Methods of inducing immune tolerance to clotting factors

Inventors

Dumont, Jennifer • Jain, Nisha • LETHAGEN, Stefan

Assignees

Swedish Orphan Biovitrum AB • Bioverativ Therapeutics Inc

Abstract

The present disclosure provides methods inducing immune tolerance in a human, comprising administering to the human an effective amount of a composition or a chimeric protein comprising a clotting factor and an Fc region.

Core Innovation

The invention relates to treating a human with hemophilia A who has developed an inhibitory response to factor VIII (FVIII). The method identifies a human subject with hemophilia A and an inhibitory immune response to FVIII and who has failed to respond to one or more previous immune tolerance therapies against FVIII. It then uses a chimeric protein comprising FVIII and an Fc region (FVIII-Fc) to induce immune tolerance.

Immune tolerance induction is performed by administering FVIII-Fc daily at 85 IU/kg to 300 IU/kg for a period sufficient to induce immune tolerance. After induction, the method administers a tapering regimen of FVIII-Fc, and after the tapering regimen it administers a prophylactic dose of FVIII-Fc. The approach thereby reduces or eliminates an inhibitory immune response to FVIII.

For severe hemophilia A, the invention specifies subject selection criteria including a historical inhibitor peak greater than or equal to 5 Bethesda units per milliliter (BU/mL) and failure to respond to one or more previous immune tolerance therapies against FVIII. The method further characterizes timing-related constraints for diagnosis history and treatment course in dependent claim embodiments, including limits on time to tolerance and a minimum duration for the tapering regimen.

Claims Coverage

Two independent claims are directed to treatment methods for hemophilia A with inhibitory FVIII responses. Across the independent claims, there are three main inventive elements: subject selection based on inhibitor status and prior immune tolerance therapy failure, daily FVIII-Fc administration at 85–300 IU/kg to induce immune tolerance, and tapering followed by prophylactic FVIII-Fc dosing to reduce or eliminate the inhibitory immune response. Quantitative criteria for immune tolerance and taper/protocol timing are provided in dependent claims.

The independent claims cover a treatment sequence in which an appropriate human subject, including severe-hemophilia subject selection in the second independent claim, is selected after failure of prior FVIII immune tolerance therapies, then FVIII-Fc is administered daily at 85–300 IU/kg to induce immune tolerance, followed by tapering and then prophylactic dosing, with the result of reducing or eliminating the inhibitory immune response to FVIII.

Stated Advantages

Documented Applications