Iptacopan safe, effective in patients with C3G

Use of iptacopan along with supportive care results in significant reductions in proteinuria at 6 months in patients with C3 glomerulopathy (C3G), a rare and severe form of proliferative glomerulonephritis brought about by the dysregulation of alternative complement pathway (AP), as shown in the APPEAR-C3G study. It is also well tolerated and has a favourable safety profile.

“Estimated glomerular filtration (eGFR) analysis showed a trend towards improvement over 6 months, while a beneficial effect on eGFR slope trajectory was demonstrated at 6 months postrandomization compared to historical slope,” said lead author Dr David Kavanagh from the National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, UK.

Kavanagh and his team conducted APPEAR-C3G, a multicentre, randomized, double-blind, placebo-controlled phase III trial, in 74 adult patients with biopsy confirmed C3G, reduced serum C3 (<77 mg/dL), urine protein creatinine ratio (UPCR) ≥1.0 g/g, and eGFR ≥30 mL/min/1.73m². They assessed the efficacy, safety, and tolerability of iptacopan versus placebo in this cohort.

Participants received maximally tolerated RAAS blockade and vaccinations against encapsulated bacteria before randomization. They were also allowed to receive mycophenolic acids, low-dose corticosteroids, SGLT2 inhibitors, and mineralocorticoid receptor antagonists provided they were stable for ≥90 days prior to randomization.

APPEAR-C3G consisted of three periods: screening (≤90 days), randomized double-blind treatment with iptacopan 200 mg bid or placebo (6 months), and open-label iptacopan treatment (6 months). The authors obtained historical eGFR data for 2 years before screening visit to be used in prespecified exploratory statistical analysis.

Superior

The primary endpoint was the superiority of iptacopan to placebo on proteinuria (reduction as measured by UPCR [24 h urine collection]) at 6 months. Secondary endpoints were a composite renal endpoint (≥50 percent UPCR reduction plus ≤15 percent eGFR reduction at 6 months vs placebo), kidney function measured by eGFR, histopathology, FACIT PRO at 6 months, and safety over 6 months.

Of the patients, 38 received iptacopan and 36 placebo. The primary endpoint was met, showing a significant reduction in 24-h UPCR at 6 months of iptacopan treatment (35.1 percent, 95 percent confidence interval [CI], 13.8‒51.1; p=0.0014) compared with placebo. [ERA 2024, abstract 98]

Additionally, patients on iptacopan were seven times (odds ratio, 7.145, 95 percent CI, 1.429‒35.723) more likely to meet the composite endpoint of ≥50-percent decrease in proteinuria and stable eGFR at 6 months relative to placebo. The iptacopan group also showed an improvement in eGFR (2.2 mL/min/1.73m² (p=0.1945) at 6 months.

Between the pre- and postrandomization slope, the changes in eGFR trajectory were 10.73 mL/min/1.73m²/year (p=0.0057) in the iptacopan arm and 4.56 mL/min/1.73m²/year (p=0.2267) in the placebo arm.

Moreover, patients on iptacopan showed a numeric decrease (‒0.833, 95 percent CI, ‒1.872 to 0.205; p=0.0579) in total histologic disease activity score relative to those treated with placebo. At 6 months, iptacopan also increased serum C3 (185 percent) and reduced AP activity (‒37.3 percent), plasma sC5b-9 (‒65.1 percent), and urinary sC5b9/creatinine (‒77.3 percent; p≤0.0001 for all biomarkers).

The safety profile of iptacopan was favourable, with no new safety signals identified. No deaths and treatment discontinuations due to adverse events occurred. However, one patient had serious pneumococcal infection (blood culture positive for Streptococcus pneumoniae), which was resolved with antibiotics. There were no episodes of meningococcal disease.

“Iptacopan is a proximal complement inhibitor that targets Factor B, selectively inhibiting the AP,” Kavanagh said.