Oral Iptacopan in C3 Glomerulopathy

Key Takeaways

• At 6 months, iptacopan was associated with lower proteinuria than placebo, and the prespecified efficacy endpoint was met.
• Treatment-emergent adverse events occurred in both groups, were mostly mild or moderate, and no deaths, discontinuations due to treatment-emergent adverse events, or meningococcal infections were reported.
• The authors described the 6-month proteinuria reduction as clinically meaningful and the overall safety profile as acceptable.

Adults with biopsy-confirmed C3 glomerulopathy who received oral iptacopan had a 35.1% relative reduction in 24-h UPCR versus placebo at 6 months in the APPEAR-C3G phase 3 trial. The double-blind comparison evaluated iptacopan versus placebo on top of supportive care, including background RAAS inhibition and immunosuppression. At 6 months, the prespecified primary proteinuria endpoint was met in the randomized adult cohort.

APPEAR-C3G was a multicentre, randomised, double-blind, placebo-controlled phase 3 study conducted at 35 hospitals or medical centres in 18 countries. Eligible participants were adults aged 18–60 years with biopsy-confirmed C3 glomerulopathy, reduced serum C3, and UPCR of at least 1.0 g/g at two screening visits. Enrollment also required eGFR of at least 30 mL/min per 1.73 m2 at screening and day –15, plus vaccination against Neisseria meningitidis and Streptococcus pneumoniae. Participants were randomized 1:1 to iptacopan 200 mg twice daily or placebo for 6 months on supportive care, including RAAS inhibitors and immunosuppression. This was followed by a 6-month open-label iptacopan period; investigators screened 132 participants, randomized 74, completed the adult cohort, and registered the trial as NCT04817618.

The prespecified primary endpoint was the relative reduction in proteinuria at 6 months, measured by the log-transformed ratio to baseline in 24-h urine UPCR. At that timepoint, the relative reduction in 24-h UPCR versus placebo was 35.1%, with a 95% CI of 13.8 to 51.1 and p=0.0014. The 24-h UPCR changed by –30.2% from baseline in the iptacopan group and by 7.6% in the placebo group. Geometric mean 24-h UPCR was 3.33 g/g at baseline and 2.17 g/g at 6 months with iptacopan, versus 2.58 g/g and 2.80 g/g with placebo. The primary analysis used the full analysis set, and the prespecified primary endpoint was met at 6 months.

Treatment-emergent adverse events during follow-up occurred in 30 of 38 participants given iptacopan and 24 of 36 participants given placebo. Most events were mild or moderate, while serious adverse events occurred in 3 of 38 and 1 of 36 participants, respectively. No deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections were reported in either group. Safety analyses included all participants who received at least one dose of study treatment. The authors concluded that iptacopan produced a statistically significant, clinically meaningful reduction in proteinuria with an acceptable safety profile at 6 months.