Discovery of (3 R ,4 R )-15: An Advanced Factor B Inhibitor Entering Phase 3 for Complement-Mediated Diseases

The alternative pathway (AP) of the complement system plays a critical role in the pathogenesis of various human diseases, including age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and several glomerular diseases. Although the approved drug Iptacopan is available, it requires twice-daily oral dosing, resulting in suboptimal patient compliance. Using a scaffold-hopping strategy, we identified the clinical candidate (3 R, 4 R )-15, which exhibits potent inhibitory activity against factor B (FB) and the AP, with IC 50 values of 10.2 nM and 59.3 nM, respectively. Furthermore, this compound exhibits significantly improved pharmacokinetic properties, including an oral bioavailability of 69.2% in mice. Preliminary clinical studies indicate that (3 R,4 R )-15 has promising efficacy in patients with PNH. Its once-daily dosing regimen also offers the potential to markedly improve patient compliance. (3 R,4 R )-15 is currently in Phase 3 trials evaluating its efficacy for the treatment of PNH.