Shikha Wadhwani, MD, MS

Unmet Needs and Unanswered Question in C3G

, Shikha Wadhwani, MD, MS, Anuja Java, MD, and Corey Cavanaugh, DO, reflect on the promise and challenges of integrating FDA-approved therapies like pegcetacoplan and iptacopan into clinical practice for patients with 

C3 glomerulopathy (C3G) and immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN)

A New Era for C3G Treatment with Pegcetacoplan

Navigating Targeted Therapies for C3 Glomerulopathy

Understanding Pegcetacoplan in C3G with VALIANT Data

Approaching Incident C3G in an Era of Targeted Therapies

Unmet Needs and Unanswered Questions in C3G

While both approvals mark a major step forward, the panel is candid about the real-world barriers that still stand in the way, with access to therapy chief among them. Cavanaugh emphasizes the logistical and financial hurdles in securing these high-cost drugs, even for young patients who may urgently need them. He anticipates that larger academic centers and designated centers of excellence will play a crucial role in helping regional providers navigate these complexities and secure timely treatment.

Java shares the same enthusiasm about having disease-targeted options but flags the persistent frustrations of insurance denials, even for long-established complement inhibitors. Both she and Cavanaugh express ongoing uncertainty about how to apply trial findings to the diverse patient populations seen in practice, especially those with atypical presentations or no clear genetic or functional complement driver. They also grapple with how best to manage transplant patients, many of whom may be on anti-C5 therapy already and raise questions about whether upstream inhibition might offer better long-term outcomes.

The discussion also touches on the lack of predictive tools to determine who will respond to therapy, who will progress, and when and how often repeat biopsies should be performed in seemingly stable patients.

As Wadhwani notes in closing, nephrologists are entering a new era in C3G marked by momentum, collaboration, and the opportunity to finally align pathophysiology with treatment. The panel agrees the key now is to ensure that the promise of clinical trial data translates into equitable, durable outcomes for patients across practice settings.

 is an associate professor of Medicine and the vice chair of Clinical Research at the University of Texas Medical Branch. Wadhwani, who is the co-host of HCPLive’s 

 and member of our advisory board, serves as the moderator for this conversation.

 is an associate professor and transplant nephrologist at Washington University School of Medicine in St. Louis and director of Kidney Transplantation at John Cochran VA Medical Center in St. Louis.

 is a staff nephrologist at the Cleveland Clinic.

 include Otsuka Pharmaceuticals, GSK, Calliditas, and Travere Therapeutics. Relevant disclosures for 

 include Alexion, AstraZeneca, Novartis, Dianthus Therapeutics, Aurinia Pharmaceuticals Inc., Apellis and UptoDate.

 include Vera Therapeutics and Travere Therapeutics.

Apellis Pharmaceuticals. FDA Approves Apellis’ EMPAVELI® (pegcetacoplan) as the First C3G and Primary IC-MPGN Treatment for Patients 12 and Older | Apellis Pharmaceuticals, Inc. Apellis Pharmaceuticals, Inc. Published July 28, 2025. Accessed August 4, 2025. 

https://investors.apellis.com/news-releases/news-release-details/fda-approves-apellis-empavelir-pegcetacoplan-first-c3g-and

Nester CM, Bomback AS, Ariceta G, et al. VALIANT: A Randomized, Multicenter, Double-Blind, Placebo (PBO)-Controlled, Phase 3 Trial of Pegcetacoplan for Patients with Native or Post-transplant Recurrent Glomerulopathy (C3G) or Primary Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN). 

Journal of the American Society of Nephrology

US Food and Drug Administration. Fabhalta approved for complement 3 glomerulopathy. U.S. Food and Drug Administration. Published March 20, 2025. Accessed August 4, 2025. 

https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-adults-complement-3-glomerulopathy-rare-kidney-disease-reduce

Videos

In the final segment of this 5-part HCPLive RX Review, experts discuss real-world barriers to implementing new C3G therapies and lingering unmet needs.

The US Food and Drug Administration approval of pegcetacoplan for 

 signals a significant shift in how clinicians approach this ultra-rare kidney disease. With this and iptacopan now available as targeted therapies, nephrologists face new questions about how best to sequence treatments and tailor strategies to individual patients.

, Shikha Wadhwani, MD, MS, Anuja Java, MD, and Corey Cavanaugh, DO, discuss how these new options are changing the treatment paradigm—and why many clinicians may move away from older, off-label immunosuppressants in favor of frontline targeted therapy.

Java explains her growing preference for initiating treatment with complement inhibitors rather than mycophenolate or prednisone. She notes C3G reflects clear alternative pathway dysregulation for which therapies like pegcetacoplan directly address the root cause. Adding short-term steroids may still be helpful in cases of acute inflammation, but she sees less justification for relying on broad immunosuppression as a first-line approach.

Wadhwani echoes this sentiment, noting that although some patients have responded well to older therapies, heterogeneity in disease course and response makes it difficult to predict who will benefit. With FDA-approved drugs now available and supported by randomized trial data she argues that complement inhibition should be strongly considered up front, with patient preference and shared decision-making guiding final choices.

The panel also tackles the complex issue of treatment duration, which remains an open question. They note that in thrombotic microangiopathy, risk stratification based on genetics and disease severity has helped guide long-term therapy decisions, and a similar framework may eventually emerge in C3G. For now, they suggest that patients with persistent circulating nephritic factors or aggressive disease may require longer-term treatment, while others could potentially taper off therapy with careful monitoring and protocol biopsies.

As more real-world experience accumulates, the panel agrees that treatment personalization and ongoing collaboration will be key to optimizing outcomes in this evolving field.

In part 4 of this 5-part HCPLive RX Review, experts discuss how the availability of new therapeutic options are changing the treatment paradigm in C3G.

The July 2025 US Food and Drug Administration approval of pegcetacoplan (Empaveli) brought not only new hope for patients with 

, but also a new set of clinical questions, particularly around how best to integrate this therapy into current practice.

, Shikha Wadhwani, MD, MS, Anuja Java, MD, and Corey Cavanaugh, DO, discuss the clinical significance of trial data from VALIANT and how these findings may influence treatment sequencing, therapeutic goals, and expectations moving forward.

A major theme in the discussion centers around the 68% reduction in proteinuria observed with pegcetacoplan by week 26 in the VALIANT trial. Both Java and Cavanaugh note that such a dramatic reduction in proteinuria is unprecedented in glomerular disease and highly relevant for both patient counseling and long-term kidney health. The group also references the trial's biopsy data, which showed elimination of C3 deposits in approximately 70% of patients, suggesting true disease modification beyond hemodynamic or anti-inflammatory effects.

The group emphasizes that proteinuria remains one of the strongest predictors of kidney survival in C3G, pointing out that this level of reduction, combined with histologic improvement, signals a shift from merely slowing disease to truly altering its trajectory. Compared with findings from the iptacopan program, the experts note both agents offer clinically meaningful benefit, though pegcetacoplan may show slightly higher magnitude of response in some metrics.

The group also raises practical considerations around treatment strategy, questioning whether clinicians should begin with the newer, targeted complement inhibitors, or reserve them after trialing traditional off-label options like steroids and mycophenolate. As the real-world use of these agents expands, they anticipate evolving practice patterns will help clarify these decisions.

In part 3 of this 5-part HCPLive RX Review, experts discuss VALIANT data supporting pegcetacoplan’s approval and how they compare to iptacopan.

The July 2025 FDA approval of pegcetacoplan (Empaveli) marked a pivotal moment in the treatment of 

, offering patients and clinicians multiple targeted therapies for this ultra-rare and often aggressive kidney disease. Just months earlier, the approval of iptacopan (Fabhalta) added to this therapeutic breakthrough, giving nephrologists a choice between 2 complement inhibitors with distinct mechanisms of action.

, Shikha Wadhwani, MD, MS, Anuja Java, MD, and Corey Cavanaugh, DO, discuss how these new therapies may be used in clinical practice and raise key questions that remain unanswered. With no established standard of care and historically limited treatment options, they say the ability to personalize therapy with these novel agents is a welcomed but complex challenge.

The group questions how clinicians decide 

 to treat, especially in the absence of reliable biomarkers or clear predictors of disease recurrence post-transplant. While some may favor preemptive therapy to avoid recurrence, others may be more cautious, weighing the long-term risks of broad complement inhibition.

The panel compares the mechanisms of action of the 2 approved agents: pegcetacoplan, a C3 inhibitor that acts centrally across all complement pathways, and iptacopan, which selectively targets factor B within the alternative pathway.

As for future directions, the group expresses cautious optimism about switching therapies in non-responders, but raises concerns about combining agents due to safety risks, particularly infection. Despite these uncertainties, they agree: having 

 FDA-approved therapies marks unprecedented progress—and sets the stage for the field to refine how best to use them through real-world experience and collaborative research.

In part 2 of this 5-part HCPLive RX Review, experts discuss how to utilize the newly FDA-approved therapies for treating C3G and what questions remain.

Shikha Wadhwani, MD, MS

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