Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY

Alnylam Pharmaceuticals — Investor Presentation (June 2013)

39 slides from Alnylam Pharmaceuticals's investor presentation, June 2013

  1. Slide 1: Corporate Overview June 2013

    Corporate Overview June 2013

  2. Slide 2: Alnylam Forward Looking Statements

    Alnylam Forward Looking Statements This presentation contains forward-looking statements, within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. There are a number of important factors that could cause actual results to differ material

  3. Slide 3: RNA Interference (RNAi): A New Class of Innovative Medicines

    RNA Interference (RNAi) A New Class of Innovative Medicines RNAi Therapeutics  Harness natural pathway » Catalytic mechanism » Mediated by small interfering RNA or “siRNA”  Treat disease with therapeutic gene silencing » Any gene in genome » Unique opportunities for innovative medicines  Clinical

  4. Slide 4: RNAi Human Translation Achieved

    RNAi Human Translation Achieved Multiple Alnylam Therapeutic Programs 1. Human Safety and PK 2. Human Proof of Mechanism  >575 Subjects/patients enrolled overall RNAi Cleavage Pre- ALN-VSP  Systemic delivery in human trials » >100 Patients dosed » >325 Doses administered » >2 Years of dosing Post-

  5. Slide 5: Alnylam 5x15: Focused Product Development Pipeline

    Alnylam 5x15 TM Focused Product Development Pipeline for Innovative Medicines RNAi for genetically defined disease as core strategy  5 Key products in clinical development through 2015 Product characteristics  Genetically defined target/disease  Existing Alnylam delivery platform  Phase I proof

  6. Slide 6: Commercialization Strategy for Value Creation

    Alnylam 5x15 TM Commercialization Strategy for Value Creation Commercialization strategy to maximize value  High unmet need indications with concentrated market access and strong patient advocacy » Commercialize in North and South America, Europe, and other territories » Selectively partner in Japa

  7. Slide 7: Transthyretin-Mediated Amyloidosis (ATTR) Program

    Transthyretin-Mediated Amyloidosis (ATTR) Program Unmet Need and Product Opportunity RNAi to treat genetic disease  ATTR is significant orphan disease » ~50,000 Patients worldwide  Clinical pathology » Onset ~40 to >60 yr » Two predominant forms – Familial amyloidotic polyneuropathy (FAP) – Famili

  8. Slide 8: Transthyretin (TTR) and ALN-TTR Program

    Transthyretin (TTR) and ALN-TTR Program Phe33Cys Ala45Asp Ser77Phe Leu12Pro Phe33Ile Ala45Ser Ser77Thy Phe33Leu Leu111Met Ala45Thr Gly53Glu Phe33Val Ala97Gly Glu61Lys Ala120Ser Pro24Ser Glu51Gly Ala97Ser Asp38Ala Ile73Val Ile68Leu Ala91Ser Ile107Val Thr118Met Val20Ile Glu42Asp Leu55Arg Val28Met Gly6

  9. Slide 9: TTR Knockdown and Clinical Outcomes

    TTR Knockdown and Clinical Outcomes Rationale for Expected Benefit ~50% Lowering in AL Amyloidosis TTR knockdown is validated endpoint  ~50% Knockdown in other systemic amyloidoses » Disease improvement or stabilization  Elimination of mutant TTR following liver transplantation » Disease improveme

  10. Slide 10: ALN-TTR02: Familial Amyloidotic Polyneuropathy

    ALN-TTR02 Familial Amyloidotic Polyneuropathy (FAP) ALN-TTR02 in clinical development  Intravenous delivery  Orphan drug status in US and EU  Positive clinical results in human volunteer Phase I study  Phase II ongoing in ATTR patients » Data at Peripheral Nerve Society, June 29 – July 3, 2013 

  11. Slide 11: ALN-TTR02 Phase I Study Results

    ALN-TTR02 Phase I Study Results Rapid, dose-dependent, durable, specific, and RNAi-mediated TTR knockdown  Randomized, placebo-controlled, single-blind, single-dose escalation study in healthy volunteers (n=17)  Up to 94% TTR knockdown at nadir and 77% knockdown sustained at 28 days  RNAi mechani

  12. Slide 12: ALN-TTR02 Phase I Safety and Tolerability

    ALN-TTR02 Phase I Study Results Safety and Tolerability – Overall AEs ≥10% Overall 0.01 0.05 0.15 0.30 0.50 ALN-TTR02 Placebo (n=3) (n=3) (n=3) (n=3) (n=1) (N=13) (N=4) Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) n (%) Skin erythema 1 (33.3%) 2 (66.7%) 0 (0%) 2 (66.7%) 1 (100%) 6 (46%) 2 (50%

  13. Slide 13: ALN-TTR02 Phase II Study

    ALN-TTR02 Phase II Study Study Design  Open-label, multi-center, multi-dose, dose-escalation study  ~30 ATTR FAP patients » Additional cohorts with once-every-three week dosing regimen and reduced steroid pre-medication regimen Primary Objective  Safety and tolerability  Clinical activity » Circ

  14. Slide 14: ALN-TTR02 Multi-Dose Pharmacology

    ALN-TTR02 Multi-Dose Pharmacology Data from Ongoing 6-Dose Non-Human Primate Study Monthly dosing of ALN-TTR02 achieves robust TTR knockdown  Ongoing NHP multi-dose study provides key data for dose/dose regimen selection in Phase III  Nadir TTR levels of >85% with evidence for cumulative knockdown

  15. Slide 15: ALN-TTRsc: Familial Amyloidotic Cardiomyopathy

    ALN-TTRsc Familial Amyloidotic Cardiomyopathy (FAC) ALN-TTRsc in clinical development  Subcutaneous delivery  Completed GLP tox studies confirming wide therapeutic index » No injection site reactions  Phase I study initiated » Normal healthy volunteer study in UK » Phase I data expected mid-2013

  16. Slide 16: ALN-TTRsc Pre-Clinical Efficacy: Non-Human Primate

    ALN-TTRsc Pre-Clinical Efficacy Non-Human Primate SC administration of ALN-TTRsc results in robust and sustained TTR suppression  ~80% Suppression at doses as low as 2.5 mg/kg  Nadir knockdown at ~day 14; sustained suppression with weekly maintenance dose  Recovery to baseline levels >40 days fro

  17. Slide 17: ALN-TTRsc Pre-Clinical Efficacy: Transgenic Mice

    ALN-TTRsc Pre-Clinical Efficacy ATTR Disease Model: hTTR V30M Transgenic Mice -40 Control siTTRsc siTTRsc Dose Group (mg/kg) Control 25.0 5.0 2.5 25.0 DRG -20 % Mean Serum TTR Knockdown 0 Nerve 20 40 Stomach 60 80 Colon 100 0 10 20 30 40 50 60 70 80 90 Days siTTRsc, qw x12 17 Oligo Ther Soc., Oct 20

  18. Slide 18: ALN-TTRsc Phase I Study

    ALN-TTRsc Phase I Study Study Design  Randomized, double-blind, placebo-controlled, single- and multi-dose, dose-escalation study  Up to 40 healthy volunteer subjects Primary Objective  Safety and tolerability » Subcutaneously administered single and multiple doses Secondary Objective  Assessmen

  19. Slide 19: ALN-TTR02 and ALN-TTRsc Commercial Opportunity

    ALN-TTR02 and ALN-TTRsc Commercial Opportunity Potentially transformative approach for progressive, fatal disease  Orphan disease with significant unmet need  ALN-TTR is a breakthrough, disease-modifying treatment approach » >80% knockdown of disease-causing TTR protein with single dose » Rapid an

  20. Slide 20: Hemophilia and Rare Bleeding Disorders Program

    Hemophilia and Rare Bleeding Disorders Program Unmet Need and Product Opportunity RNAi to treat hemophilia and rare bleeding disorders (RBD)  Hemophilias are recessive X-linked monogenic bleeding disorders » Hemophilia A: loss of function in Factor VIII – >40,000 Patients in EU/US » Hemophilia B: l

  21. Slide 21: Antithrombin and ALN-AT3 Program

    Antithrombin and ALN-AT3 Program Antithrombin (AT) is genetically defined target Intrinsic system Extrinsic system  AT (also known as “antithrombin III”) Hemophilia B FVIIa FVII defines key natural anticoagulant pathway FIXa FX FIX » Inactivates factors Xa and thrombin » Attenuates thrombin generat

  22. Slide 22: ALN-AT3 Pre-Clinical Efficacy

    ALN-AT3 Pre-Clinical Efficacy ALN-AT3 SC administration results in potent and durable AT knockdown and efficacy in hemophilia models  Potent activity in animal models; multi-dose ED50 for AT knockdown <0.75 mg/kg  Nadir knockdown at ~day 10, with effects lasting over 25 days after single dose  Ef

  23. Slide 23: ALN-AT3 Pre-Clinical Efficacy: Non-Human Primate

    ALN-AT3 Pre-Clinical Efficacy Non-Human Primate ALN-AT3 SC administration results in potent AT knockdown and increased thrombin generation  Multi-dose ED80 for AT knockdown achieved at 0.5 mg/kg; estimate ED50 at 0.15-0.3 mg/kg  Increase in ex vivo thrombin generation with up to 4x increase in pea

  24. Slide 24: ALN-AT3 Commercial Opportunity

    ALN-AT3 Commercial Opportunity Significant potential for new therapeutic approach in hemophilia and rare bleeding disorders  Differentiated product with SC dosing that could change disease management by re-balancing coagulation system  Hemophilia A and B represent >$6 Billion market » Premium pric

  25. Slide 25: Acute Intermittent Porphyria (AIP) Program

    Acute Intermittent Porphyria (AIP) Program Unmet Need and Product Opportunity AIP is autosomal dominant disorder  Ultra-rare orphan disease  Loss of function mutations in porphobilinogen deaminase, key step in heme synthesis » ~5,000 Patients with annual attacks US/Europe » ~500 Patients with recu

  26. Slide 26: Aminolevulinate Synthase-1 and ALN-AS1 Program

    Aminolevulinate Synthase-1 and ALN-AS1 Program Glycine Succinyl CoA ALN-AS1 Aminolevulinate synthase-1 (ALAS-1) is key regulator of pathway ALA Synthase d-Aminolevulinic acid (ALA)  ALAS-1 rate-limiting enzyme in ALA Dehydratase heme synthesis Porphobilinogen (PBG)  PBGD deficiency results in PBG

  27. Slide 27: ALN-AS1 Pre-Clinical Efficacy

    ALN-AS1 Pre-Clinical Efficacy RNAi mediated silencing of ALAS-1 results in potent, rapid, dose-dependent, and durable suppression of toxic heme biosynthesis intermediates that cause symptoms and disease pathology of AIP  Following induction, ALAS-1 silencing completely blocks ALA and PBG in both tr

  28. Slide 28: Additional Programs (I)

    Alnylam 5x15 TM Additional Programs (I) Hypercholesterolemia ALN-PCS  Significant unmet medical need  Targets both intracellular and » Elevated LDL-C (“bad” cholesterol) extracellular PCSK9 is validated risk factor for coronary  Efficacy in multiple pre-clinical artery disease and MI animal model

  29. Slide 29: ALN-PCS Phase I Study Results

    ALN-PCS Phase I Study Results Pharmacodynamics and Clinical Efficacy PCSK9 knockdown and LDL-C reduction after single dose without statins  Randomized, placebo-controlled, single dose escalation study in healthy volunteers with elevated LDL (n=32)  Rapid, dose-dependent, and durable knockdown of P

  30. Slide 30: ALN-CC5 Pre-Clinical Efficacy

    ALN-CC5 Pre-Clinical Efficacy Efficient Hemolysis Inhibition in Rat Hemolytic Activity C5 Western Blot 5.0 mg/kg 2.5mg/kg PBS 100 C5 80 0 4 7 14 18 25 32 % Hemolysis Day of Study 60 40 20  Subcutaneous dosing  Efficient serum C5 lowering 0 0 5 10 15 20 25 30 35  ~90% Hemolytic activity inhibition

  31. Slide 31: Additional Programs (II)

    Alnylam 5x15 TM Additional Programs (II) Beta-thalassemia and ALN-TMP Iron-overload Disorders  Targets transmembrane  Need for disease-modifying protease, serine 6 (TMPRSS6) therapy in beta-thalassemia, for hepcidin activation improve anemia and manage iron  Efficacy in pre-clinical animal levels

  32. Slide 32: Alnylam 5x15 Programs: Definable Clinical Paths

    Alnylam 5x15 Programs TM Definable Clinical Paths with Phase I POC Gene Tissue Human Genetic Program Target Expression Validation ALN-TTR Transthyretin Liver  ALN-AT3 Antithrombin Liver  Aminolevulinate ALN-AS1 synthase-1 Liver  ALN-PCS PCSK9 Liver  Complement ALN-CC5 component 5 Liver  ALN-TMP

  33. Slide 33: Alnylam 5x15 Programs: Phase I POC

    Alnylam 5x15 Programs TM Definable Clinical Paths with Phase I POC Advanced Program Indication: Unmet Need Phase I POC Development • TTR ATTR: Significant morbidity and mortality 45-60 yrs of FAP: Improvement in ALN-TTR • Vitamin A age with neuropathy and cardiomyopathy neuropathy score • Retinol bi

  34. Slide 34: Alnylam 5x15 Development Pipeline

    Alnylam 5x15 Development Pipeline Discovery Development Phase I Phase II Phase III ALN-TTR02 TTR-Mediated Amyloidosis Japan/Asia Pacific ALN-TTRsc Hemophilia and ALN-AT3 Rare Bleeding Disorders Acute Intermittent Porphyria ALN-AS1 Hypercholesterolemia ALN-PCS Complement-Mediated Diseases ALN-CC5 Bet

  35. Slide 35: Financials and Goals

    Financials and Goals 35 a ZL Alnylam

  36. Slide 36: Financial Summary

    Financial Summary 2013 Q1 Financial Results  Cash ~$401M  GAAP Revenues ~$18.6M » Cubist, Takeda, Monsanto, The Medicines Company, and other licenses  GAAP Operating Expenses ~$28.4M  Shares Outstanding ~62M 2013 Guidance  Year-end Cash >$320M 36

  37. Slide 37: Alnylam Goals: Pipeline Goals 2013-2014

    Pipeline Goals 2013-2014 Alnylam Goals 2013 Early Mid Late 2014 Phase II data ALN-TTR02 Phase III FAP start Ext study data Ext study start ALN-TTRsc  Phase I start Phase I data Phase II start Phase III FAC start ALN-AT3 IND filing Phase I start Phase I data ALN-AS1  Pre-clin POC Dev candidate IND

  38. Slide 38: Scientific Meetings

    Scientific Meetings Mid-Year 2013  Biennial Meeting of the Peripheral Nerve Society ALN-TTR02 » June 29 – July 3 in St. Malo, France (Pres: Sunday, June 30)  Congress of the International Society on Thrombosis and ALN-AT3 Haemostasis » June 29 – July 4 in Amsterdam (Pres: Tuesday, July 2) ALN-AS1

  39. Slide 39: Thank You

    WL Alnylarn. Thank You www.alnylam.com

Alnylam Pharmaceuticals — Investor Presentation (June 2013) on 6ix