#288 Pegcetacoplan demonstrates clinically significant responses in C3G and primary (idiopathic) IC-MPGN Patients with or without concomitant immunosuppression in VALIANT

Abstract Background and Aims C3 glomerulopathy (C3G) and primary (idiopathic) immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases where uncontrolled C3 activation results in excessive glomerular deposition of C3 breakdown products, which may lead to kidney damage and ultimately kidney failure. Current treatments, such as mycophenolate mofetil (MMF) and corticosteroids, are used off-label, primarily targeting inflammatory changes rather than the underlying disease mechanism. These treatments are associated with adverse effects and lack robust clinical evidence of efficacy. As a result, up to 50% of patients progress to kidney failure within 10 years. Pegcetacoplan (PEG) selectively binds to C3 and C3b to strongly block C3 activation by classical/lectin/alternative pathways, C3/C5 convertase activity and activation of downstream effectors. PEG targets the pathogenic process in C3G/primary IC-MPGN with the aim of stopping kidney damage. In the Phase 3 VALIANT study (NCT05067127) in pts aged ≥12 years with native or post-transplant recurrent C3G/primary IC-MPGN, PEG led to a 68.1% relative proteinuria reduction vs placebo (PBO), glomerular C3 clearance in 71% of pts and stabilization of estimated glomerular filtration rate (eGFR). Participants were permitted to continue pre-existing MMF, glucocorticoids (maximum dose 20 mg prednisone daily or equivalent) and other immunosuppressive therapies, provided that the doses of these, as well as other drugs impacting proteinuria, remained stable throughout the randomized controlled period and preceding 12-week screening period. The aim of this analysis was to evaluate the efficacy and safety of PEG versus PBO in VALIANT patients with and without concomitant immunosuppressants (IS) (IS-treated vs non-IS treated). Method VALIANT study participants were randomized 1:1 to receive PEG (subcutaneous infusion twice weekly) or PBO for 26 weeks as add-on to their stable treatment regimen. The primary endpoint was the log-transformed ratio of urine protein-to-creatinine ratio at Week 26 vs baseline. Key secondary endpoints included the proportion of pts achieving a reduction in C3c staining on kidney biopsy and change in eGFR from baseline for PEG vs PBO. Results Overall, 124 pts were randomized (63 PEG, 61 PBO). At baseline, 48 (76%) PEG and 42 (69%) PBO participants received concomitant IS (Table 1). Baseline characteristics of these 90 pts did not differ from those not receiving concomitant IS. At Week 26, PEG-treated pts achieved a significant and clinically meaningful relative reduction in proteinuria vs PBO in IS-treated (70.3% [p < 0.0001]) and non-IS treated (64.5% [p = 0.0005]) pts. The number of pts achieving ≥50% reduction in proteinuria at Week 26 vs baseline was 30 (62.5%) in the PEG group vs 2 (4.8%) in the PBO group among IS-treated pts (p < 0.0001), and 8 (53.3%) vs 1 (5.3%) among non-IS treated pts (p = 0.0087). Reduction (≥2 orders of magnitude) in glomerular C3c staining was achieved in 18/26 (69.2%) of the PEG group vs 2/21 (9.5%) of the PBO group among IS-treated pts (p = 0.0013) and 8/9 (88.9%) of the PEG group vs 2/13 (15.4%) of the PBO group among non-IS treated pts (p = 0.0046). In the PEG vs PBO group, there was a relative difference of +6.8 mL/min/1.73 m2 in change in eGFR (p = 0.0710) in IS-treated and +5.0 mL/min/1.73 m2 (p = 0.2200) in non-IS treated pts. Rates of treatment-emergent adverse events and infections of interest (e.g. pneumonia and viral infection) were comparable between PEG and PBO groups in both IS- and non-IS treated pts. There were no meningococcal infections. One death occurred in the IS-treated PEG group (COVID-19 pneumonia unrelated to PEG). Conclusion In this pre-specified analysis, C3G/primary IC-MPGN pts receiving stable concomitant IS achieved robust proteinuria reduction, glomerular C3 reduction, and eGFR stabilization with PEG treatment, with outcomes similar to pts without concomitant IS treatment. PEG was well-tolerated with no new safety signals and no difference in adverse event profiles with/without IS treatment.