Is Fabhalta the long-term IgAN solution we've needed?

IgA nephropathy, a chronic autoimmune disease, causes IgA deposits in the kidney glomeruli, leading to inflammation and progressive kidney damage. Patients often present with hematuria and proteinuria, which can advance to chronic kidney disease (CKD) and, eventually, end-stage kidney disease (ESKD). Current management primarily involves renin-angiotensin system (RAS) blockade and corticosteroids, but many patients still face an inexorable decline in renal function. The need for targeted therapies that address the underlying pathophysiology has been substantial.

Fabhalta (iptacopan), an oral, selective complement factor B inhibitor, gained accelerated FDA approval for IgAN in December 2023 based on its ability to reduce proteinuria. The full approval, announced this week, stems from the comprehensive data from the Phase III APPLY-IgAN trial, which evaluated the drug's impact on kidney function preservation. The trial enrolled 517 adult patients with primary IgAN, persistent proteinuria (urine protein-to-creatinine ratio ≥1 g/g), and an eGFR of 30-90 mL/min/1.73 m² despite maximal supportive care, including RAS inhibition. Investigators randomised patients 1:1 to receive either iptacopan 200 mg twice daily or placebo. The primary endpoint for the full approval was a composite of sustained 30% eGFR reduction, sustained 40% eGFR reduction, ESKD, or death from kidney cause.

The mechanism and the numbers

Iptacopan targets factor B, a key component of the alternative complement pathway, which plays a central role in the pathogenesis of IgAN. By inhibiting factor B, the drug aims to reduce complement activation and subsequent kidney damage. The APPLY-IgAN trial demonstrated that iptacopan significantly reduced the risk of the composite kidney endpoint by 35% compared to placebo (HR 0.65; 95% CI, 0.43-0.99; P=.04). This primary endpoint included sustained eGFR decline of 30% or 40%, progression to ESKD, or death due to kidney disease. The median follow-up for this endpoint was 22 months.

The trial also confirmed the earlier proteinuria findings, showing a significant reduction in urine protein-to-creatinine ratio (UPCR) from baseline to month 9. Patients receiving iptacopan achieved a 38.3% reduction in UPCR compared to a 15.1% reduction in the placebo group (P<.001). This proteinuria reduction was sustained throughout the study period. The magnitude of proteinuria reduction is clinically meaningful, as proteinuria is a well-established surrogate marker for IgAN progression. The trial's design, which included a diverse patient population across multiple global sites, strengthens the generalisability of these findings.

Safety and remaining questions

Iptacopan demonstrated a safety profile consistent with previous observations. The most common adverse events (AEs) reported were headache, nasopharyngitis, and diarrhoea, generally mild to moderate in severity. Serious adverse events occurred in 15.6% of iptacopan-treated patients and 19.8% of placebo-treated patients. Discontinuations due to AEs were low, at 5.4% for iptacopan and 7.4% for placebo. No new safety signals emerged with longer-term exposure, which is reassuring for a chronic condition requiring sustained treatment. The drug's oral formulation also offers a practical advantage over intravenous therapies, potentially improving patient adherence and quality of life.

But the trial was not without its limitations. The follow-up period for the composite kidney endpoint, while sufficient for regulatory approval, was relatively short for a slowly progressive disease like IgAN. Longer-term data will be essential to fully understand the sustained impact of iptacopan on kidney function and patient outcomes over decades. The trial also excluded patients with rapidly progressive glomerulonephritis or those requiring immunosuppression beyond corticosteroids for IgAN, meaning the benefits in these more severe populations remain uncharacterised. Additionally, while the eGFR decline was a robust endpoint, direct histological evidence of reduced kidney damage was not a primary outcome, leaving some questions about the drug's impact on the underlying pathology beyond complement inhibition. Clinicians may find the Oxford Handbook of Nephrology and Hypertension a useful resource for managing complex renal conditions.

The full approval of Fabhalta marks a significant step forward in the treatment landscape for IgAN. It provides a targeted, oral therapy that has now demonstrated a clear benefit in slowing kidney disease progression, moving beyond just proteinuria reduction. The next trials will need to explore its role in combination therapies and in patient populations currently excluded from the APPLY-IgAN study.