Internal medicine

Eculizumab

Angioedema

Glomerulopathy

Complement system

Factor H

Alternative complement pathway

Antibody

Complement factor I

Complement factor B

Chemistry

Immunology

Paroxysmal nocturnal hemoglobinuria

Atypical hemolytic uremic syndrome

Kidney

Hemolysis

C1-inhibitor

Glomerulonephritis

Complement component 5

Medicine

Pharmacology

Proceedings of the National Academy of Sciences

Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead to complement-driven nephropathies. Here we describe the discovery of a highly potent, reversible, and selective small-molecule inhibitor of factor B, a serine protease that drives the central amplification loop of the AP. Oral administration of the inhibitor prevents KRN-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous nephropathy in rats. In addition, inhibition of factor B prevents complement activation in sera from C3 glomerulopathy patients and the hemolysis of human PNH erythrocytes. These data demonstrate the potential therapeutic value of using a factor B inhibitor for systemic treatment of complement-mediated diseases and provide a basis for its clinical development.

Small-molecule factor B inhibitor for the treatment of complement-mediated diseases