Pegcetacoplan works for teens with rare kidney diseases

Off-label use of the central C3/C3b inhibitor pegcetacoplan is well tolerated and delivers improved outcomes for adolescents with C3 glomerulopathy (C3G) and immune complex-membranoproliferative glomerulonephritis (IC-MPGN), according to a subgroup analysis of the phase III VALIANT trial.

After 26 weeks of treatment, pegcetacoplan yielded a substantial reduction in the primary endpoint of the log-transformed ratio of urine protein-to-creatinine ratio (uPCR) compared with placebo (mean change from baseline, –73.6 percent vs 3.7 percent; relative reduction, 74.5 percent, 95 percent confidence interval, 58.5–84.3; p<0.0001), reported first study author Dr Bradley Dixon from the University of Colorado School of Medicine in Aurora, Colorado, US. [PAS 2025, abstract 1050.1]

“Proteinuria reduction with pegcetacoplan was observed as early as week 4 and continued through week 26,” Dixon noted.

Results for the key secondary endpoints at week 26 also favoured the central C3/C3b inhibitor. Notably, more adolescents who received pegcetacoplan achieved the composite renal endpoint of a ≥50-percent uPCR reduction and a ≤15-percent eGFR reduction (57.1 percent vs 3.7 percent), with the odds of achieving this endpoint being 37 times greater than those who received placebo (p<0.0016).

A reduction of at least 50 percent in proteinuria occurred in 71 percent of adolescents on pegcetacoplan as opposed to only 3.7 percent of those on placebo, translating to 62 times greater odds of achieving this level of proteinuria reduction (p<0.0002).

Finally, Dixon pointed out that pegcetacoplan stabilized eGFR among adolescents. Over 26 weeks, eGFR increased by a mean of 0.7 mL/min/1.73m² with the central C3/C3b inhibitor and decreased by a mean of 9.0 mL/min/1.73m² with placebo (p=0.05).

Well-tolerated

As for safety, pegcetacoplan demonstrated an acceptable safety profile, with the frequency and severity of treatment-emergent adverse events (TEAEs) being similar between the treatment arms for the adolescent population, he said.

TEAEs occurred in 82.1 percent of adolescents in the pegcetacoplan arm and in 96.3 percent of those in the placebo arm. Serious TEAEs occurred in 10.7 percent and 11.1 percent, respectively, with a case of pyrexia in the pegcetacoplan arm deemed related to treatment.

None of the TEAEs led to study discontinuation or death, and no incidences of serious infections caused by encapsulated bacteria were reported. Graft loss or rejection did not occur in the single adolescent patient who had received a kidney transplant.

Meaningful data

Pegcetacoplan is the first treatment to induce meaningful proteinuria reduction and eGFR stabilization in adolescent patients with C3G and primary IC-MPGN, according to Dixon.

The efficacy results are consistent with those of the full VALIANT population, while the safety results are in line with previous trials and >2,200 patient-years of pegcetacoplan exposure, he said.

Taken together, the data may hold important clinical implications, with Dixon noting that C3G and ICMPGN are associated with poor prognoses, and current treatments are limited to symptomatic treatment until patients reach kidney failure.

VALIANT included 124 patients with C3G or primary ICMPGN. The inclusion criteria were as follows: evidence of active disease; ≥1 g/d of proteinuria at baseline and uPCR of ≥1 g/g in ≥2 first-morning spot urine samples; eGFR of ≥30 mL/min/1.73m²; mandatory vaccination against Streptococcus pneumoniae, Neisseria meningitidis (types A, C, W, Y, and B), and  Haemophilus influenzae (type B); and stable, optimized antiproteinuric regimens (ACEis, ARBs, SGLT2is). Previous kidney transplants were allowed.

The patients were randomly assigned to receive subcutaneous infusions of pegcetacoplan 1,080 mg or placebo twice weekly for 26 weeks. Then, the patients entered a 26-week open-label period, during which all of them received pegcetacoplan. Stable, optimized supportive care were provided to all patients throughout the study.

The subgroup analysis included 55 adolescent patients, including 38 with C3G and 17 with primary IC-MPGN, from VALIANT and covered the 26-week randomized controlled period. Of the adolescents, 28 were in the pegcetacoplan arm (mean age 14.6 years, 64.3 percent female, 71.4 percent White), and 27 were in the placebo group (mean age 14.8 years, 51.9 percent female, 70.4 percent White).

At baseline, the mean 24-h uPCR was 4.6 g/g in the pegcetacoplan arm and 4.0 g/g in the placebo arm. Baseline eGFR was 92.0 and 94.0 mL/min/1.73m² in the respective arms.