Novartis achieves 2 trial successes in rare kidney diseases with IgAN trio

Novartis, a Swiss pharmaceutical giant, is making strides in the treatment of immunoglobulin A nephropathy (IgAN), a rare autoimmune kidney disease. The company recently shared progress updates on two of its three investigational drugs targeting IgAN.

One of the drugs, atrasentan, is anticipated to be submitted to the U.S. Food and Drug Administration (FDA) by the end of June for potential accelerated approval. This move is supported by promising results from the phase 3 ALIGN trial, where atrasentan demonstrated a 36.1% reduction in proteinuria compared to a placebo after 36 weeks of treatment. This data was presented at the European Renal Association Congress and positions atrasentan as a potential contender against Travere Therapeutics’ drug, Filspari (sparsentan). However, analysts from William Blair and Leerink Partners suggest that atrasentan may not have a decisive advantage over Filspari.

In the ALIGN study, atrasentan showed a 38.1% decrease in proteinuria, measured by the urine protein to creatinine ratio (UPCR), compared to a 3.1% reduction seen with placebo. In contrast, Travere’s Filspari demonstrated a 49.8% reduction in proteinuria in its phase 3 PROTECT trial, translating to a 41% relative reduction when compared to off-label irbesartan. The patient populations in both trials were similar, yet differences, such as the percentage of Asian patients, might affect cross-trial comparisons.

Despite some differences, analysts from Leerink Partners argue that atrasentan does not significantly differentiate itself from Filspari. A survey conducted by Leerink indicated that clinicians might divide their use of Filspari and atrasentan equally. Filspari holds two primary advantages: it already secured accelerated approval in February 2023 and has a full approval decision expected in September, giving it a potential two-year lead over atrasentan. Moreover, Filspari’s dual mechanism, which negates the need for an additional angiotensin receptor blocker like irbesartan, could reduce the pill burden for patients. However, separate pills might allow more tailored dosing, a factor for doctor-patient decision-making.

Travere’s early launch of Filspari has been successful, with around 2,000 patient start forms by the end of March. The drug, however, did not achieve statistical significance in its confirmatory trial regarding kidney function improvement, leaving room for Novartis’ atrasentan to potentially distinguish itself if it shows positive results in its ongoing ALIGN study, which will provide final eGFR analysis in 2026.

In addition to atrasentan, Novartis is advancing Fabhalta, an oral factor B inhibitor, which recently showed a 38.3% reduction in proteinuria in the phase 3 APPLAUSE-IgAN trial. Approved by the FDA for paroxysmal nocturnal hemoglobinuria (PNH) in December, Fabhalta is now under priority review for an IgAN indication. At the European Renal Association Congress, Novartis also presented phase 3 results for Fabhalta in C3 glomerulopathy (C3G), showing a 35.1% reduction in proteinuria. Novartis aims to file for this indication later this year.

The third investigational drug, zigakibart, is a subcutaneous anti-APRIL antibody, expected to show phase 3 results for IgAN in 2026. Novartis hopes zigakibart will be a disease-modifying therapy, intervening early in the disease process.

Shreeram Aradhye, M.D., explained that these drugs target different pathological mechanisms of IgAN. Fabhalta targets the alternative complement pathway involved in kidney damage, while atrasentan inhibits endothelin receptor-mediated processes in mesangial cells. Zigakibart aims to modify the disease by addressing abnormal IgA formation early on.

Together, these investigational drugs reflect Novartis' comprehensive approach to tackling IgAN from multiple angles, with hopes of significant market impact and improved patient outcomes.

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