Pegcetacoplan Sustains Proteinuria Reduction at 76 Weeks in Adolescents

Adolescents with C3 glomerulopathy (C3G) or primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) maintained a nearly 68% reduction in proteinuria after 76 weeks of pegcetacoplan (Empaveli) treatment, with stable kidney function and no new safety signals, according to a post hoc analysis of the phase 3 VALIANT trial and its open-label extension, VALE.¹

Bradley P. Dixon, MD, FASN, associate professor of pediatrics and medicine and head of the Section of Nephrology at the University of Colorado School of Medicine, presented the findings at the American Society of Nephrology (ASN) Kidney Week 2026 in Denver, Colorado. The results build on previously reported 52-week findings, providing longer-term evidence of sustained proteinuria reduction in adolescents receiving complement-targeted therapy.¹

Diagnostic Delays in Rare Complement-Mediated Kidney Disease

C3G and primary IC-MPGN are rare, chronic glomerular diseases associated with dysregulation of the complement system. Excessive complement activation can contribute to inflammation and progressive kidney damage, with both diseases frequently presenting during childhood or early adulthood.²

In July 2025, the US Food and Drug Administration (FDA)approved pegcetacoplan, a targeted C3 and C3b inhibitor, for patients aged 12 years and older with C3G or primary IC-MPGN. It was the first approved treatment for primary IC-MPGN and the first for adolescents with either disease.³ The indication was subsequently expanded in August 2026 to include reducing the loss of kidney function.⁴

Despite advances in treatment, disease rarity can complicate timely diagnosis.

“C3 glomerulopathy and immune complex MPGN are rare diseases, and so there can be a lack of familiarity with these diseases. I would say that’s more true for the adult nephrology population,” Dixon said in an interview with HCPLive. “We in the pediatric nephrology world are more tuned into rare diseases, so we will diagnose these patients a little bit more quickly. But nevertheless, rare diseases can go undiagnosed for a longer period of time.”

Shifting the Treatment Paradigm for C3G and IC-MPGN

Historically, treatment for C3G and primary IC-MPGN has relied on supportive care and nonspecific immunosuppression, including corticosteroids and mycophenolate. Complement-targeted therapies offer an approach directed at a central mechanism of disease activity.

Dixon noted that earlier Kidney Disease: Improving Global Outcomes (KDIGO) guidance generally positioned complement therapeutics after conventional immunosuppressive treatment in patients with severe or refractory disease.

“That ultimately delays the initiation of targeted and highly effective therapies until some amount of damage has been done by uncontrolled disease activity,” Dixon said.

The concern is particularly relevant for adolescents, who may face decades of disease burden following diagnosis. Although the VALIANT+VALE analysis did not directly evaluate treatment timing, sustained proteinuria reduction and stable eGFR provide additional evidence of disease control during extended complement inhibition.

Related: The Case for Earlier Complement Inhibition in C3G, With Bradley Dixon, MD

VALIANT+VALE Adolescent Analysis Design

VALIANT (NCT05067127) was a phase 3, randomized, placebo-controlled trial evaluating pegcetacoplan in patients with C3G or primary IC-MPGN. Participants were randomized 1:1 to receive subcutaneous pegcetacoplan or placebo twice weekly for 26 weeks, followed by a 26-week open-label period in which all participants received pegcetacoplan. Eligible participants could subsequently enter the VALE open-label extension (NCT05809531).¹,²

The initial randomized adolescent analysis included 55 patients aged 12 to 17 years, of whom 28 received pegcetacoplan and 27 received placebo. At week 26, pegcetacoplan was associated with a 75% relative reduction in proteinuria compared with placebo (95% CI, 59%–84%; nominal P < .001).²

Additionally, 71% of adolescents receiving pegcetacoplan achieved at least a 50% reduction in proteinuria, compared with 4% receiving placebo. A composite kidney endpoint requiring both a reduction in proteinuria of at least 50% and no more than a 15% decline in eGFR was achieved by 57% and 4% of patients, respectively.²

For the 76-week post hoc analysis, investigators reported outcomes from 53 adolescents receiving pegcetacoplan across VALIANT and VALE. Results were aligned by duration of pegcetacoplan exposure, combining patients originally assigned to pegcetacoplan with those who crossed over from placebo. Efficacy endpoints included changes from baseline in urine protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR), along with treatment-emergent adverse events.¹

Sustained Proteinuria Reduction and Stable eGFR Through 76 Weeks

At 76 weeks, the geometric mean reduction in UPCR from baseline was 67.5% (95% CI, 54.1%–77.0%). The reduction was consistent with findings at week 26 (68.4%) and week 52 (69.3%), suggesting the initial proteinuria response was maintained with continued treatment.¹

Kidney function also remained stable over the extended treatment period. At week 76, the least squares mean change in eGFR from baseline was +8.4 mL/min/1.73 m² (SE, 4.43).¹

The sustained response was consistent with findings from the overall VALIANT population, in which a separate 76-week analysis reported a 64.1% reduction in proteinuria and stable eGFR.⁵

No new safety signals were identified in the adolescent analysis through 76 weeks.¹

The findings support sustained proteinuria reduction and eGFR stabilization during pegcetacoplan treatment in adolescents with C3G or primary IC-MPGN. However, because the longer-term analysis was post hoc and lacked a concurrent placebo group after the randomized treatment period, it cannot establish the comparative benefit of extended treatment or whether earlier initiation prevents long-term kidney function decline.

For clinicians managing adolescents with these rare diseases, the results add to evidence supporting complement inhibition as a targeted treatment approach, while longer-term follow-up will be important for understanding its effects on kidney outcomes over time.

Editor's Note: Dixon reports relevant disclosures with Apellis Pharmaceuticals, Novartis, and others.

References

1. Dixon BP, Greenbaum LA, Ariceta Iraola G, et al. Pegcetacoplan for 76 weeks maintains proteinuria reduction and eGFR stabilization for pediatric patients: VALIANT+VALE subgroup analysis. Abstract TH-OR070. Presented at: American Society of Nephrology Kidney Week 2026; October 22-25, 2026; Denver, CO. https://www.asn-online.org/education/kidneyweek/2026/program-abstract.aspx?controlId=4555106

2. Vivarelli M, Ariceta G, Borovitz Y, et al. Pegcetacoplan for adolescents with C3 glomerulopathy or primary immune complex membranoproliferative GN: phase 3 VALIANT subgroup analysis. Clin J Am Soc Nephrol. 2026;21(8):1404-1413. doi:10.2215/CJN.0000001077

3. US Food and Drug Administration. Orphan drug designations and approvals: pegcetacoplan (Empaveli), C3 glomerulopathy. Accessed November 4, 2026. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=633418

4. Empaveli (pegcetacoplan) injection, for subcutaneous use. Prescribing information. Apellis Pharmaceuticals, Inc. Revised August 2026. Accessed November 4, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c23d89e9-b00b-4520-e053-2995a90a95af

5. Nester CM, Bomback AS, Ariceta Iraola G, et al. Pegcetacoplan for 76 weeks maintains proteinuria reduction and stabilizes kidney function in C3 glomerulopathy or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN). Abstract SA-OR054. Presented at: American Society of Nephrology Kidney Week 2026; October 22-25, 2026; Denver, CO. https://www.asn-online.org/education/kidneyweek/2026/program-abstract.as