POS-041 BCX9930, AN ORAL FACTOR D INHIBITOR, SUPPRESSES COMPLEMENT ALTERNATIVE PATHWAY ACTIVITY IN PATIENTS WITH COMPLEMENT 3 GLOMERULOPATHY

IntroductionComplement 3 glomerulopathy (C3G) is characterized by dysregulation of the alternative pathway (AP) of complement. C3G is often associated with a prolonged half-life of C3 convertase linked either to autoantibodies that stabilize the AP C3 convertase, known as C3 nephritic factors, or to mutations in genes encoding proteins that regulate AP activity. Factor D, a serine protease, is the rate-limiting enzyme of the AP and has the lowest concentration in plasma among all complement proteins. Factor D is essential for the formation of the AP C3 convertase, as well as for the AP amplification loop that amplifies complement activity initiated by any of the 3 complement pathways. BCX9930 is an orally administered, potent, and selective inhibitor of Factor D under development for the treatment of complement-mediated diseases, including C3G. This study assessed the effects of oral dosing of BCX9930 on AP activity in ex vivo activated serum from healthy subjects and subjects with C3G.MethodsBCX9930-104 was a phase 1, open-label study to evaluate the pharmacokinetics and pharmacodynamics of a single oral dose of BCX9930 in subjects with varying degrees of renal impairment. Serum samples from 16 healthy subjects (with an estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2) and 6 subjects with C3G (eGFR 33 to 123 mL/min/1.73 m2), dosed with 600 mg of BCX9930, were used to evaluate complement activity. 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 supernatants from the AP Wieslab assay were further analyzed by multiplex assays. Two of the 6 subjects with C3G had very weak baseline AP activity and were not included in the AP Wieslab analysis. Formation of AP C3 convertase was analyzed using immunofixation electrophoresis for 6 of the 16 healthy subjects and all 6 C3G subjects.ResultsA single oral dose of BCX9930 600 mg resulted in rapid (within ≤ 1 hour) and maximal (median ≥ 98% relative to pre-dose levels) suppression of AP activity in both healthy subjects and subjects with C3G. Greater than or equal to 97% median inhibition of AP activity was achieved and sustained 24 hours post-dose for both groups (Figure 1). BCX9930 administration reduced Bb, C3a, and C5a by > 95% in the supernatants from AP Wieslab assays of serum samples both from C3G subjects and from healthy subjects. Mean inhibition of Bb, C3a, and C5a generation was 100%, 100%, and 96%, respectively, in C3G subjects at 8 hours post-dose and 97%, 88%, and 98%, respectively, in healthy subjects at 12 hours post-dose. BCX9930 potently inhibited formation of AP C3 convertase by > 90% through 8 hours post-dose for both groups.ConclusionsOral administration of BCX9930 potently suppressed AP activity and inhibited the formation of AP C3 convertase and complement split products in both healthy subjects and C3G subjects with dysregulation of complement activity. These results support further development of BCX9930 for the treatment of C3G and other complement-mediated diseases.Conflict of interest Corporate sponsored research or other substantive relationships:Employee of BioCryst Pharmaceuticals, Inc. IntroductionComplement 3 glomerulopathy (C3G) is characterized by dysregulation of the alternative pathway (AP) of complement. C3G is often associated with a prolonged half-life of C3 convertase linked either to autoantibodies that stabilize the AP C3 convertase, known as C3 nephritic factors, or to mutations in genes encoding proteins that regulate AP activity. Factor D, a serine protease, is the rate-limiting enzyme of the AP and has the lowest concentration in plasma among all complement proteins. Factor D is essential for the formation of the AP C3 convertase, as well as for the AP amplification loop that amplifies complement activity initiated by any of the 3 complement pathways. BCX9930 is an orally administered, potent, and selective inhibitor of Factor D under development for the treatment of complement-mediated diseases, including C3G. This study assessed the effects of oral dosing of BCX9930 on AP activity in ex vivo activated serum from healthy subjects and subjects with C3G.