POS-045 Evaluating BCX9930, an Oral Factor D Inhibitor for Treatment of Complement-Mediated Kidney Disease: A Proof-of-Concept Study (RENEW)

IntroductionBCX9930 is a potent, selective, orally administered, small-molecule inhibitor of complement Factor D being developed for the treatment of complement-mediated diseases. Factor D is the rate-limiting enzyme of the alternative pathway (AP) and AP amplification loop of complement. Dysregulation of AP is the key pathophysiological mechanism underlying multiple diseases associated with complement-mediated injury. Factor D inhibition may represent a unified, targeted, therapeutic strategy for the treatment of complement-mediated kidney diseases, such as Complement 3 Glomerulopathy (C3G), Immunoglobulin A Nephropathy (IgAN), and Primary Membranous Nephropathy (PMN), that have limited treatment options. Here, we present the design of the proof-of-concept (POC) RENEW study (NCT05162066) evaluating BCX9930 in participants with C3G, IgAN, and PMN.MethodsRENEW is a 24-week, phase 2, open-label, POC study evaluating therapeutic potential, safety, and tolerability of BCX9930 500 mg orally twice daily (BID). Approximately 42 participants will be enrolled, including adults (≥ 18 years old) with either IgAN (n=14) or PMN (n=14) and adults or adolescents (12-17 years old, where approved) with C3G (n=14). All participants must have persistent proteinuria despite adequate blood pressure control while receiving a maximally tolerated dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Enrollment is initially limited to participants with an estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73 m2 and may be expanded to participants with an eGFR ≥ 30 mL/min/1.73 m2 after recommendation by the Data Monitoring Committee. Background immunosuppressive treatments are exclusionary, except for enrollment of up to 7 participants with C3G receiving a stable regimen of mycophenolate mofetil/mycophenolate sodium. A kidney biopsy is required during screening, or within 30 days of screening for adults (or within 90 days for adolescents), for confirmation of disease diagnosis and activity. An additional biopsy will be conducted at the Week 24 Visit in adults (optional for adolescents) for evaluation of changes from baseline. All study biopsies will be read and reviewed by the study central pathologist.ResultsPrimary endpoint is change from baseline (CFB) in 24-hour urinary protein excretion normalized to urine creatinine (uPCR) measured by percentage CFB in urine protein-to-creatinine ratio. Key secondary endpoints are proportion of participants with a uPCR response defined as partial remission (≥ 50% reduction from baseline), complete remission (≤ 500 mg/g), or normalization (≤ 200 mg/g); proportion of participants with histologic response, CFB in 24-hour urinary protein excretion, eGFR, serum albumin, and blood and urine complement biomarkers. Safety will be assessed via adverse events, physical exam findings, electrocardiograms, and laboratory evaluations. Participants continuing to derive clinical benefit from BCX9930 at the Week 24 visit will be offered extended access, where approved.ConclusionsThe ongoing RENEW study is designed to evaluate the therapeutic potential, safety, and tolerability of BCX9930, an oral Factor D inhibitor, in adult and adolescent participants with C3G and adults with IgAN or PMN to provide clinical data supporting the potential benefit of BCX9930 for the treatment of complement-mediated kidney diseases.Conflict of interest Corporate sponsored research or other substantive relationships:This study is funded by BioCryst Pharmaceuticals, Inc. IntroductionBCX9930 is a potent, selective, orally administered, small-molecule inhibitor of complement Factor D being developed for the treatment of complement-mediated diseases. Factor D is the rate-limiting enzyme of the alternative pathway (AP) and AP amplification loop of complement. Dysregulation of AP is the key pathophysiological mechanism underlying multiple diseases associated with complement-mediated injury. Factor D inhibition may represent a unified, targeted, therapeutic strategy for the treatment of complement-mediated kidney diseases, such as Complement 3 Glomerulopathy (C3G), Immunoglobulin A Nephropathy (IgAN), and Primary Membranous Nephropathy (PMN), that have limited treatment options. Here, we present the design of the proof-of-concept (POC) RENEW study (NCT05162066) evaluating BCX9930 in participants with C3G, IgAN, and PMN.