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

Area of Science:

• Biochemistry
• Pharmacology
• Immunology

Background:

• Complement factor D (FD) is crucial for the alternative pathway (AP) of complement activation.
• Dysregulation of the AP is implicated in various complement-mediated diseases, including paroxysmal nocturnal hemoglobinuria (PNH).

Purpose of the Study:

• To identify and develop small molecular inhibitors of FD.
• To discover compounds with characteristics suitable for clinical investigation in complement-mediated diseases.

Main Methods:

• Synthesis and in vitro testing of compounds for potency, selectivity, and metabolic stability.
• In vitro pharmacology assays assessing inhibition of FD, complement pathways, and disease models.
• In vivo pharmacokinetic and pharmacodynamic evaluations in animal models.

Main Results:

• Danicopan and vermicopan were identified as clinical candidates, demonstrating potent and selective inhibition of FD and AP.
• Both compounds exhibited suitable pharmacokinetic profiles for oral administration and efficacy in PNH in vitro models.
• Vermicopan showed improved in vitro potency, lower clearance, and higher bioavailability in animal studies compared to danicopan.

Conclusions:

• Preclinical data for danicopan and vermicopan support their clinical investigation in complement-mediated diseases.
• Danicopan has been approved as an adjunctive therapy for PNH, targeting extravascular hemolysis.