Factor D Inhibition Lacks Efficacy For IgAN in Phase 2 ALXN2050 Trial, With Sayna Norouzi

New data from the phase 2 study of ALXN2050 (vemircopan) showed a non-statistically significant urine protein reduction compared to placebo, suggesting factor D inhibition is not an effective therapy for IgA nephropathy (IgAN).1

Findings from the randomized, placebo-controlled phase 2 trial of ALXN2050, presented by study investigator Sayna Norouzi, MD, an assistant professor of medicine and clinical nephrologist at Loma Linda University Medical Center, at the American Society of Nephrology Kidney Week 2025, showed a clear lack of efficacy and signaled emerging safety concerns in adults with IgAN.¹

With an evolving understanding of the pathogenesis of IgAN, clinical research has investigated the potential of immune and complement-targeted therapies to change the disease course. In line with this, ALXN2050 is an oral small-molecule designed for the selective inhibition of factor D, a serine protease largely produced in adipocytes, and the rate-limiting enzyme in the activation sequence of the alternative pathway.2

“Since iptacopan showed significant benefits and aligns with our understanding of IgAN pathophysiology, it made sense to evaluate a factor D inhibitor in IgAN to see whether it could interrupt the disease process at Hit 4,” Norouzi said in an interview with HCPLive. “But early data from this study suggest we should not continue pursuing a factor D inhibitor in IgAN.”

In the 26-week initial evaluation period, participants who were diagnosed with IgAN, had urine protein ≥1 g/d, an estimated glomerular filtration rate (eGFR) of >30 mL/min/1.73m2, and were on stable renin-angiotensin system inhibitors were randomly assigned in a 3:1:3 ratio to ALXN2050 180mg, ALXN2050 120mg, or placebo. Investigators measured the primary endpoint as the percent change in urine protein from baseline to week 26, through 24-hour urine collection.1

Of the 61 enrolled patients, 47 (77.0%) completed the initial evaluation period. At baseline, mean urine protein was similar between the ALXN2050 and placebo groups (2.2 vs 2.1 g/d), as was mean eGFR (65.9 vs 70.6 mL/min/1.73m²).1

By week 26, patients receiving ALXN2050 180 mg had a 26.2% reduction in urine protein compared with a 10.3% reduction with placebo, corresponding to a relative treatment effect of −17.7% (90% CI, −37.5% to 8.3%), with similar findings in sensitivity analyses. When all ALXN2050 doses were combined, the relative treatment effect was −18.6% (90% CI, −37.0% to 5.1%).1

Investigators paused the phase 2 study after a serious adverse event in the lupus nephritis cohort, with a patient exhibiting jaundice and marked liver enzyme elevation consistent with acute hepatic failure, resulting in a fatal outcome. Ultimately, the trial was terminated with concerns regarding confounded data when it came to re-initiating dosing.1

In the IgAN cohort, most adverse events during the initial evaluation period were mild and unrelated to treatment, and no serious treatment-related adverse events or discontinuations occurred. However, during the extension period, a patient receiving ALXN2050 180 mg experienced liver enzyme elevation with a positive rechallenge signal.1

“It’s also important to talk about trials like this. We often hear about positive results and successful recruitment, but many trials encounter safety issues or disappointing efficacy,” said Norouzi. “These trials still matter; they help us learn, refine study design, and understand which therapeutic pathways are worth pursuing. This is how we continue navigating treatment development in IgA nephropathy.”

Editors’ note: Norouzi has relevant disclosures with Calliditas, Novartis, Otsuka, and Boehringer Ingelheim.

References

1. Roccatello D, Sayna Norouzi, Mohsen El Kossi, et al. Efficacy and Safety of ALXN2050 in IgAN: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial. Journal of the American Society of Nephrology. 2025;36(10S). doi:https://doi.org/10.1681/asn.20250j8aqeht

2. ‌Caravaca-Fontán F, Gutiérrez E, Sevillano ÁM, Praga M. Targeting complement in IgA nephropathy. Clinical Kidney Journal. 2023;16(Supplement_2):ii28-ii39. doi:https://doi.org/10.1093/ckj/sfad198