Antithrombin Reduction Improves Coagulation in Rare Bleeding Disorder Plasma

Transcription

1 Antithrombin Reduction Improves Coagulation in Rare Bleeding Disorder Plasma Alfica Sehgal, Kun Qian, Julia Hettinger, Benny Sorensen and Akin Akinc Alnylam Pharmaceuticals, Cambridge, MA, United States 1 June 23, 215 ISTH 215 Toronto, Canada

2 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 Co-inheritance of thrombophilic traits in hemophilia 1 Associated with milder bleeding, reduced factor requirements, fewer complications Includes heterozygous Antithrombin deficiency Factor V Leiden Protein C deficiency Protein S deficiency Hemophilia B FIX Hemophilia A Intrinsic system FVIII FIXa FVIIIa Prothrombin FX FXa Fibrinogen Extrinsic system FVIIa AT Thrombin FVa Fibrin Blood clot ALN-AT3 in clinical development Extensive pre-clinical efficacy and safety data in hemophilia models 2 Orphan drug status in U.S./EU (HA/HB) Positive initial Phase 1 results; new Phase 1 data at ISTH, June 23 Additional data late 15 FVII FV 2 1 Kurnik et al., Haematologica; 92:982-5 (27); Ettingshausen et al., Thromb Haemost; 85:218-2 (21); Negrier et al., Blood; 81:69-5 (1993); Shetty et al., Br J Haematol; 138:541-4 (27) 2 Seghal et al., Nat Med, doi:1.138/nm.3847

3 Antithrombin Lowering for RBDs Intrinsic system Extrinsic system Applying the therapeutic hypothesis of AT lowering more broadly Hemophilia is a bleeding disorder of insufficient thrombin generation Many rare bleeding disorders (RBDs) similarly arise from insufficient thrombin generation Includes FV, FVII, FXI deficiencies, among others FVIII FVIIa FX FVIIIa FIX FIXa FXa AT FXI FXIa FVa Prothrombin Thrombin Fibrinogen Fibrin Blood clot FVII FV 3

4 Rare Bleeding Disorders (RBDs) Collection of rare (1-2 per million), recessive bleeding disorders caused by deficiency of functional clotting factors 3% 7% 8% 8% 1% RBDs in EN- RBD (N = 592) 1% 1% 2% 38% 22% FVII FXI FV Fibrinogen FX FXIII FV+FVIII FII FXII Other combined 7% 9% RBDs in 213 WFH Global Survey (N = 19,664) 8% 3% 1% 6% 29% 37% FVII FXI FV Fibrinogen FX FXIII FV+FVIII FII Distribution of RBDs is very similar in EuroNet database (EN-RBD) and 213 WFH Global Survey 4 Peyvandi et al., J Thromb Haemost; 1, (212)

5 Medical Impact Impact can be similar to hemophilia Less well characterized, due to rarity Fewer and less established treatment options Clinical Bleeding Severity Asymptomatic Grade I Grade II Grade III Definition No documented bleeding episodes Bleeding that occurred after trauma or drug ingestion (antiplatelet or anticoagulant therapy) Spontaneous minor bleeding: Bruising, ecchymosis, minor wounds, oral cavity bleeding, epistaxis and menorrhagia Spontaneous major bleeding: Hematomas, hemarthrosis, CNS, GI and umbilical cord bleeding Peyvandi et al., J Thromb Haemost; 1, (212) 5

6 Current Management and Unmet Need Unmet Need Subset of patients with grade II/III bleeding phenotype could benefit from chronic prophylaxis Current Management Depending on severity of clinical phenotype and type of factor deficiency, treated with fresh frozen plasma, factor VII concentration, recombinant factor VIIa, factor XI concentrations and/or anti-fibrinolytics Product half-lives vary from hours to few days Acharya et al., J Thromb Haemost; 2, (24) 6

7 Generating Ex Vivo Proof-of-Concept Investigate impact of AT depletion of thrombin generation in factordepleted human plasma samples Approach previously applied in hemophilia A and hemophilia B settings 1,2 Experimental overview Obtain human plasma samples deficient in coagulation factor of interest FV, FVII, and FXI deficient Immunodeplete antithrombin from samples to generate model plasmas Add affinity purified sheep anti-at antibody (HTI, PAHAT-S) to deplete AT Add isotype matched control antibody Measure resultant AT activity levels Chromogenic AT activity assay (Biophen, Antithrombin 5 kit) Measure thrombin generation in model plasmas Calibrated automated thrombogram (CAT) method (1 pm tissue factor, 4 mm phospholipids) 7 1 Sehgal et al., Nat Med, 21(5): (215) 2 Thrombin Generation in Human Hemophilia Plasma at Reduced Antithrombin Levels and Concomitant Factor or Bypass Agent Addition,; Tuesday, 6:PM 7:3PM, Poster 154

8 Impact of AT Levels in FV Deficient Plasma Thrombin Generation 2 FV deficient FV deficient -2 Thrombin (nm) 15 1 FV<1%, AT=1% FV<1%, AT=2% Normal Thrombin (nm) FV<1%, AT = 2% FV<1%, AT = 1% Normal Mins Mins Ø Improved thrombin generation (peak and ETP) with AT reduction in FV deficient plasma samples 8

9 Impact of AT Levels in FVII Deficient Plasma Thrombin Generation 2 FVII deficient -1 2 FVII deficient -2 Thrombin Levels (nm) FVII=%, AT=2% FVII=%, AT=1% normal Thrombin ( nm) FVII=%, AT=2% FVII=%, AT=1% normal mins mins Ø Improved thrombin generation (peak and ETP) with AT reduction in FVII deficient plasma samples 9

10 Impact of AT Levels in FXI Deficient Plasma Thrombin Generation 2 FXI deficient FXI deficient -2 Thrombin (nm) FXI=%, AT=1% FXI=%, AT=2% Normal Thrombin (nm) FXI=%, AT=2% FXI=%, AT=1% Normal Mins Mins Ø Improved thrombin generation (peak and ETP) with AT reduction in FXI deficient plasma samples 1

11 Impact of AT Levels in FXI Deficient Plasma Activated Thromboplastin Time (aptt) FXI deficient plasma displays prolonged aptt, characteristic of contact pathway defect 12 FXI deficient FXI deficient aptt (sec) aptt (sec) Normal FXI=%, AT=1% FXI=%, AT=3% Normal FXI=%, AT=1% FXI=%, AT=2% Ø Correction of prolonged aptt with AT reduction in FXI deficient plasma samples 11 Confidential

12 Summary and Conclusions AT reduction is currently being investigated in a Phase 1 trial as a means to enhance thrombin generation and improve hemostasis in hemophilia patients This therapeutic hypothesis may be applicable to other RBDs arising from insufficient thrombin generation Thrombin generation studies demonstrate that AT reduction can enhance thrombin generation in FV, FVII, and FXI deficient human plasma Further, prolonged aptt in FXI deficient plasma was shortened upon AT depletion These data support the investigation of AT reduction via ALN-AT3 in patients with FV, FVII, and FXI deficiencies 12

13 13 Thank You