POS-040 BCX9930, AN ORAL FACTOR D INHIBITOR IN DEVELOPMENT FOR THE TREATMENT OF COMPLEMENT-MEDIATED KIDNEY DISEASES, INHIBITS COMPLEMENT ALTERNATIVE PATHWAY ACTIVITY IN HEALTHY SUBJECTS

IntroductionComplement Factor D, a serine protease, is the rate-limiting enzyme of the alternative pathway (AP) and has the lowest concentration in plasma among all the complement proteins. Factor D is essential for the formation of AP C3 convertase, as well as for the amplification of complement activity initiated by all 3 complement pathways, including amplification of up to 80% of classical and lectin pathways’ complement responses (Harboe et al, Clin Exp Immunol 2004). BCX9930 is an orally administered, potent and selective inhibitor of Factor D under development for the treatment of complement-mediated kidney diseases, including C3 glomerulopathy, IgA nephropathy, and primary membranous nephropathy. This study assessed the effects of oral dosing of BCX9930 on AP activity in ex vivo activated serum from healthy subjects.MethodsSerum samples from healthy subjects enrolled in the BCX9930-101 study (NCT04330534) were used to evaluate complement activity. Plasma Factor B split product Bb was analyzed by ELISA (Quidel). Serum AP activity was analyzed by an AP-specific Wieslab C5b-9 (AP Wieslab) assay. Levels of complement split products Bb, C3a, and C5a in the supernatants from the AP Wieslab assay were analyzed by multiplex assays. Formation of AP C3 convertase was analyzed by immunofixation electrophoresis.ResultsOral dosing of healthy subjects with BCX9930 resulted in dose-dependent and sustained inhibition of plasma Bb levels. BCX9930 dosing led to rapid (within ≤ 1 hour) and maximal (median > 98% relative to pre-dose levels) suppression of activity in the AP Wieslab assay at all dose levels, and the duration of suppression was dose-dependent. At steady state for doses ≥ 200 mg every 12 hours (Q12h), maximal suppression persisted for at least 2 dosing intervals (24 hours) following the last dose (Figure 1). BCX9930 dosing also led to rapid and sustained inhibition of Bb, C3a, and C5a levels in the supernatants from AP Wieslab assays of serum samples. At the highest dose level analyzed, 500 mg Q12h, mean inhibition of the generation of Bb, C3a, and C5a was 99.6%, 93.4%, and 98.4%, respectively, at 12 hours post-dose at steady state. BCX9930 dose-dependently inhibited formation of AP C3 convertase, with doses of 200 and 500 mg Q12h reducing the formation of AP C3 convertase by a mean of > 70% through 12 hours post-dose at steady state.ConclusionsConflict of interest Corporate sponsored research or other substantive relationships:Employee of BioCryst Pharmaceuticals, Inc. IntroductionComplement Factor D, a serine protease, is the rate-limiting enzyme of the alternative pathway (AP) and has the lowest concentration in plasma among all the complement proteins. Factor D is essential for the formation of AP C3 convertase, as well as for the amplification of complement activity initiated by all 3 complement pathways, including amplification of up to 80% of classical and lectin pathways’ complement responses (Harboe et al, Clin Exp Immunol 2004). BCX9930 is an orally administered, potent and selective inhibitor of Factor D under development for the treatment of complement-mediated kidney diseases, including C3 glomerulopathy, IgA nephropathy, and primary membranous nephropathy. This study assessed the effects of oral dosing of BCX9930 on AP activity in ex vivo activated serum from healthy subjects.