Novel Drug Shows Benefits in Rare C3G and Primary IC-MPGN

SAN DIEGO — The investigational drug pegcetacoplan, a C3/C3b inhibitor, showed significant benefits in the treatment of patients with C3 glomerulopathy or primary immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN) in the largest trial of its kind of these rare and debilitating kidney diseases.

For the primary endpoint of a change in proteinuria from baseline, as measured by the urine protein-to-creatinine ratio (uPCR) at week 26, the reduction was 67.2% with pegcetacoplan vs 2.9% with placebo, for a relative reduction of 68.1% (P

“This was a highly statistically and clinically meaningful proteinuria reduction,” said first author Carla M. Nester, MD, of the University of Iowa Stead Family Children’s Hospital, in Iowa City, Iowa, who presented the findings at the Kidney Week 2024: American Society of Nephrology Annual Meeting.

Importantly, the benefits were noted as early as of 4 weeks of therapy, she added.

Commenting on the study, Matthias Kretzler, MD, the Warner-Lambert/Parke-Davis professor of medicine/nephrology and Computational Medicine and Bioinformatics at the University of Michigan, Ann Arbor, Michigan, called the research “groundbreaking.”

“This is a rare disease with tremendous treatment challenges, with many patients rapidly progressing to kidney failure,” Kretzler, co-moderator of the conference session, told Medscape Medical News.

C3 glomerulopathy and IC-MPGN lead to kidney failure in approximately 50% of patients within 5-10 years of diagnosis, resulting in the need for a kidney transplant or lifelong diagnosis. Even when patients do receive a kidney transplant, approximately two thirds experience disease recurrence.

The conditions are characterized by excessive deposits of the complement protein C3c; however, no treatments are available that target the underlying causes.

The current study findings with pegcetacoplan introduce a potential “kidney- and life-saving option” for these patients, said Kretzler.

VALIANT Trial

Pegcetacoplan, which targets C3, is designed to regulate excessive activation of the immune system’s complement cascade, which can result in disease progression. The drug is already approved for the treatment of paroxysmal nocturnal hemoglobinuria and is being studied for other rare diseases in hematology and nephrology.

To evaluate the efficacy of pegcetacoplan in C3 glomerulopathy and IC-MPGN, the authors conducted the phase 3, multicenter, double-blind VALIANT trial, involving 124 patients aged 12 years or older who had native or post-transplant recurrent C3 glomerulopathy or primary IC-MPGN.

Inclusion criteria included having an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m², evidence of active disease, at least 1 g/d of proteinuria on screening urine collection, and a uPCR of at least 1 g/g in two or more first-morning spot urine samples.

Exclusionary criteria included evidence of transplant rejection, a diagnosis of secondary C3 glomerulopathy or IC-MPGN, or severe infection within 14 days prior to the first dose.

The patients had mean ages of 28.2 and 23.6 years in the pegcetacoplan and placebo groups, respectively; 58.7% and 54.1% of patients, respectively, were women.

The mean baseline eGFR was 78.5 mL/min/1.73 m² in the pegcetacoplan group and 87.2 mL/min/1.73 m² in the placebo group; in both the groups, the time since diagnosis was about 3.7 years.

Patients were randomized to treatment with either pegcetacoplan in subcutaneous infusions two times per week (n = 63) or placebo (n = 61) for 26 weeks.

As noted, there was a relative reduction in proteinuria of 68.1% for patients taking pegcetacoplan vs those taking placebo (P

The results also strongly favored pegcetacoplan in secondary endpoints, including a composite renal endpoint of a 50% or more reduction in uPCR, achieved in 60.3% in the pegcetacoplan group vs 4.9% in the placebo group (P

The proportion of patients in the pegcetacoplan group that achieved a composite renal endpoint of at least 50% reduction in uPCR, as well as up to 15% reduction in eGFR, at week 26 vs baseline was 49.2% compared with 3.3% in the placebo group (P

Those treated with pegcetacoplan also had robust reductions in C3c staining, with 71.4% of pegcetacoplan-treated patients achieving zero intensity staining.

There were no significant differences between the groups in terms of treatment-emergent adverse event frequency or severity.

Of four serious infections that occurred, including three in the pegcetacoplan group and one in the placebo group, none was attributed to encapsulated bacteria, and one death occurred in the pegcetacoplan group, which was attributed to COVID-19 pneumonia, unrelated to pegcetacoplan.

“Pegcetacoplan has been well tolerated with no encapsulated meningitis reported, consistent with previous trials and more than 2000 patient-years of pegcetacoplan exposure,” Nester said.

Further commenting on the study, Kretzler told Medscape Medical News that the study “shows that clinical trials in rare kidney complement driven diseases can be efficiently executed.”

“The trial data are consistent with full reversal of the disease process, showing both clinical outcomes and structural histological features being reversed close to the healthy state,” he added.

Noting the key caveat that the “long-term impact and need of duration of therapy all will need to be worked out,” he said that the study importantly illustrates that “we can define causal mechanisms in glomerular diseases, and if we treat them, we can stop a disease with a single targeted therapy.”

The study was sponsored by Apellis. Nester reported relationships with Novartis, Apellis, BioCryst, Alexion, Retrophin, Kira, and FIT4KID. Kretzler had no disclosures relating to the study.