Alnylam Pharmaceuticals R&D Day. July 11, 2013

Transcription

1 Alnylam Pharmaceuticals R&D Day July 11, 2013

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 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. 2

3 Hemophilia: Now and in the Future Opportunities for More Effective Care July, 2013 Craig M. Kessler, MD, MACP Professor of Medicine and Pathology Director, Comprehensive Hemophilia and Thrombophilia Treatment Center Georgetown University Medical Center Washington, DC

4 Disclosures Research Bayer, Baxter, Grifols, NovoNordisk, Octapharma Advisory board member/dsmb member/consultant Alnylam, AskBio, Baxter, Bayer, Biogen Idec, Chugai, Green Cross, NovoNordisk, Octapharma Speakers panels None Stock ownership None Other Director, 340B program

5 COAGULATION PATHWAY Intrinsic pathway (Activated within minutes) Contact activation Extrinsic pathway (Activated within seconds) Tissue damage XII XIIa III (Tissue factor) XI XIa, Ca 2- TF- VIIa VII IX VIII PS-PC Irreversible platelet aggregation IXa VIIIa X V Soluble fibrin XIII XIIIa Ca+2 PF3, Ca +2 Va Thrombin (IIa) Cross-linked fibrin clot ATIII Xa Fibrinogen Ca 2- PL Ca 2- X Prothrombinase complex Prothrombin (II) TFPI KEY Conversion to Causes conversion or release Inhibition of

6 Hemophilia Background X-linked, recessive bleeding disorders caused by deficiency of functional clotting factors VIII and IX Percent of Hemophilic Population Hemophilia A Hemophilia B 80% 20% Deficient Clotting Factor Factor VIII (FVIII) Factor IX (FIX) Approximate Incidence 1 1 in 5,000 male births 1 in 20,000 male births Reported number of Hemophilia Patients in US/EU* 400 new cases each year in USA ~41,000 ~9,600 *WFH Global survey CDC Data 2013

7 Worldwide Hemophilia Statistics Hemophilia A Hemophilia B Hemophilia A & B Total Inhibitor Total Inhibitor Total Inhibitor US 13, , , Japan 4, , France 4, , Germany 3, , Italy 2, , Spain 1, , UK 5, , , Major Markets 35,890 1,552 8, ,731 1,678 Worldwide 98,531 4,554 25, ,691 4,856 China: Estimated total hemophiliacs = 7980 India: Estimated total hemophiliacs = 14,000 Under/misdiagnosed and unregistered Source: 2010 WFH Global Survey Report; Indian J Hematol Blood Transfus. 2011; 27:

8 Rare Bleeding Disorders (RBDs) Rare (1-2 per million), autosomally inherited clotting factor deficiencies with large geographic variation Both sexes equally affected, but females often bleed more due to pregnancy & menses Overall bleeding risk not wellpredicted by factor levels Severe bleeding more common in FV, FVII, FX and FXIII deficiencies 8% 8% RBDs in 2010 WFH Global Survey (N = 14,406) 8% 3% 1% 6% 32% 34% FVII FXI FV Fibrinogen FX FXIII FV+FVIII FII

9 Clinical classification Classification of severity of disease Severe Moderate Mild (% of affected patients) (50%- 70%) (10%) (30%- 40%) FVIII or FIX activity <1% 1% 5% 6% 30% Frequency of bleeding episodes ~2 4 per month ~4 6 per year Uncommon Cause of bleeding episodes Spontaneous Minor trauma Major trauma, Surgery Adapted from Arun B, Kessler CM. In: Coleman RW, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:

10 Bleeding events and disease sequelae Bleeding Events 60% occur in joints, 30% in muscles Other sites may be involved including CNS, GI, deep tissues etc. Disease Sequelae Bleeding events Joint disease - end stage arthropathy Impaired ability to perform in school and work Decreased QOL Inhibitor development (~ 35%) Increased risk of all sequelae and death

11 Hemophilia A and B Clinical Features Soft Tissue Bleed Joint Bleed For severe hemophilia (<1% normal FVIII or IX) recurrent bleeding episodes beginning first year of life Joints Muscles Intra-abdominal CNS Collins et al., BMC Research Notes; 3: 161 (2010) Hemophilic arthropathy Subdural hemorrhage Bleeding results in chronic damage to joints and muscles, can be can be life-threatening Acquired hemophilia-1 case/1 million C/O Prof Claude Negrier, Univ Lyons, Fra

12 General Management Principles Severe Hemophilia Replacement Factor Typically life-long IV infusion 3x/week, beginning ~1yr age Supportive care Assure hemostasis during surgical and dental procedures Treatment of complications Musculoskeletal» Physical therapy, joint replacement surgery Inhibitors» 1/3 of severe patients develop IgG against rfviii (>6,500 patients EU/US)» Managed by use of bypass agents (rfviia, PCC, APCC (FEIBA)) acting via tissue factor pathway and/or immune tolerance induction (ITI)» Extreme costs to healthcare system per patient Viral infections Psycho-social issues

13 Areas of Unmet Need in Hemophilia A Impact of Prophylaxis vs. On-Demand Factor Treatment Median number of bleeding episodes per year Liou et al. Hemophilia 2011 Strategy Prophylaxis (N=13) On-demand (N=37) P value # of bleeding episodes 7.76 ( ) ( ) < # of joint bleeding episodes 5.18 ( ) ( ) < Minimum to maximum value in parenthesis Only ~50% US Patients are Prophylaxis Convenience Compliance Venous access issues Number increases greatly outside of US and EU

14 Primary Findings of Joint Outcome Study Proportion of children with no cartilage/bone changes on MRI in the six index joints at study exit Median number of joint bleeds Episodic 58% Prophylaxis vs Episodic arm: 0.2 vs 4.4 / yr Prophylaxis 84% relative risk reduction Prophylaxis 93% 0% 20% 40% 60% 80% 100% Manco-Johnson M et al NEJM 2007; 357:

15 Frequency % Areas of Unmet Need in Hemophilia A Impact of Inhibitor Development Bleeding episodes and other events Description Overall bleeding episodes No. of Episodes Patient % 488 (0.60) 80.8 Joints 376 (0.46) Italian patients followed prospectively for 18 mos (Gringeri et al., Blood, 2003) Muscles 94 (0.12) 44.4 Other sites 18 (0.02) 22.2 Surgery 11 (0.01) 19.2 Accidents 4 (0.005) 7.7 Distribution of patients according to monthly cost of clotting factors used % <5,000 5,000-10,000 13% 15% 10,000-20,000 12% 12% 20,000-50,000 Monthly cost (Euro) 50, ,000 2% 100, 000 or more Consumption of health care resources Resource Joint and muscle hemorrhages Other Reasons Total No. hospitalizations 11(0.16) 19 (0.28) 30 (0.44) In-hospital days 89(1.32) 323 (4.78) 412 (6.10) Days in ICU 27 (0.40) 96 (1.42) 123 (1.82) Surgery Orthopedic NA 6 (0.09) 6 (0.09) Other NA 5 (0.7) 5 (0.7) Visits to hemophilia center 219 (3.24) 234 (3.47) 453 (6.71) Visits to general practitioner 36 (0.53) 223 (3.30) 259 (3.84) Physiotherapy sessions 702 (10.4) (10.40)

16 Case 9 months old male Familial severe haemophilia A (HA) no inhibitor in family No prenatal counseling Vacuum delivery produced large cephalhematoma Severe Hemophilia A diagnosed with FVIII <1% activity rfviii therapy initiated post delivery 22 doses At 9 months: knee haemarthrosis Alloantibody FVIII inhibitor (4 BU) detected at 30 exposure days Immune tolerance induction initiated (rfviii 200 IU/Kg twice daily) Successful induction within 6 months followed by indefinite prophy

17 Treatment Options for Acute Hemorrhage in Hemophilia with Inhibitors High dose human/recombinant FVIII Porcine FVIII PCCs/APCCs rfviia DDAVP IVIgG Exchange plasmapheresis +/- Extracorporeal adsorption PRIMARY OBJECTIVE: STOP THE BLEEDING

18 Median Annual Cost (US $) Financial burden of inhibitors Total costs Inpatient costs Outpatient factor *Costs shown are median values. Patients with Inhibitors Patients on Prophylaxis Patients Receiving Ondemand Therapy Ullman M & Hoots WK. Haemophilia 2006; 12(Suppl. 6):

19 Outcomes of HTC care: Hemophilia surveillance study Relative Mortality HTC population non-htc population Soucie et al. Blood 2000;96: % reduction in mortality among HTC patients Better outcomes even though HTC patients had more severe disease and higher rate of viral complications Significant reduction in bleeding related hospitalizations, especially for patients also on home therapy Significant increase in cost/benefit

20 Strategies Towards Improving the Clinical Profiles of Factor VIII/IX Products Emerging Therapeutic Approaches Half life extension by re-engineered coagulation proteins Alternate routes of administration Diminishing immunogenicity Gene therapy Bispecific antibody Anticoagulant targeting or rebalancing approaches

21 Strategies Towards Longer-Acting Factor VIII/IX Products Polyethylene glycol conjugation (PEGylation) PEGylated liposomes Polysialic acid polymers Stabilized forms of rfviiia (IR8, DSB) Modification of receptor-mediated catabolism of FVIII by site-directed mutagenesis Hybrid (porcine-human) constructs Combination of technologies New entities from structure-function studies

22 Therapeutic Hypothesis Targeting Antithrombin to Rebalance the Coagulation System Intrinsic system Extrinsic system Hemophilia B FIX FIXa FX FVIIa FVII Hemophilia A FVIII FVIIIa FXa AT FVa FV Prothrombin Thrombin Fibrinogen Fibrin Blood clot

23 Genetic Rationale for Targeting AT3 in Hemophilia Co-inheritance of thrombophilic traits in hemophilia Associated with milder bleeding, reduced factor requirements, fewer complications Includes heterozygous antithrombin deficiency, factor V leiden, Protein C or S deficiency Phenotypic Characteristics Prothrombotic factors AT-deficient patients Clinically Mild N=35 (28 HA, 7 HB) FVIII, FIX <0.01 IU/mL 26/35 >10 y.o at diagnosis 8/35 with joint involvement Median #bleeds 0.2 p.a. Median #replacement factor Rx 0.2 p.a. 43% with evidence of thrombophilia 14/35 functional or genetic PC (FVL), PS, AT3, or TFPI defect 2/35 with low tpa activity 2/35 with functional AT defects AT activity 36 and 51%, respectively (NR: %) Age at diagnosis 15 and 23, respectively Clinically Severe N=37 (36 HA, 1 HB) FVIII, FIX <0.01 IU/mL 1/37 >10 y.o at diagnosis Median #bleeds 3.4 p.a. Median #replacement factor Rx 3.2 p.a. 13.5% with evidence of thrombophilia 4/37 functional or genetic defect of PC (FVL), or TFPI 1/37 with low tpa activity No AT deficient patients Shetty et al., B J Hematol, 138; (2007)

24 Summary Significant unmet need remains in hemophilia A and B and other rare bleeding disorders On demand patients have frequent bleeds resulting in progressive joint damage Inhibitor patients is area of highest unmet need due to absence of prophylaxis Patients are very difficult and costly to manage ALN-AT3 is a promising new approach for Patients with inhibitors Symptomatic/poorly controlled On-demand patients Prophylaxis patients seeking a safe and convenient alternative to a 3x/week IV treatment Other rare bleeding disorders deficiency of FV etc