The FDA has approved Novartis’ oral therapy Fabhalta (iptacopan) as the first and only treatment for adults with complement 3 glomerulopathy (C3G).
C3G is an extremely rare and progressive kidney disease that arises from excessive activity in the alternative complement pathway. This part of the immune system normally combats infections, but in this case, it mistakenly targets the kidneys. The resulting inflammation and scarring damage the glomeruli, the tiny filtering units that cleanse the blood.
Over time, this leads to proteinuria, where protein leaks into the urine, and eventually to kidney failure. Although doctors diagnose only two to three people per million with C3G, about half of these patients may develop kidney failure within a decade.
Without effective disease-modifying therapies and optimal management strategies, the constant fatigue, swelling and mental health challenges surrounding those living with C3G profoundly disrupt daily life and overall quality of life.
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Fabhalta works by inhibiting factor B, a key enzyme in the alternative complement pathway, thus calming the damaging immune response.
The APPEAR-C3G Phase III study enrolled 74 adults with biopsy-confirmed C3G. In this study, Fabhalta produced a 35% reduction in proteinuria after six months compared to placebo.
Proteinuria reductions were seen as early as 14 days and were sustained at 12 months, with similar benefits in patients switching from placebo.
Due to a risk of serious infections from encapsulated bacteria, its use is limited to a Risk Evaluation and Mitigation Strategy requiring specific vaccinations.
The most common side effects were mild, including nasopharyngitis (the common cold) and viral infections.
Last month, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion on Fabhalta for C3G. Regulatory reviews in China and Japan are underway.
According to Q4 2024 updates, Fabhalta’s launch generated $57 million, showing steady traction for its use in paroxysmal nocturnal hemoglobinuria (PNH) around the world and for primary IgA nephropathy (IgAN) in the US.
This latest approval marks Fabhalta’s third milestone. It was first approved for PNH and later for IgAN. In the Phase III APPLAUSE-IgAN trial, Fabhalta reduced proteinuria by 44% compared with 9% in the placebo arm.
Who Else Is Working on IgAN Treatments?
Novartis is expanding its renal pipeline with experimental therapies such as atrasentan, which targets endothelin pathways to reduce kidney fibrosis. The company is also working on zigakibart, designed to neutralize APRIL, a protein that contributes to kidney inflammation.
Meanwhile, Arrowhead Pharmaceuticals recently reported part two results from its Phase I/ II study of ARO-C3 in IgAN patients. The study showed up to a 65% reduction in complement component 3 (C3) levels and promising decreases in proteinuria.
Takeda is making progress with TAK-279, an oral TYK2 inhibitor. Early data show it can reduce key inflammatory biomarkers in immune-mediated conditions like IgAN.
Vertex is advancing povetacicept, a dual inhibitor of the BAFF and APRIL pathways. Its global Phase III RAINIER study is enrolling IgAN patients across the US, Europe and Asia. The trial is expected to complete its interim analysis cohort enrollment in 2025. Vertex plans to apply for potential accelerated approval in the US after 36 weeks of treatment.
Vertex is also advancing VX-147, an APOL1 inhibitor in Phase II studies. Interim results showed around a 47% reduction in proteinuria in patients with APOL1-mediated kidney disease. The company plans to expand these trials to include IgAN.
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