PB0249 - Development of the first small molecule therapy for the treatment of hemophilia A and B

Background: Current treatment options for hemophilia A and B cannot adequately address the needs of patients in the developing world. Existing biologic and gene therapies are prohibitively expensive and can prove difficult to transport and store in these environments. As a result, a large population of patients lacks reliable access to prophylactic and emergency treatment.

Aims: We sought to demonstrate the in vitro efficacy of our novel coagulant small molecule compounds and their compositions in FVIII and FIX deficient plasma via a modified aPTT assay.

Methods: The Stago STartMax analyzer was used for these assays. To 50 µl of FVIII or FIX deficient plasma (George King Bio-Medical) was added up to 5 µl of activator (STA-CK Prest 5, Stago), 5 µl of a vehicle containing our compounds or compositions and 50 µl of 0.025 M calcium chloride. Assays were conducted in a 4-well format with control and test wells run simultaneously. Experiments were repeated in triplicate at minimum and the paired t-test was used to assess statistical significance. Four individual compounds and four compositions were tested across a concentration gradient of 0.16-13.3 mM.

Results: Several compounds and compositions exhibited statistically significant reductions in coagulation times in FVIII and FIX deficient plasmas. Of particular interest was the compound YSISK-CH, which exhibited a ~35% reduction (equivalent to ~8% of regular FVIII levels) at ~7mM in FVIII deficient human plasma and an ~80% reduction (superior to ~80% of regular FVIII levels) at ~7 mM in FVIII deficient canine plasma. YSISK-CH also exhibited a ~40% reduction at ~7 mM in FIX deficient human plasma.

Conclusion(s): The efficacy of our novel compounds and compositions in the modified aPTT assay in both FVIII and FIX deficient plasmas reveals a set of potential drug candidates from which we hope to develop the first small molecule therapy for hemophilia A and B.