Ravulizumab Meets Primary Endpoint in IgA Nephropathy Trial

AstraZeneca's (LSE/STO/NYSE: AZN) Alexion unit reported that ravulizumab (Ultomiris) met the proteinuria primary endpoint in a prespecified interim analysis of the Phase III I CAN trial in adults with immunoglobulin A nephropathy, adding a potential new indication to a drug already approved across four complement-mediated diseases.

The I CAN trial (ALXN1210-IgAN-320) is a global, randomized, double-blind, placebo-controlled study enrolling approximately 510 adults with IgAN who are at risk of disease progression, randomized 1:1 to ravulizumab or placebo for 106 weeks across 28 countries.

At the week-34 interim analysis, ravulizumab produced a statistically significant reduction in proteinuria measured by 24-hour urine protein-to-creatinine ratio (UPCR) compared with placebo. The company reported that the reduction was detectable as early as week 10. No specific effect sizes, p-values, or confidence intervals were disclosed in the announcement; full data are expected at a forthcoming medical meeting. The second primary endpoint — change from baseline in estimated glomerular filtration rate at week 106 — remains pending at the final analysis. Safety was described as consistent with the established Ultomiris profile, with no new concerns identified.

The decision to pursue accelerated approval in key markets on the basis of proteinuria reduction reflects a regulatory strategy that has precedent in IgAN. The FDA granted accelerated approval to sparsentan (Filspari, Travere Therapeutics) in 2023 on the basis of proteinuria reduction, with confirmatory eGFR data required. Iptacopan (Fabhalta, Novartis), a factor B inhibitor targeting the alternative complement pathway, received FDA approval for IgAN in 2024, also using proteinuria as the primary basis. The I CAN trial results position ravulizumab as a terminal complement inhibitor entering a space where upstream and midstream complement blockade already have regulatory footholds.

The mechanistic distinction matters for how the data will be interpreted. IgAN pathogenesis involves aberrant IgA1 glycosylation leading to immune complex deposition in the glomerular mesangium, which activates the complement cascade. Iptacopan acts at factor B in the alternative pathway, upstream of C5. Ravulizumab blocks C5 cleavage directly, preventing generation of both the anaphylatoxin C5a and the membrane attack complex C5b-9. Whether terminal inhibition at C5 offers a different or additive clinical profile compared with upstream blockade is a question the field has not yet resolved, and cross-trial comparisons are limited by differences in patient populations, background therapy, and endpoint definitions across studies.

Ravulizumab is an engineered variant of eculizumab with modifications that extend its half-life, allowing every-eight-week intravenous dosing in adults rather than the fortnightly schedule required for eculizumab. That pharmacokinetic profile has been central to its commercial positioning across its approved indications — paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder. In IgAN, the dosing interval could be relevant for patient adherence, though the intravenous route itself remains a practical consideration relative to oral agents such as iptacopan or sparsentan.

The IgAN treatment landscape has shifted substantially since 2021, when the field had few options beyond renin-angiotensin-aldosterone system blockade and corticosteroids. Budesonide (Tarpeyo/Kinpeygo, Calliditas Therapeutics) received accelerated FDA approval in 2021 targeting mucosal IgA production. Sparsentan, a dual endothelin and angiotensin receptor antagonist, followed in 2023. Iptacopan, the first complement-targeted oral therapy for IgAN, added another mechanistic layer. The entry of a terminal C5 inhibitor with an established safety record across multiple approved indications introduces a drug with a known tolerability profile into this evolving treatment algorithm, though its precise positioning — monotherapy, add-on, or use in specific complement-driven subpopulations — will depend on the full week-106 dataset and regulatory review.

The absence of numerical efficacy data in the current disclosure limits clinical interpretation. Proteinuria reduction is an accepted surrogate in IgAN, but the magnitude of that reduction, and whether it is sustained, carries weight for both regulatory and clinical decision-making. The FDA's accelerated approval pathway for IgAN has explicitly tied post-marketing requirements to longer-term kidney function outcomes, meaning the eGFR readout at week 106 will be the more consequential dataset for understanding whether ravulizumab modifies disease trajectory rather than simply attenuating a biomarker.

AstraZeneca said it plans to file for accelerated approval in key markets while the trial continues toward its final analysis, with full results to be presented at an unspecified medical meeting.

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