Phase 1 Study of ALN-AT3 An Investigational RNAi Therapeutic for the Treatment of Hemophilia and Rare Bleeding Disorders.

Transcription

1 Phase 1 Study of ALN-AT3 An Investigational RNAi Therapeutic for the Treatment of Hemophilia and Rare Bleeding Disorders January 12,

2 Agenda Welcome Cynthia Clayton Vice President, Investor Relations and Corporate Communications Introduction John Maraganore, Ph.D. Chief Executive Officer Review of Interim ALN-AT3 Phase 1 Data Akshay Vaishnaw, M.D., Ph.D. Executive Vice President and Chief Medical Officer Q&A Session 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, successfully demonstrate the efficacy and safety of our drug candidates, obtain, maintain and protect intellectual property, enforce our patents and defend our patent portfolio, obtain regulatory approval for products, establish and maintain business alliances; our dependence on third parties for access to intellectual property; and the outcome of litigation, 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 forwardlooking 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 John Maraganore, Ph.D. Chief Executive Officer Introduction 4

5 Hemophilia and Rare Bleeding Disorders Program Unmet Need and Product Opportunity High unmet needs in 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/U.S. Hemophilia B: loss of function in Factor IX ~9,500 Patients in EU/U.S. Segments of high unmet need remain E.g., Inhibitor patients 1,2 2,000 Patients in major markets; up to 6,000 WW >15-25 Bleeds/year; >5 in-hospital days/year ~$300,000/year avg. cost; up to $1M/year Hemophilia A and B represent >$9B market Premium pricing established Value supported by pharmacoeconomics Well organized patient advocacy Significant opportunity for global expansion 5 1 WFH 2012 Global Survey; 2 Antunes et al., Haemophilia. 20:65-72 (2014)

6 Akshay Vaishnaw, M.D., Ph.D. Executive Vice President and Chief Medical Officer Review of Initial ALN-AT3 Phase 1 Data 6

7 Antithrombin and ALN-AT3 Program Antithrombin (AT) is genetically defined target AT is key natural anticoagulant Inactivates Factor Xa and thrombin Attenuates thrombin generation Human AT deficiency associated with increased thrombin generation Expressed in liver; circulates in plasma Hemophilia B Co-inheritance of thrombophilic traits in hemophilia 1 Associated with milder bleeding, reduced factor requirements, fewer complications Fibrinogen Fibrin Blood clot Includes heterozygous ALN-AT3 in clinical development Antithrombin deficiency Extensive pre-clinical efficacy and safety data Factor V Leiden in hemophilia models Protein C deficiency Orphan drug status in U.S./EU (HA/HB) Protein S deficiency Positive initial Phase 1 results; study ongoing Additional data mid- and late 15 FIX Hemophilia A Intrinsic system FVIII FIXa FVIIIa Prothrombin FX FXa Extrinsic system FVIIa AT Thrombin FVa FVII FV 7 1 Kurnik et al., Haematologica; 92:982-5 (2007); Ettingshausen et al., Thromb Haemost; 85: (2001); Negrier et al., Blood; 81:690-5 (1993); Shetty et al., Br J Haematol; 138:541-4 (2007)

8 ALN-AT3 Phase 1 Study Dose-Escalation Study in Two Parts Primary objectives Safety, tolerability Secondary objectives AT knockdown, thrombin generation Part A Single- Ascending Dose (SAD) 30 mcg/kg x 1 SC f Randomized 3:1, N=4 Single-blind Placebo-controlled Healthy volunteers 15 mcg/kg qw x 3 SC G Open-label Hemophilia A or B N=3/cohort Part B Multiple-Ascending Dose (MAD) 45 mcg/kg qw x 3 SC G TBD mcg/kg qw x 3 SC Up to 4 additional cohorts 8

9 Mean % AT Knockdown ALN-AT3 Phase 1 Study Part B (MAD) Cohort 1 and 2 Interim Pharmacodynamics and Clinical Activity* Initial data on AT knockdown after multi-dose in hemophilia subjects Cohort 1 (n=3) results Mean maximum AT knockdown of 29 ± 12% (n=3; mean ± SEM) Maximum AT knockdown up to 53% Cohort 2 (n=3) results Mean AT knockdown of 44 ± 6.5% (n=3, mean ± SEM; p=0.02) on Day 16 Mean AT knockdown of 64 ± 6.8% (n=2; mean ± SEM) on Day 21 Maximum AT knockdown up to 70% mcg/kg 0 45 mcg/kg Days *Data as of Jan. 6, 2015

10 Thrombin (nm) Relative Thrombin Generation Thrombin Generation and Hemophilia Correlation with Bleeding Phenotype in Hemophilia Patients Thrombin generation correlates with disease severity Ex vivo assay sensitive to overall coagulation cascade Both endogenous thrombin potential (ETP) and peak thrombin correlate with severity of hemophilia, bleeding frequency, and replacement factor requirement 1 Control Tissue factor = 1 pm Phospholipids = 4 µm Peak Thrombin ETP 0.8 FVIII = 10% (Mild) 0.6 FVIII = 2.7% (Moderate) 0.4 FVIII < 1% (Severe) 0.2 Time (min) 0 (N = 40) Normal Severe (N=23) Moderate (N=10) Hemophilia A Mild (N=13) 10 1 Dargaud et al., Thromb Haemost; 93, (2005)

11 Peak Thrombin, nm Thrombin Generation (% Change Relative to Group Baseline) ALN-AT3 Phase 1 Study Part A and B Preliminary Evaluation of Thrombin Generation* Increased thrombin generation in hemophilia subjects Up to 334% increase (relative to baseline) in thrombin generation in hemophilia subjects Mean increase in thrombin generation of 112 ± 38% (p<0.05, relative to baseline) at AT KD 50% Maximum increase in peak thrombin at low end of range for thrombin generation in normal subjects Healthy Volunteers Baseline Hemophilia Baseline Hemophilia AT KD <50% Hemophilia AT KD 50% *Data as of Jan. 6, 2015 Analysis excludes data points influenced by replacement factor -100 Hemophilia Baseline Hemophilia AT KD <50% Hemophilia AT KD 50%

12 Whole Blood Clot Formation Materials and Methods ROTEM Thromboelastometry Evaluates viscoelastic changes in blood following physiologic coagulation stimulus CTI stabilized citrate whole blood; diluted tissue factor (Innovin); CaCl2 Normal Hemophilia 12 J Thromb Haemost Mar;1(3): Blood Mar 14;121(11):

13 Replicate 3 Replicate 2 Replicate 1 Hemophilia Subject Whole Blood Clot Formation Day 1 Day 8 Day 15 Day 21 13

14 ALN-AT3 Phase 1 Study Part B (MAD) Cohort 1 and 2 Interim Safety/Tolerability; All TEAEs* Preferred Term Cohort 1 (N=3) 15 mcg/kg n (%) Cohort 2 (N=3) 45 mcg/kg n (%) Haemorrhage 3 (100.0%) 0 (0.0%) Abdominal pain 1 (33.3%) 0 (0.0%) Epistaxis 1 (33.3%) 0 (0.0%) Mouth haemorrhage 0 (0.0%) 1 (33.3%) Muscle haemorrhage 1 (33.3%) 0 (0.0%) Myalgia 1 (33.3%) 0 (0.0%) Myalgia - Right Thigh Bleed 1 (33.3%) 0 (0.0%) Post procedural haemorrhage 1 (33.3%) 0 (0.0%) Skin haemorrhage 0 (0.0%) 1 (33.3%) Thermal burn 1 (33.3%) 0 (0.0%) Tongue haematoma 0 (0.0%) 1 (33.3%) Traumatic haematoma 0 (0.0%) 1 (33.3%) Vessel puncture site haematoma 0 (0.0%) 1 (33.3%) No serious adverse events All adverse events mild/moderate No discontinuations No injection site reactions No thromboembolic events or clinically significant D-dimer increases Normal physical exams, vital signs, and ECG No laboratory AEs (LFTs, CBC, coagulation parameters) 14 *Data as of Jan. 6, 2015

15 ALN-AT3 Phase 1 Study Summary and Next Steps ALN-AT3 represents novel approach for treatment of hemophilia and RBD In ongoing Phase 1 in healthy volunteers (n=3) and subjects with hemophilia (n=6), single- and multi-dose administration of ALN-AT3 generally well tolerated No SAEs; all AEs mild or moderate, and transient; no discontinuations In Part A in healthy volunteers, single 30 mcg/kg dose of ALN-AT3 resulted in an up to 28% knockdown in AT with durable effect lasting >60 days In Part B in hemophilia subjects, ALN-AT3 resulted in up to 70% knockdown in AT Most advanced hemophilia subject receiving 45 mcg/kg demonstrates a durable effect, with 54% AT KD at Day 42 (28 days post last dose) Initial evidence for potential correction of hemophilia phenotype observed At AT KD >50%, mean peak thrombin generation increase of 112 ± 38%, with max peak thrombin increase of 334% Marked and durable improvement in whole blood clot formation as measured by ROTEM Most advanced subject receiving 45 mcg/kg remains bleed free for 47 days (as of Jan 6, 2015) Additional results expected to be presented in mid- and late 15 15

16 Review of Interim ALN-AT3 Phase 1 Data Q&A 16

17 Thank You 17