and Results of Lung Transplant Study with ALN-RSV01 July 30, 2009

Transcription

1 ALN-RSV Program Overview and Results of Lung Transplant Study with ALN-RSV01 July 30, 2009

2 Alnylam Forward Looking Statements This presentation contains forward-looking statements. 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 those that we discuss 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. 6

3 RNA Interference (RNAi) A Discovery that Happens Only Every Decade or So Potential for a whole new class of drugs Harness natural pathway» Catalytic mechanism Potent t and selective» Mediated by small interfering RNAs or sirnas Achieve therapeutic gene silencing» Upstream of today s medicines» Any gene in the genome 7

4 Alnylam Strategy Build a New Top-Tier Tier Biopharmaceutical Company Founded on RNAi Leadership Lead translation of science to products Products Advance innovative medicines Intellectual Property Build value with leading IP estate Business Forge value-creating alliances 8

5 Building our RNAi Therapeutics Pipeline Opportunity to target any gene in genome Enables building company with multiple shots on goal Platform drives value, not any single product Many opportunities for partnerships to achieve capital efficient profile Selected criteria for target selection Unmet need and opportunity to develop breakthrough medicines for patients» Drives magnitude of commercial opportunity Target expressed in cell/tissue accessible with today s delivery solutions» Expands in future with new delivery solutions Target as highly validated as possible based on genetic or other clinical data a Human POC achievable early in development to achieve early de-risking» Possible fast to market /orphan indications desirable Competitive advantage vs. other drug classes 9

6 Alnylam Development Pipeline Key Programs Discovery Development Phase I Phase II Phase III RSV Infection Liver Cancers PCSK9/Hypercholesterolemia TTR Amyloidosis IND 2009 candidate Huntington s Disease Alnylam Proprietary Programs Co-development Programs 3 programs in clinical trials in

7 ALN-RSV Program Overview Introduction Pre-clinical data Clinical development plan Key Gemini i proof of concept results RSV in lung transplant patients ALN-RSV lung transplant study design ALN-RSV lung transplant results Next steps 11

8 Respiratory Syncytial y Virus (RSV) Significant unmet medical need» >125,000 pediatric hospitalizations/yr in US» >170,000 adult hospitalizations/yr in US RSV is associated with mortality and significant morbidity» Upper Respiratory Tract Disease Cold symptoms (nasal congestion and discharge) Otitis media (ear infection)» Lower Respiratory Tract Disease Bronchiolitis (wheezing) Pneumonia Croup Development of chronic childhood asthma Annual cost is >$750 million No effective therapies to treat RSV infection» Synagis used for prevention 12

9 Respiratory Syncytial Virus (RSV) Program ALN-RSV Harness RNAi for a major infectious disease ALN-RSV01 in clinical i l development» Target: RSV nucleocapsid N gene Essential for viral replication» Six clinical studies» >300 patients enrolled» Phase II naturally infected adult study recently completed Lung transplant patients Active 2 nd generation program» Opportunity for product differentiation Partnership with Cubist Partnered with Kyowa Hakko in Asia 13

10 ALN-RSV Program Overview Introduction Pre-clinical data Clinical development plan Key Gemini i proof of concept results RSV in lung transplant patients ALN-RSV01 study design and objectives ALN-RSV01 results Next steps 14

11 Histology of RSV Infection In Humans RSV infects lung epithelium at airways Infection occurs at sites accessible by sirnas Image: Johnson et al, Modern Pathology (2007) 20: Confidential

12 RNA Replication Cycle of RSV Selecting Targets Infection G F L N P Packaging Leader N protein 3' 5' 3' 5' Genes: N P M G F L (-) strand (Genome) RdRP (L, P) RdRP (L, P) (Transcription mode) (More replication) 5' 3' mrna: (+) strand (Antigenome) Hypothesis Cap Translation De novo viral proteins N, P, L, M, G etc. Poly(A) N 3' 5' RdRP (L, P) (Replication mode) 5' (-) strand (Genome) Nascent (+) strand Silencing proteins present in the nucleocapsid, (N, P, L), required for RSV replication, can result in rapid viral elimination 16

13 sirnas Targeting N, P, and L Effectively Inhibit RSV In Vitro 120 P N L 100 ing % plaqu ues remain ALN-RSV01 sirnas (5nM) RSV Symposium, Aug

14 Clade Distribution of Clinical Isolates Evaluated at ALN-RSV01 Target Site NH/A4 NH/B4 NH/2037 NH/2491 NH/ A NH593 A3 NH1244 A NH1205 A3 96 NH908 A AY AY AY AY AY VAN 1160 AY MOT 0972 AY AY LEO 0713 NH418 NH492 HOU NH NH/ AY ICAAC, Sep NH382 NH511 NH/2502 NH/ NH/2188 NH/ NH/2447 NH/ NH532 NH/A AY AY JEN 1133 LAP 0824 NH401 AY RUG 0420 AY AY AY AY AY AY AY AY NH409 NH AY RSV A Subtype AY AY AY AY BE/GA2 BE/A1 BE/GA1 AY BE/GA4 NH/B2 BE/GB5 NH1516 NH/1565 NH/1203 NH/1701NH/1982 NH/1810 NH/1718 NH/1707 NH/1728 NH/1937 NH/1365 NH/2516 NH/ NH/760 NH/1022 NH/1617 AY AY Challenge study strain Conserved ALN-RSV01 target site Mismatched ALN-RSV01 target site BEN 0819 AY AY AY AY AY AY AY AY AY AY AY AY LAM 1238 AY AY AY AY AY AY AY AY BE/GB2 NH/2339 AY AY NH/2172 NH/B3 BE/GB6 AY AY AY AY PEP 121 AY AY AY PEP 162 AY NH/1981 NH/1979 NH/2243 NH/B1 NH/1154 NH/1142 NH/1433 NH/940 NH/2270 NH/1060 NH/ AY NH/1377 TRI 0347 AY NH/2054 NH/1742 NH/2471 NH/2027 NH/1984 AY AY AY AY AY HAN 1135 AY AY AY AY BE/G B3 AY AY AY AY AY AY AY AF AY BE/GB1 RSV B Subtype AY751267

15 In Vivo Anti-viral Activity of sirnas Mouse Prophylaxis Model Multiple sirnas targeting distinct RSV genes screened in vivo 6 Lo og10 PFU/g lung LLOD 1 mg/kg 2 mg/kg 4 mg/kg 0 ALN-RSV01 P1 P2 P3 N2 L1 L2 L3 P4 P4-MM P gene N gene L gene sirna in i.n. (25-100ug) 4 hrs Virus (RSV/A 2 ) in i.n. (10 6 pfu) 4 days Viral Titer in Lung 19 RSV Symposium, Aug. 2005

16 FU/g lung Log10 P In Vivo Anti-viral Activity of sirnas Mouse Treatment Model Day 1 Day 2 Day 3 Day 4 1 LLOD 0 PBS P1 ALN-RSV01 L3 P4-MM Virus (RSV/A2) in i.n. (10 6 pfu) Day 1 Day 2 Day 3 Day 4 sirna Single dose i.n. (2 mg/kg) Day 5 Viral Titer in Lung RSV Symposium, Aug

17 Improved Treatment Effect with Multi-Dosing Mouse Treatment Model Log(10) PFU/g lung 1 0 PBS -4 D1 D2 D3 D1+D2 D2+D3 D1+D2+D3-4 D1 D2 D3-4 D1 D2 D3-4 D1 D2 D3 D1+D2 D2+D3 D1+D2+D3 120ug Keystone: RNAi, Feb ug 80ug 120ug 40ug per day 40ug per day Control RSV01

18 6 Direct Delivery in Lung Inhibition of RSV by sirna is Specific 2 mg/kg 5 Log10 PFU/g lung LLOD PBS P1 P1-MM N1 N1-MM L3 L3-MM P4 P4-MM Mismatch Controls RSV Target P N L sirna i.n. (50ug) 4 hrs Virus (RSV/A 2 ) i.n. (10 6 pfu) 4 days Viral Titer in Lung RSV Symposium, Aug slide 22

19 TNFa [pg/ml] IFNa [pg g/ml] Immune Stimulatory sirnas do not Inhibit RSV In Vivo In vitro TNFa assay Neg controls Pos Ctrl P4-MM Log10 PFU/g lung In vitro IFNa assay Neg Controls Pos Control AAC Accepts, AOP June PBS In vivo efficacy 5 ug 50 ug ALN- RSV01 N1-MM P4 P4-MM N1-MM N P

20 RNAi Silencing is Independent of Toll-Like Receptors RNAi efficacy is achieved in Toll-Like Receptor (TLR) knock-out mice Demonstrates unambiguous distinction of RNAi effects from TLR-related biology Addresses concerns raised by Ambati et al. paper (Nature, 452:591-7, Apr. 2008) TLR 3 Knock-Out TLR 7 Knock-Out WT TLR3 KO WT TLR7 KO Virus tit ter 100 Virus tite er sicontrol sirsv sicontrol sirsv 24 Keystone: RNAi, Feb 2009

21 cleavage site Viral Inhibition is Mediated by RNAi In Vivo 5 RACE RSV N gene Step I. Ligation of adaptor RNA adaptor RSV GR5N Rev2 RNAi Specific Clones (cleavage site 26/27nt) 3 Step II. Amplification PBS RSV01 Specific clones 0/24 (0%) 18/22 (82%) Keystone: RNAi, Feb Confidential

22 ALN-RSV 2 nd Generation Program 2 nd Generation program advanced to take advantage of greater understanding of sirnas and RSV Successful optimization of many RSV-specific sirnas Target same site on N gene» Maintenance of ALN-RSV01 potency» Maintenance of conserved site for viral targeting Key properties include improved stability and reduced immune stimulation Increased flexibility and development options» e.g., Product differentiation Adult and pediatric populations Product profile and pricing 26

23 ALN-RSV Program Overview Introduction Pre-clinical data Clinical development plan Key Gemini i proof of concept results RSV in lung transplant patients ALN-RSV01 study design and objectives ALN-RSV01 results Next steps 27

24 Phase I Studies Intranasal» 65 ALN-RSV01, 36 placebo» Safe and well tolerated Inhalation» 71 ALN-RSV01, 38 placebo» Safe and well tolerated ALN-RSV Clinical Development Plan To-Date Dose-fractionation» Ongoing Phase II Gemini» 44 ALN-RSV01, 44 placebo» First human proof of concept for an RNAi therapeutic demonstrated anti-viral activity» Safe and well tolerated t Naturally infected lung transplant» 16 ALN-RSV01, 8 placebo» Safe and well tolerated» Certain clinical i l measurements favored ALN-RSV01 28

25 ALN-RSV Program Overview Introduction Pre-clinical data Clinical development plan Key Gemini i proof of concept results RSV in lung transplant patients ALN-RSV01 study design and objectives ALN-RSV01 results Next steps 29

26 RSV Infection in Humans Alnylam "Pre-GEMINI GEMINI" Study Results ad PFU/mL) ean viral loa Ue/mL or Log P me (Log PFU in noculation Timing of Mean Viral Load and Symptomatic Disease (n=27) viral load by qpcr viral load by qculture mean symptom score mean symptom score am pm am pm am pm am pm am pm am pm am pm am pm am pm am pm am pm am Study Day *N-gene genomic 2-step RT-PCR, using fixed RT primer (not random hexamers) DeVincenzo, Submitted for publication 30

27 GEMINI Study Design Randomized, double-blind, placebo-controlled trial of safety and efficacy of ALN-RSV01 in human experimental RSV infection Goal» Establish anti-viral activity of ALN-RSV01 in experimental infection model Objectives» Safety and tolerability» Primary efficacy outcome Infection rate» Other efficacy outcomes Viral quantification measures Disease measures N=88 Int l Symp Res Vir Infect, Feb

28 Primary Efficacy Outcome-Infection Rate Cohorts 1-6 Magnitude of Fisher s Mantel- Placebo All ALN-RSV01 Effect Exact Haenszel Detection Method (N=42) (N=43) relative to placebo P value P value l ti t l b Plaque RT-qPCR Infected 30 (71.4%) 19 (44.2%) 38.1% Uninfected 12 (28.6%) 24 (55.8%) 95.1% Infected 36 (85.7%) 29 (67.4%) 21.4% Uninfected 6 (14.3%) 14 (32.6%) 128.0% Spin Infected 31 (73.8%) 22 (51.1%) 1%) 30.8% Enhanced Culture Uninfected 11 (26.2%) 21 (48.8%) 86.3% Infected 37 (88.1%) 29 (67.4%) 23.5% Any Test Uninfected 5 (11.9%) 14 (32.6%) 173.9% Int l Symp Res Vir Infect, Feb

29 Phase II GEMINI Study RSV Infection Over Time Placebo Plaque Assay ALN-RSV Placebo RT-PCR ALN-RSV % Infected % Infected P= P= Study Day Study Day Int l Symp Res Vir Infect, Feb

30 Evaluating Independent Effects on Infection* Multivariate Logistic Regression ALN-RSV01 treatment effect was independent of other variables Variable P Value Odds Ratio 95% CI ALN-RSV01 vs. Placebo RSV inoculum Day -2 RSV microneut titer TNFα AUC (d2-4) (post inoculation, during incubation period) * Infection defined by plaque assay Int l Symp Res Vir Infect, Feb

31 What we learned GEMINI Study Summary First human proof of concept for an RNAi therapeutictic» Intranasal delivery of ALN-RSV01 for experimentally induced upper respiratory infection with prophylactic p regimen» ALN-RSV01 was safe and well-tolerated in infected subjects» ALN-RSV01 was associated with statistically significant reduction in culture-defined d RSV infection Unanswered questions What is the safety and activity it of inhaled ALN-RSV01 in naturally acquired lower respiratory track infection with treatment regimen? 35

32 ALN-RSV Program Overview Introduction Pre-clinical data Clinical development plan Key Gemini i proof of concept results RSV in lung transplant patients ALN-RSV01 study design and objectives ALN-RSV01 results Next steps 36

33 Most common conditions» Emphysema / COPD» Idiopathic pulmonary fibrosis» Cystic fibrosis» Idiopathic pulmonary hypertension» Alpha-1 antitrypsin deficiency Overview of Lung Transplantation Actuarial survival at 1-, 3-, 5-, and 10-years is 81%, 68%, 63%, and 36% Immunosuppression therapy post-transplant» Corticosteroids, calcineurin inhibitors and cell cycle inhibitors Primary causes of mortality» Obliterative bronchiolitis manifests as bronchiolitis obliterans syndrome (BOS) +/- lower respiratory tract infection 37

34 RSV in Lung Transplant Patients Community acquired respiratory viruses (CARV) are most common cause of RTI*» Respiratory syncytial virus (RSV)» Parainfluenza virus (PIV)» Influenza A and B» Adenovirus» Human metapneumovirus After transplant, RSV may present at any time» Cough and sputum» Crackles and high pitched mid inspiratory squeaks» Shortness of breath» Tachypnea Median duration of symptoms to presentation: 5 days Methods of diagnosisi» Nasopharyngeal swab, nasopharyngeal wash, BAL» Detection methods: antigen detection (EIA,IFA), multiplex PCR, viral culture (RRV, shell-vial) *Wendt CH. Am J Med 1997;102:

35 Outcomes in RSV-Infected LT Patients Death: 90-day mortality rates of 0-12% Acute rejection at 90 days post-transplant» Occurred in 16% of LT patients following RSV compared to 0% without infection 1 Bronchiolitis Obliterans Syndrome (BOS) 1,2» CARV are a risk for BOS, death, and death from BOS Median survival of only 2-3 years after onset of BOS 3 Impact of ribavirin, current standard of care, not assessed in randomized controlled trials 1 Kumar D, et al. Am J Transplant 2005;5: Khalifah AP, et al. Am J Resp Crit Care Med 2004;170: Boehler A and Estenne M, Eur Respir J 2003;22:

36 ALN-RSV Program Overview Introduction Pre-clinical data Clinical development plan Key Gemini i proof of concept results RSV in lung transplant patients ALN-RSV01 study design and objectives ALN-RSV01 results Next steps 40

37 Primary Objectives Study Objectives Safety and tolerability of inhaled ALN-RSV01 in RSV-infected LT patients Secondary Objectives RSV infection characteristics» Treatment related changes in various viral parameters» Patient symptom scores Characterization of plasma PK Clinical impact of treatment on Day 90 41

38 Study Design and Flow Respiratory symptoms, FEV 1 RSV+ (N=24) Placebo + SOC* (N=8) ALN-RSV01 + SOC* (N=16) d0 d1 d2 d3 d4 d5 d6 d8 d10 d12 d14 d30 d90 Rx Rx Rx 0.6 mg/kg/d x 3d aerosolized Procedures Symptom score (2x/d) Viral load FEV 1 recovery, Rejection, Survival, Intubation Adverse events 42 *Institutional standard of care for RSV

39 ALN-RSV Program Overview Introduction Pre-clinical data Clinical development plan Key Gemini i proof of concept results RSV in lung transplant patients ALN-RSV01 study design and objectives ALN-RSV01 results Next steps 43

40 Demographics ALN-RSV01 N = 16 n (%) Placebo N = 8 n (%) Gender Male 13 (86.7) 3 (37.5) Female 3 (18.8) 5 (62.5) Race (Caucasian) 16 (100) 8 (100) Age (years) Weight (kg) Height (cm) Mean values shown BIT, Summit of Antivirals, July

41 Type of transplant Characteristic Single Bilateral Baseline Characteristics Per Protocol Population ALN-RSV01 N = 15 n (%) 2 (13.3) 13 (86.7) Placebo N = 8 n (%) 3 (37.5) 5 (62.5) Years since transplant 3.3 ± ± 1.9 BOS grade at enrollment 0 0p (80.0) 2 (13.3) 0 1 (6.7) 7 (87.5) 0 1 (12.5) 0 Baseline (Day 0) viral load (log 10 PFUe/mL)* 1.95 ± ± 2.36 Time from symptom onset to screening (days) 3.33 ± ± 1.36 Time from symptom onset to first dose (days)* 5.33 ± ± 1.6 Key concomitant medications Any ribavirin (oral, IV or inhaled) 12 (80.0) 0) 6(75 (75.0) Inhaled ribavirin High-dose steroids IVIG Palivizumab 6 (40.0) 11 (73.3) 2 (13.3) 1 (6.7) 5 (62.5) 4 (50.0) 2 (25.0) 1 (12.5) * Difference between treatment groups not statistically significant Mean values shown BIT, Summit of Antivirals, July

42 Treatment Emergent Adverse Events Number of Patients ALN-RSV01 Placebo N = 16 N = 8 n (%) n (%) With any TEAE 16 (100) 8 (100) With TEAE by highest relationship to study drug Probably 0 0 Possibly Unrelated 3 (18.8) 13 (81.3) 3 (37.5) 4 (50.0) With TEAE by maximum severity Severe Moderate Mild Who interrupted, discontinued or adjusted drug due to TEAE 2 (12.5) 6 (37.5) 8 (50.0) 3 (37.5) 1 (12.5) 4 (50.0) 1* (6.3) 0 With any serious AE 2 (12.5) 1 (12.5) With TEAE with outcome of death 0 0 * Patient discontinued drug after 2 days because of pneumothorax (unrelated to study drug) BIT, Summit of Antivirals, July

43 Serious Adverse Events 4 serious adverse events (SAEs) were reported in 3 patients between Day 0 and Day 30 None were considered related to study drug Description of Start of Resolution Relationship to Study drug SAE SAE of SAE study drug ALN-RSV01 Placebo Left pneumothorax Worsening diarrhea Fungal pneumonia Day 1 Day 10 No (scored by PI as related to inhaled ribavirin) Day 4 Day 14 No Day 8 Day 20 No SIADH* Day 23 Day 26 No *Syndrome of inappropriate p antidiuretic hormone secretion BIT, Summit of Antivirals, July

44 Treatment Emergent Respiratory Adverse Events Respiratory, Thoracic and Mediastinal Disorders ALN-RSV01 N = 16 n (%) Placebo N = 8 n (%) TOTAL 13 (81.3) 6 (75.0) Nasal congestion 7 (43.8) 1 (12.5) Cough 5 (31.3) 0 Dyspnoea exertional 4 (25.0) 1 (12.5) Rhinorrhoea 4 (25.0) 3 (37.5) Wheezing 4 (25.0) 5 (62.5) Pharyngolaryngeal pain 3 (18.8) 8) 1 (12.5) Dyspnoea 2 (12.5) 0 Epistaxis 2 (12.5) 0 Hemoptysis 2 (12.5) 0 Productive cough 2 (12.5) 1 (12.5) Sneezing 2 (12.5) 0 All respiratory TEAEs were mild to moderate in intensity, except for two (dyspnoea exertional and productive cough), both in the placebo group BIT, Summit of Antivirals, July

45 Cytokine and Spirometry Safety Cytokines Baseline values for CRP and IL1RA were higher in placebo group No effect of ALN-RSV01 on cytokines (measured post first and third dose) Spirometry Screening values for FEV1 were slightly lower in placebo group No effects of treatment t t on FEV1 measured 1 hour after each dose BIT, Summit of Antivirals, July

46 Pre- and Post-Dose Spirometry 2.5 Pre-Dose ALN-RSV01 Post-Dose ALN-RSV01 Pre-Dose Placebo Post-Dose Placebo FEV 1 (Liters) Day 0 Day 1 Day 2 Study Day Error bars = SEM, Post-dose = 1 hour post study drug administration BIT, Summit of Antivirals, July

47 Mean Daily Viral Load Days 0 to 6 All Patients Patients with Moderate to High Viral Load* 5 ALN-RSV01 (N=13) Placebo (N=7) 5 ALN-RSV01 (N=8) Placebo (N=6) Mean Daily Vira al Load (Log 10 PFUe/ /ml) Mean Daily Vira l Load (Log 10 PFUe/m ml) Rx Rx Rx Study Day Rx Rx Rx Study Day Error bars = SEM Arrows indicate dosing days; samples collected prior to administration of each dose *Analysis of Moderate to High Viral Load subgroup pre-specified in statistical analysis plan BIT, Summit of Antivirals, July

48 Assessment Day 0-1 (log 10 PFUe/mL/day) Day 0-2 (log 10 PFUe/mL/day) Day 0-3 (log 10 PFUe/mL/day) Day 0-6 (log 10 PFUe/mL/day) Patients ALN-RSV01 Mean ± SD Viral Clearance Placebo* Mean ± SD All patients -0.46± ± ± ± Moderate to high viral load ± ± 1.42 All patients ± ± 0.96 Moderate to high viral load ± ± 1.05 All patients ± ± 0.65 Moderate to high viral load ± ± 0.71 All patients ± ± 0.30 Moderate to high viral load ± ± 0.32 *Differences shown between ALN-RSV01 and Placebo not statistically significant BIT, Summit of Antivirals, July

49 Other Viral Parameters Assessment Patients ALN-RSV01 Mean ± SD Placebo* Mean ± SD Duration of viral shedding (days) Overall viral load 0-6 days (log 10 PFUe/mL*day) Maximum viral load post 1 st dose (log 10 PFUe/mL) All patients 5.35 ± ± 4.47 Moderate to high viral load 6.51 ± ± 4.84 All patients 6.60 ± ± Moderate to high viral load ± ± 9.49 All patients 234± 2.34 ± ± 4.16 ± Moderate to high viral load 2.93 ± ± 1.28 Time to maximum viral load All patients 3.73 ± ± 4.98 (days) Moderate to 3.96 ± ± 5.16 high viral load *Differences shown between ALN-RSV01 and Placebo not statistically significant BIT, Summit of Antivirals, July

50 Mean Daily Symptom Scores Over Time All Patients Patients with Moderate to High Viral Load 25 ALN-RSV01 (N=15) Placebo (N=8) 25 ALN-RSV01 (N=8) Placebo (N=7) Mean Da aily Symptom Scores Mean Da aily Symptom Scores Study Day Study Day Error bars = SEM BIT, Summit of Antivirals, July

51 Patient Symptom Scores Assessment Patients ALN-RSV01 Mean ± SD Placebo Mean ± SD P-value Cumulative daily total symptom score All patients ± ± Moderate to high viral load ± ± Overall daily total symptom score mean All patients 9.26 ± ± Moderate to high viral load 949± 9.49 ± ± BIT, Summit of Antivirals, July

52 Day 90 Outcomes ALN-RSV01 vs Placebo Day 90 Outcome ALN-RSV01 N=15 Placebo N=8 P-value Survival 100.0% 100.0% n.s. Intubation ti 00% 0.0% 00% 0.0% n.s. Acute Rejection 13.3% 12.5% n.s. Respiratory Infections After Day % 12.5% 0.62 Change in BOS from baseline*: Total New Onset or Progressive 7.1% 50.0% 0.02 *N=14 for ALN-RSV01 due to missed day 90 follow-up in one patient BIT, Summit of Antivirals, July

53 Percent of Patients with FEV1 at least 20% Below Baseline* Screening Versus Day 30 and Day ALN-RSV01 Placebo 38% 35 33% bjects Percent of Su % 13% 25% 14% Screening Day 30 Day 90 Study Day *Baseline data are pre-infection FEV1 values for each patient BIT, Summit of Antivirals, July

54 ALN-RSV01 was safe and well tolerated Conclusions» No study drug related SAE» No study drug related dropouts» Slightly greater incidence of mild/moderate respiratory AEs in ALN-RSV01 group» No acute or subacute exacerbation of lower respiratory tract t disease Baseline imbalances for viral load and time from symptom onset to first dose confounded interpretation of trends favoring ALN-RSV01 in certain antiviral measures Clinical measurements favored ALN-RSV01 in:» Cumulative mean daily symptom scores» Improved Day 90 FEV1» Reduced incidence of new or progressive BOS at Day 90 58

55 ALN-RSV Program Overview Introduction Pre-clinical data Clinical development plan Key Gemini i proof of concept results RSV in lung transplant patients ALN-RSV01 study design and objectives ALN-RSV01 results Next steps 59

56 Complete key development studies ALN-RSV Clinical Development Plan Next Steps» Complete ongoing dose-fractionation study» Complete 2 nd generation program studies KOL input and regulatory strategy Potential options for path forward in pediatric and adult RSV patient populationsp» Advance ALN-RSV01 in both pediatric and adult» Advance ALN-RSV01 in adult and 2 nd generation in pediatric» Advance 2 nd generation in both pediatric and adult Alnylam/Cubist to determine path forward by YE 60

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