Ethoxyindole-based CFB inhibitor for complement-mediated diseases

INDICATION: Renal; nephropathy; paroxysmal nocturnal hemoglobinuria (PNH); arthritis

In vitro, cell culture, mouse and rat studies identified an ethoxyindole-based CFB inhibitor that could help treat the complement-mediated diseases C3 glomerulopathy, PNH, arthritis and membranous nephropathy. Screening of a small compound library in proteolytic activity assays, followed by optimization of the top hit, yielded the ethoxyindole-based compound LNP023 that bound CFB with a K_d of 7.9 nM and inhibited the protein with an IC₅₀ of 10 nM. In serum from patients with C3 glomerulopathy, LNP023 decreased abnormal C3 cleavage, a marker of disease, compared with vehicle. In erythrocytes from PNH patients, the compound decreased lysis, a marker of disease. In a rat model of membranous nephropathy, the compound decreased complement activation, proteinuria, glomerulopathy and tubular degeneration. In a mouse model of arthritis, the compound decreased complement activation in the joints, inflammatory cell infiltration in the joints, bone erosion and clinical disease scores. Ongoing work by Novartis AG includes Phase I testing of LNP023 in PNH and IgA nephropathy...