Pegcetacoplan in C3 Glomerulopathy and Primary Immune-Complex MPGN

Background: In VALIANT (phase 3 trial), pegcetacoplan (C3/C3b inhibitor) demonstrated significant proteinuria reduction at week 26 versus placebo (prespecified primary endpoint), stable eGFR, and glomerular C3 clearance in participants with C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis. Methods: In VALIANT’s 26-week randomized controlled period, participants (≥12 years) received subcutaneous pegcetacoplan ( n =63) or placebo ( n =61) twice weekly plus supportive care. During the 26-week open-label period, all received pegcetacoplan. Here we report prespecified exploratory endpoints during the open-label period. Results: Fifty-nine participants who received pegcetacoplan and 55 who received placebo in the randomized controlled period completed the open-label period. At week 52, the pegcetacoplan-to-pegcetacoplan group maintained the 26-week proteinuria reduction (mean [95% confidence interval (CI)] urine protein-to-creatinine ratio changes from baseline: week 26, −67.1% [−74.9 to −56.8]; week 52, −67.2% [−75.8 to −55.4]). The placebo-to-pegcetacoplan group showed proteinuria changes of 3.2% (–9.6 to 17.9) (26 weeks of placebo), and −53.9% (−64.5 to −40.1) (26 weeks of pegcetacoplan [pegcetacoplan start [week 26] to week 52; post hoc]). In the pegcetacoplan-to-pegcetacoplan group, eGFR changes from baseline (least-squares [LS] mean [95% CI]) were −1.2 mL/min/1.73 m 2 (−5.6 to 3.2) (week 26) and –3.7 mL/min/1.73 m 2 (–8.9 to 1.6) (week 52). In the placebo-to-pegcetacoplan group, mean (95% CI) eGFR changes from baseline were –7.9 (–11.7 to –4.2) (week 26) and –4.7 (–9.1 to –0.3) (week 52); week-26-to-52 change was +3.0 (–1.0 to 7.1) (post hoc). Post hoc analyses of 52 weeks of pegcetacoplan ( n =118) showed proteinuria reduction (geometric mean [95% CI] −63.0% [−69.9 to −54.7]) and eGFR stabilization (LS mean [95% CI] change from realigned baseline, +0.1 [−3.8 to 4.0] mL/min/1.73 m 2 ). No new safety concerns were identified. No encapsulated meningococcal infections, deaths, or allograft losses occurred. Conclusions: Results demonstrate sustained proteinuria reduction and eGFR stabilization after 1 year of pegcetacoplan.