Targeted dosing for the treatment of complement mediated disorders

Inventors

Huang, Mingjun • Podos, Steven D.

Assignees

Achillion Pharmaceuticals Inc

Abstract

The dosages and methods described herein provide desirable pharmacokinetic (PK) and pharmacodynamics (PD) characteristics which inhibit alternative pathway complement activity, for example at least 85% or more inhibition of AP activity in vivo at dosages from about 120 mg to 200 mg BID that provides a plasma level Ctrough at least about 65 ng/ml, which provides sufficient AP inhibition to reduce the risk of complement breakthrough. In addition, the dosage form described herein provides a significantly low Cmax, providing additional safety margin and better dosing flexibility.

Core Innovation

The invention relates to a method of modulating immune function in a patient by administering (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl) acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0] hexane-3-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof. The method uses a twice a day (BID) dosing regimen at a dosage of between about 100 mg and about 200 mg.

The disclosed approach emphasizes a diurnal PK/PD profile, targeting minimum mean plasma Ctrough while keeping Cmax low. The dosing regimen is described as intended to maintain alternative pathway activity inhibition while controlling plasma exposure through concentration-related constraints such as Ctrough and Cmax.

Human study results described in the partial content report ex vivo alternative pathway hemolysis and Wieslab inhibition with sustained inhibition at steady state for BID regimens of 120 mg and 200 mg. The partial content further describes duration of inhibition (DURATION0-12) and integrated effect (%AUEC0-12) associated with the disclosed Compound 1 dosing, and includes comparison to a related Compound 2.

Claims Coverage

The partial content includes one independent claim covering immune modulation by Compound 1 administered BID at a defined dosage range, with dependent claims refining exposure and diurnal plasma concentration targets, and restricting the measurement of Ctrough to patients with selected disorders. Across the claim set, the inventive features include the specific Compound 1 identity (or pharmaceutically acceptable salt), BID dosing within 100–200 mg, and concentration constraints involving Cmax and diurnal Ctrough levels that support alternative pathway modulation.

Overall claim coverage is centered on immune modulation using Compound 1 (or a pharmaceutically acceptable salt) with BID dosing in a 100–200 mg range, and dependent claim refinements that include Cmax constraints, minimum treatment duration, a diurnal Ctrough target, and disorder-restricted applicability for measuring Ctrough.

Stated Advantages

Documented Applications