Advancing C3G Care with the Approval of a Complement Factor B Inhibitor

The FDA’s latest approval of Novartis’ Fabhalta adds a significant chapter to the evolving treatment landscape for rare renal diseases as it marks the first authorized therapy for C3 glomerulopathy (C3G), a condition long characterized by therapeutic voids and unpredictable clinical trajectories. With this new indication, Fabhalta (iptacopan), a small molecule factor B inhibitor targeting the alternative complement pathway, now carries three FDA approvals.

C3G is a progressive kidney disease marked by abnormal complement activation and deposition of protein fragments within the glomeruli, typically culminating in irreversible kidney failure. Despite its rarity, the disease disproportionately affects young adults, with an average age at diagnosis of just 23. The need for disease-modifying treatments has been acute—until now, management strategies centered largely on non-specific immunosuppression, with variable results.

Fabhalta’s approval follows the APPEAR-C3G Phase III trial, which demonstrated a statistically significant reduction in proteinuria over six months compared to placebo. The twice-daily oral regimen showed clinical effects as early as two weeks into treatment, with sustained benefit across a one-year span in the open-label extension. While proteinuria reduction remains a surrogate marker, the consistency and durability of response observed in the trial set the stage for its regulatory success.

Crucially, Fabhalta’s mechanism targets the root pathophysiology of C3G—overactivation of the alternative complement pathway—rather than downstream inflammatory sequelae. This mechanistic precision provides a biologically rational treatment that aligns with the evolving understanding of complement dysregulation in glomerular diseases. Carla Nester, co-investigator of the trial, emphasized this point, calling the approval “historic” for its potential to define a new standard of care for patients who, until now, had few viable options.

Safety data from the trial did not raise new concerns, although the class-related risk of serious infections from encapsulated bacteria—such as Neisseria meningitidis and Streptococcus pneumoniae—remains a critical consideration. As with other complement inhibitors, Fabhalta will be distributed under a Risk Evaluation and Mitigation Strategy (REMS), requiring prescribers to ensure patients receive appropriate vaccinations before initiating therapy. Common side effects included upper respiratory infections and viral illnesses, aligning with the known safety profile established in prior Fabhalta studies.

This milestone extends Fabhalta’s reach beyond its initial approval in paroxysmal nocturnal hemoglobinuria (PNH) and the more recent accelerated approval for primary IgA nephropathy. In both cases, the drug's benefit in reducing proteinuria and mitigating complement-mediated damage has underscored its promise as a platform therapy for complement-driven diseases. Its oral route of administration also gives it an edge in terms of patient adherence and accessibility compared to intravenous complement inhibitors.

The broader implications of this approval are twofold. First, it affirms the viability of targeting the complement system across a spectrum of indications, reinforcing the role of precision immunology in nephrology. Second, it positions Novartis to expand Fabhalta’s indications further, potentially accelerating development timelines for other complement-mediated conditions through both regulatory precedent and mechanistic continuity.

As Fabhalta moves into clinical practice for C3G, nephrologists and care teams will need to navigate patient selection, vaccination protocols, and ongoing monitoring. Yet the emergence of a targeted, oral therapy for a relentlessly progressive disease provides something long overdue: a clear therapeutic pathway where previously there was only clinical uncertainty.

Reference:

Samorodnitsky D. Novartis’ Fabhalta approved as first therapy for rare kidney disease. BioSpace. March 21, 2025. Accessed April 1, 2025. https://www.biospace.com/fda/novartis-fabhalta-approved-as-first-therapy-for-rare-kidney-disease.