First-in-Class Clinically Investigated Oral Factor D Inhibitors for the Treatment of Complement-Mediated Diseases.

Objective: The goal of the study was to discover small molecular inhibitors of complement factor D (FD), an essential protease for activation of the alternative pathway (AP) of complement, that possess the characteristics for clinical investigation in complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria (PNH).

Methods: Compounds were synthesized and tested in vitro for potency, selectivity, and metabolic stability. The optimized compounds were subjected further to a panel of in vitro tests for primary and secondary pharmacology including inhibitory effects on FD, different complement pathways and disease models, as well as to pharmacokinetic and pharmacodynamic evaluations in animals.

Results: Following multiple rounds of optimization, danicopan and later vermicopan were chosen as candidates for clinical investigation. Both compounds demonstrated potent and selective inhibitory effects on FD and AP, suitable pharmacokinetic characteristics for oral dosing, and efficacy in PNH in vitro disease models. In addition to enhanced in vitro potency, vemircopan exhibited lower clearance and higher bioavailability in animal studies compared with danicopan.

Conclusion: Preclinical evaluations of danicopan and vermicopan provided rationales to conduct clinical studies in complement-mediated diseases. Recently, danicopan was approved as an add-on therapy to the C5 inhibitors ravulizumab or eculizumab for the treatment of extravascular hemolysis in patients with PNH.