AST (8x ULN), CRP and D-dimer; no increase in total bilirubin Extensive evaluation unremarkable; VTE excluded by serial CT angiograms and liver and lower extremity ultrasound This event resolved with symptomatic management, including antacids and analgesics No thromboembolic events or laboratory evidence of pathologic clot formation (D-dimer, platelet count, fibrinogen, and/or PT/INR) With exception of case noted above, no other clinically significant drug-related changes in laboratory parameters No instances of anti-drug antibody (ADA) formation Bleed events successfully managed with infusion of standard replacement factor or bypass agents 54 *Data transfer up to 11July2016 Pasi et al., WFH, July 2016 Adverse event grouping based on MedDRA-coded terms, excluding bleed events

55 % Mean (+/- SEM) AT Activity Relative to Baseline Interim Fitusiran Phase 1 Study Results* AT Lowering, Part C Return to Previous Slide AT lowering after monthly dosing in patients with hemophilia A and B 125 Cohort mcg/kg (N=3) Cohort mcg/kg (N=3) Cohort mcg/kg (N=3) Cohort mcg/kg (N=3) Cohort 5 80 mg (N=6) Days since first dose Onset Observation 55 *Data transfer: 30Jun2016 Pasi et al., WFH, July 2016

56 Relative Nadir AT Level (Mean +/- SEM, %) Interim Fitusiran Phase 1 Study Results* AT Lowering, Parts A, B & C Return to Previous Slide Dose-dependent AT lowering Mean maximal AT lowering of 87 ± 1% at 80 mg fixed dose mcg/kg (n=3) 15 mcg/kg (n=3) 45 mcg/kg (n=6) 75 mcg/kg (n=3) 225 mcg/kg (n=3) 450 mcg/kg (n=3) 900 mcg/kg (n=3) 1800 mcg/kg (n=3) 80 mg (n=6) Part A (Single dose) Part B (Weekly dose) Part C (Monthly dose) 56 *Data transfer: 30Jun2016 Pasi et al., WFH, July 2016

57 Peak Thrombin Generation (nm) Interim Fitusiran Phase 1 Study Results* Thrombin Generation, Part B & C Return to Previous Slide Post hoc analysis of thrombin generation by AT lowering quartiles Mean thrombin generation increase of 289% relative to baseline at AT lowering >75% (p<0.001 ) 250 Boxes denote median and interquartile range N=4 Healthy Volunteers AT Lowering < 25% (N=30) AT Lowering 25-50% (N=25) AT Lowering 50-75% (N=25) Patients with Hemophilia *Data transfer: 30Jun2016; Pasi et al., WFH, July 2016 %Change in Peak TG: p<0.001 by Mann-Whitney test, when compared with AT3 lowering than <25% group AT Lowering >75% (N=16)

58 ABR ABR Interim Fitusiran Phase 1 Study Results* Exploratory Analysis of Bleed Events, Part C Return to Previous Slide Summary of Median ABR (All Cohorts) Summary of Median ABR (80 mg) PPx OD Onset Observation Pre-Study Pre-study Onset Observation 0 0 PPx Onset Observation Pre-Study Pre-study Onset Observation All Part C patients^ Median ABR, Pre-study period: 2 (PPx); 28 (OD) Median ABR, Observation period: 0 53% of patients report no bleeds 82% of patients report no spontaneous bleeds Part C, 80 mg dosing cohort ^ Median ABR, Pre-Study (all PPx patients): 6 Median ABR, Observation period: 0 58 *Data transfer: 30Jun2016; Pasi et al., WFH, July 2016 PPx: Prophylaxis, OD: On-Demand; ABR, annualized bleeding rate; Post hoc analysis of treated bleed events during Onset (Day 0-28) and Observation periods (Day 29 to last study visit or last dose+56 days, whichever is earlier; Pre-study ABR derived from medical records; ^Patient C5-4 withdrawn, excluded from analysis

59 AT Activity (%) AT Activity (%) AT Activity (%) AT Activity (%) AT Activity (%) AT Activity (%) Interim Fitusiran Phase 1 Study Results* AT, Peak Thrombin, Part D (Cohort 1, 50 mg) Return to Previous Slide Initial AT lowering and thrombin generation results in patients with inhibitors Comparable AT lowering and thrombin generation as observed with similar doses in non-inhibitor patients Thrombin generation with fitusiran consistently exceeds transient levels achieved with BPA administration D1-1 D1-2 D Peak Thrombin (nm) Days Days Days Peak Thrombin (nm) Peak Thrombin (nm) 140 D1-4 D1-5 D Days *Data transfer: 11July2016 Pasi et al., WFH, July Peak Thrombin (nm) Pre-dose BPA Peak Thrombin Days AT % Lowering Peak Thrombin (nm) Peak Thrombin Days Peak Thrombin (nm)

60 Interim Fitusiran Phase 1 Study Results* Exploratory Analysis of Bleed Events, Part D (Cohort 1, 50 mg) Return to Previous Slide Dose Patient Hemophilia Prior Tx 50 mg Prescribed BPA Pre-study ABR Onset ABR Days in Obs Period Observation Period Bleeds, n D1-1 HA w/ inh OD apcc D1-2 HB w/ inh OD rfviia/apcc D1-3 HA w/ inh OD rfviia 0 0 0** N/A N/A D1-4 HA w/ inh OD apcc D1-5 HA w/ inh OD PCC D1-6 HA w/ inh OD rfviia ABR Data suggest partial effect at 50 mg (49-100% reduction in Pre-study ABR) Further follow-up ongoing to explore safety and bleed efficacy with longer-term dosing; all eligible patients (reaching Day 84) have rolled over to extension study Second cohort dosed at 80 mg; follow-up ongoing 60 *Data transfer: 11Jul2016 Pasi et al., WFH, July 2016 w/ inh, with inhibitors; PPx, Prophylaxis; OD, On-Demand; ABR, annualized bleeding rate **As of data transfer date, patient does not have sufficient follow up in Observation period Post hoc analysis of treated bleed events during Onset (Day 0-28) and Observation periods (Day 29 to last study visit or last dose+56 days, whichever is earlier); Pre-study ABR derived from medical records

61 Initial ALN-CC5 Phase 1/2 Part C Study Results* Safety and Tolerability Summary ALN-CC5 is generally well tolerated in patients with PNH after multiple doses No SAEs or discontinuations due to adverse events (AEs) All 6 patients reported at least one AE Majority of AEs were mild to moderate in severity 1 severe AE reported as hepatotoxicity Asymptomatic, transient grade 3 elevation of ALT and AST without increase in total bilirubin Event considered possibly related to study drug resulting in dose interruption Other concomitant medications suspended (cyclosporine and anabolic steroid) AEs reported in 2 patients: contusion, oropharyngeal pain (N=2 each) 4 patients reported at least one possibly or definitely related AE Hepatotoxicity (N=1, listed above) Mild injection site reactions (ISRs) reported in 3 patients» Contusion (N=2), listed above; erythema and pain (N=1) No other clinically significant changes in vital signs, EKG, physical exams or clinical laboratories (hematology, biochemistry, coagulation and urinalysis) Return to Previous Slide 61 Based on data transferred up to 06June2016. *Hill, EHA, June 2016

62 C5 (mcg/ml) Values CCP Activity (%) Hemolysis (%) Initial ALN-CC5 Phase 1/2 Part C Study Results* C5 KD and Complement Inhibition in Ecu Naïve Patients Serum C5 KD following multiple doses of ALN-CC5 Mean maximum C5 knockdown (relative to baseline) of %; maximum up to 98.7% Minimum residual C5 levels of 0.9 mcg/ml Complement Classical Pathway inhibition (CCP C5b-9 ELISA) Mean maximum CCP inhibition (relative to baseline) of %; maximum up to 96.7% Similar results observed with alternative pathway assay (CAP C5b-9 ELISA) Inhibition of sheep red blood cell (srbc) hemolysis Mean maximum hemolysis inhibition (relative to baseline) of %; maximum up to 81.5% Similar results to those observed in healthy volunteers Return to Previous Slide Serum C5 CCP srbc Hemolysis Days since first visit Days since first visit Days since first visit 62 Based on data transferred up to 06June2016. *Hill, EHA, June mg ALN-CC5 x 13 q1w, then 400 mg x 4 q1w mg ALN-CC5 x 13 q1w, then 400 mg x 4 q1w mg ALN-CC5 x 8 q1w

63 Initial ALN-CC5 Phase 1/2 Part C Study Results* Exploratory Data Analysis of Potential for Reducing Ecu Standard treatment of PNH with Ecu requires high doses and frequent IV infusions Initial induction doses are 600 mg qw x4 followed by maintenance doses of 900 mg q2w Effect of ALN-CC5-mediated C5 knockdown on LDH with reduced Ecu dose and frequency After ALN-CC5 dosing was completed, Ecu naïve patients were initiated on Ecu for residual hemolysis In the setting of ongoing ALN-CC5-mediated knockdown of serum C5 (>95%), investigators chose to administer a single dose of Ecu (600 mg) and monitor clinically All 3 patients achieved lowering of LDH <1.5x ULN which was sustained out to 4 weeks Provides exploratory evidence for potential to reduce Ecu dose and frequency of administration To be confirmed and explored further in Phase 2 studies Return to Previous Slide Patient LDH (UI/L) Days post Ecu single dose (600mg) Day 0 Day 14 Day ND ND 280 LDH ULN: (1.5 X ULN values: ) ND not determined; samples were not collected 63 Based on data transferred up to 06June2016. *Hill, EHA, June 2016

64 LDH (IU/L) Initial ALN-CC5 Phase 1/2 Part C Study Results* Effects on LDH in Ecu Inadequate Responder Patient In Ecu inadequate responder (Patient 0083), ALN-CC5 demonstrated preliminary evidence of clinical activity LDH of 966 IU/L at Day 0 while patient received Ecu at above labeled dose (1200 mg, q2w) LDH lowering to within reference range by Day 35 with ALN-CC5 treatment Hemoglobin improved from 10.0 g/dl (Day 0) to up to 11.1 g/dl Occurrence of viral gastroenteritis on Day 63 associated with transient breakthrough hemolysis Ecu reduced to labeled dose (900 mg, q2w) on Day 56 LDH control maintained out to Day Return to Previous Slide Patient mg ALN-CC5 x 12 qw ULN ALN-CC5 Ecu, 1200 mg q2w Ecu, 900 mg q2w Days since first visit 64 Based on data transferred up to 06June2016. Sample collected at Day 140 was found hemolyzed; data not shown *Hill, EHA, June 2016

65 Ecu Plasma Concentration (mcg/ml) Initial ALN-CC5 Phase 1/2 Part C Study Results* Increased Pre-Dose Ecu Levels with ALN-CC5 Treatment 700 Return to Previous Slide Serum C5 KD with ALN-CC5 results in >3x increase in pre-dose Ecu trough levels Consistent with well-defined pharmacokinetics and target-mediated elimination of highaffinity antibodies Post-Ecu dose Pre-Ecu dose mg Ecu 900 mg Ecu Days ALN-CC5, 200 mg q1w Ecu, 1200 mg q2w Ecu, 900 mg q2w 65 Based on data transferred up to 06June2016. *Hill, EHA, June Wang W et al. Clin Pharmacol & Ther; 84: (2008)

66 ALN-AS1 Phase 1 Study Interim Results Part A (SAD) and Part B (MAD) Safety and Tolerability Return to Previous Slide 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 Sardh: A Randomized, Placebo Controlled, Phase 1 Study of ALN-AS1, Sep *All Safety Data in database as of 28 Jun 2016 with the exception of the MAD SAE which was as of 03 Sept 2016

67 Mean [+/- SEM] cerd Normalized ALAS1 mrna Serum R2BASE ALN-AS1 Phase 1 Study Interim Results SAD Pharmacodynamic Data: Serum ALAS1 mrna by cerd Return to Previous Slide 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 1.3 P< SAD Placebo (N=5) 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) Days since first dose Normal healthy individual Data in database as of 28 Jun 2016 Sardh: A Randomized, Placebo Controlled, Phase 1 Study of ALN-AS1, Sep

68 Mean [+/- SEM] Creatinine Normalized Local ALA R2BASE Mean [+/- SEM] Creatinine Normalized Local PBG R2BASE ALN-AS1 Phase 1 Study Interim Results SAD Pharmacodynamic Data: Urinary ALA and PBG Return to Previous Slide 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 ALA/PBG achieved at higher dose levels ALA Dose (mg/kg) ALA Placebo 0/ / / / / / PBG Dose (mg/kg) PBG Placebo 0/ / / / / / Month Month Excluding subject , Day 0: 0-6 hour ALA measurement Data in database as of 28 Jun 2016 SAD Placebo (N=5) 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) 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 Sardh: A Randomized, Placebo Controlled, Phase 1 Study of ALN-AS1, Sep

69 ALN-GO1 Phase 1/2 Interim Study Results* Safety: Part A (Healthy Volunteers) Return to Previous Slide ALN-GO1 was generally well-tolerated in healthy volunteers No drug-related SAEs or discontinuations due to AEs Total of 61 AEs reported in 5 placebo and 21 ALN-GO1 treated healthy volunteers AEs occurring in greater than 10% of ALN-GO1 treated subjects included nasopharyngitis (N=6), headache (N=5), and transient injection site pain (N=4). All AEs were mild to moderate with the exception of one healthy volunteer in the lowest dose cohort who had transient, asymptomatic CPK elevation which was unrelated to study drug. No clinically significant changes in vital signs or EKG 69 *Data as of: 17 August 2016 Milliner et al., IPNA, September 2016

70 Mean [± SEM] Plasma Glycolate (nmol/ml) ALN-GO1 Phase 1/2 Interim Study Results* Plasma Glycolate: Part A (Healthy Volunteers) Return to Previous Slide Days from single dose Normal range: <14 nmol/ml Treatment Group: Placebo (N=8) ALN-GO1 0.3 mg/kg (N=6) ALN-GO1 1.0 mg/kg (N=6) ALN-GO1 3.0 mg/kg (N=6) ALN-GO1 6.0 mg/kg (N=6) A dose-dependent increase in plasma glycolate levels is observed, with earliest onset of activity at higher doses evident by Day 29 post dose and sustained until Day 85 The lowest dose with appreciable glycolate increase is 1 mg/kg 70 SEM; Standard error of the mean *Data as of: 02 September 2016 Milliner et al., IPNA, September 2016

71 ORION-1 Phase 2 Study of Inclisiran Safety Summary Return to Previous Slide Generally well tolerated with no material safety issues observed (N=501 patients with ASCVD, LDL-C > 70mg/dL) No elevations of liver enzymes related to study drug One SAE of elevated ALT and AST attributed to increased dose of statin therapy which resolved upon lowering to original dose No neuropathy or changes in renal function One patient died of fatal MI, deemed not related to study drug Patient had 20-year history of CVD, including prior MI and unstable angina Death occurred >3 months after single dose of inclisiran Overall incidence of treatment emergent adverse events (TEAE) 54% both in patients randomized to placebo and in patients randomized to inclisiran No differences between inclisiran doses Injection site reactions (ISRs) infrequent and transient Observed in 3.2% of patients Mild or moderate ISR started or was still present 4 hours after dosing in 2.4% of patients 71 Inclisiran also knowns as ALN-PCSsc and PCSK9si Preliminary Phase 2 study results; Ray et al., AHA, November 2016

72 Efficacy of One Dose of Inclisiran up to Day 90 Significant, Durable PCSK9 and LDL-C Lowering Return to Previous Slide 72 Inclisiran also knowns 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

73 One Dose and Two Doses of Inclisiran up to Day 180 Efficacy of 300mg versus Placebo on LDL-C Return to Previous Slide 73 Inclisiran also knowns 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

74 Change in LDL-C (mg/dl) Individual Patient Response at Day 180 Absolute Change In LDL-C From Baseline Return to Previous Slide Mean -3.1 Median 2 mg/dl Placebo Two doses (N=23) mg Two doses (N=28) -125 Mean Median -64 mg/dl -122 Available data as of 25 Oct 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

75 log 10 Δ Viral Load (relative to average pre-dose) log 10 Δ HBsAg (relative to average of pre-dose values) RNAi Therapeutics for HBV Efficacy in HBV-Infected Chimpanzees Return to Previous Slide Dose-dependent antiviral response with intra-subject ascending doses Mean 2.9 log 10 decrease in viral DNA day 2-6 post 0.5 mg/kg dose >4 log 10 reduction in circulating viral DNA achieved in highest titer animal Mean 2.0 log 10 reduction in HBsAg at 0.5 mg/kg dose Up to 2.3 log 10 reduction achieved Plasma Viral Load (bdna) sirna (mg/kg) Plasma HBsAg (Surface Antigen) sirna (mg/kg) A C* B D Days *low titer animal dropped below LLOQ from day 23-day 98 Meyers, TIDES, May Days A B C D

76 % HBsAg serum levels (normalized to pre-dose) % HBsAg Plasma Levels (Normalized to d0) ALN-HBV Development Candidate (DC) Potent ESC-GalNAc Conjugate for SC Administration Return to Previous Slide Potent, multi-log HBsAg knockdown in murine model Mouse model with AAV-HBV vector ALN-HBV DC achieves potent and highly durable knockdown of HBsAg Up to 3.6 log 10 HBsAg reduction Single SC dose achieves >2 log 10 HBsAg reduction lasting >30 days Multiple SC doses achieve >2 log 10 HBsAg reduction lasting >90 days 100 Single SC Dose Control 9 mg/kg 3mg/kg 1mg/kg 0.3mg/kg Multiple SC Doses LLOQ 0.1 ng/ml Time (days) Pre-dose HBsAg titer range ~ ng/ml Sepp-Lorenzino, Liver Meeting, November Time (days) AAV-HBV VG ALN-HBV 3 mg/kg qwx3, SC LLOQ