BCX9930: A Promising Oral Therapy for Complement Factor D-Mediated Diseases with a Focus on PNH

Complement factor D, a serine protease, is pivotal in the alternative pathway (AP) of the complement system, catalyzing the cleavage of factor B to Ba and Bb. Its scarcity in plasma makes it a crucial enzyme in AP function. Targeting factor D could be a viable therapeutic approach for AP-related diseases such as PNH, aHUS, and C3G.

While terminal complement inhibition by eculizumab or ravulizumab can halt intravascular hemolysis in PNH patients, many still suffer from symptomatic anemia due to extravascular hemolysis caused by ongoing AP activity and C3 binding to red blood cells.

BioCryst Pharmaceuticals has developed an oral small-molecule inhibitor of factor D, BCX9930, which is currently in Phase 1 clinical trials for treating PNH patients. The compound has been shown to be a potent and selective inhibitor of factor D, effectively blocking AP activation on PNH red blood cells in vitro.

In vitro assays were used to evaluate the enzymatic activity of factor D, its selectivity among other human serine proteases, and its ability to inhibit AP-mediated hemolysis. The Ham test and flow cytometry were employed to assess the inhibition of hemolysis and C3 fragment deposition on PNH red blood cells, respectively. The impact on the classical pathway (CP) was also measured.

Results indicate that BCX9930 is highly effective in inhibiting factor D activity and AP-mediated hemolysis with low IC50 values. It showed no significant inhibition of other serine proteases at tested concentrations and did not affect CP activity. Following oral administration in monkeys, BCX9930 completely suppressed AP activity as measured by the generation of C5b-9.

In conclusion, BCX9930 exhibits potent and specific inhibitory effects on factor D in vitro, effectively preventing hemolysis and C3 fragment accumulation on PNH red blood cells. Its ability to suppress AP activity after oral dosing in monkeys suggests its potential as a treatment for PNH and other diseases mediated by the AP.