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The treatment proved efficacy across all 3 key markers of C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN).
The FDA approved pegcetacoplan (Empaveli; Apellis Pharmaceuticals) as the first treatment for C3 glomerulopathy (C3G) or primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) to reduce proteinuria in patients ages 12 years or older. The updated indication follows positive results from the phase 3 VALIANT study (NCT05067127), which demonstrated the treatment’s reduction in proteinuria, stabilization of kidney function, and clearance of C3 deposits.1,2
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Trial Name: Phase III Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis (VALIANT)
ClinicalTrials.gov ID: NCT05067127
Sponsor: Apellis Pharmaceuticals, Inc
Completion Date: January 14, 2025
Pegcetacoplan is a targeted C3 therapy designed to regulate the excessive activation of the complement cascade, a part of the body’s immune system that can lead to the onset and progression of many serious diseases. It is indicated for C3G, IC-MPGN, and paroxysmal nocturnal hemoglobinuria.1
Both C3G and IC-MPGN are serious and rare but debilitating kidney diseases that can lead to chronic kidney failure, or chronic kidney disease (CKD). Excessive C3 deposits are a key marker of disease activity, which can lead to kidney inflammation, damage, and failure. Additionally, CKD or kidney failure can increase a patient’s risk of other health conditions, such as cardiovascular disease or stroke. Approximately 50% of people living with C3G and primary IC-MPGN suffer from kidney failure within 5 to 10 years of diagnosis, which requires kidney transplant or lifelong dialysis. Additionally, approximately 90% of patients who previously received a kidney transplant will experience disease recurrence.1
“I’m excited to now have a highly effective therapy for a broad range of patients living with C3G and primary IC-MPGN,” Carla Nester, MD, MSA, FASN, lead principal investigator for the VALIANT study, professor of internal medicine and pediatrics, and director of pediatric nephrology, University of Iowa Stead Family Children's Hospital, said in a news release. “With standard of care, patients living with these rare and severe diseases frequently progress to kidney failure, necessitating lifelong dialysis and/or a kidney transplant. Given the urgent need, particularly in children, the approval of [pegcetacoplan] marks a pivotal moment in the treatment of rare kidney diseases.”1
VALIANT is a randomized, placebo-controlled, double-blinded, multicenter phase 3 study that evaluated the efficacy and safety of pegcetacoplan when reducing proteinuria in patients ages 12 years and older with C3G or IC-MPGN. A total of 124 patients were enrolled and randomly assigned to receive subcutaneous infusions of pegcetacoplan (20mL or 1080 mg for adults or adolescents > 50 kg; n = 63) or placebo (n = 61) twice a week for a 26-week duration. Following the 26-week randomized, controlled phase, patients were able to proceed to a 26-week open-label phase in which all patients received pegcetacoplan.1-3 The investigators noted that VALIANT was the largest single trial conducted in these populations as well as the only study to include both pediatric and adult patients with native and post-transplant kidneys.1
The trial’s primary end point was the log-transformed ratio of urine protein-to-creatinine ratio (UPCR) at week 26 compared with baseline.1-3 Secondary end points included the proportion of those who met criteria for achieving a complete renal end point, change from baseline in estimated glomerular filtration rate, and the change from baseline in the activity score of the C3G histologic index score.2
The findings indicated that, compared with placebo, treatment with pegcetacoplan resulted in a 68.3% reduction in proteinuria (95% CI –76.3, –57.7), stabilization of kidney function, and a substantial clearance of C3 deposits (measured by C3 staining). Notably, these effects were consistent across all subgroups, including disease type, age, and transplant status. Treatment-emergent adverse event frequency and severity were also similar between the treatment arms. There were few serious infections, of which 3 were in the pegcetacoplan group and 1 in the placebo group; however, none of these were attributed to encapsulated bacteria. The investigators reported that 1 death occurred in the pegcetacoplan arm, but this was a result of COVID-19 pneumonia and unrelated to treatment.1,3
“[Pegcetacoplan] has the potential to be truly transformational for patients with C3G and primary IC-MPGN, who until now have had very few treatment options. In the largest pivotal study of these diseases, [pegcetacoplan] demonstrated its potential to preserve kidney function by controlling all three key markers of disease,” Cedric Francois, MD, PhD, cofounder and CEO of Apellis Therapeutics, said. “[We] look forward to building on this momentum as we advance pivotal studies of [pegcetacoplan] in other rare kidney diseases.”1
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