PREVAIL: Felzartamab’s Sustained Clinical Outcomes In IgAN, With Jurgen Floege, MD

Key research on felzartamab highlights the long-lasting effects of CD38-targeted therapy and its potential for improved outcomes in patients with IgA nephropathy (IgAN), emphasizing the promise of immune-targeted treatment.1

Data from the completed phase 2 study, IGNAZ, and ongoing phase 3 trial, PREVAIL, investigating the effect of an anti-CD38 agent, felzartamab, in IgAN patients, were presented by Jürgen Floege, MD, senior professor at RWTH Aachen University’s Medical School, at the American Society of Nephrology (ASN) Kidney Week 2025 in Houston, Texas.

IGNAZ phase 2 data showed felzartamab treatment successfully depleted plasma cells, while immunoglobulins recovered, IgA remained suppressed, proteinuria remained reduced, and galactose-deficient IgA (GDiGA) rebounded. The ongoing phase 3 PREVAIL trial aims to further evaluate efficacy and safety.

Over the past decade, the IgAN treatment landscape has evolved significantly. In 2015, Floege led the STOP-IgAN trial as principal investigator, describing the minimal benefits and potential harms of corticosteroids. Further research on anti-CD20 therapies, such as rituximab, demonstrated a lack of significant improvement in patient outcomes, suggesting B cells alone are insufficient drivers of pathogenic IgA. The phase 3 PROTECT trial showed the combination of renin-angiotensin system blockade with sparsentan reduced proteinuria and slowed GFR decline over 2 years, but did not alter immunoglobulin levels.2

Against this backdrop, emerging immune-targeted therapies offer a novel approach to IgAN treatment. An investigational monoclonal antibody targeting CD38, felzartamab, depletes long-lived plasma cells involved in IgA production. In the phase 2 study, investigators noted patients were able to remain off treatment for up to 1.5 years, with the potential to maintain immunologic and biologic responses for even longer.

“With felzartamab, proteinuria reduction persists when you stop treatment, even for 1.5 years. As you destroy these long-lived plasma cells, all the immunoglobulins go down, but IgM and IgG go right back up to baseline. The moment you stop treatment, IgA stays low, whereas proteinuria stays low,” said Floegle in an interview with HCPLive. “GDiGA reduces, so you can dissociate the treatment benefit from the course of IgA, a potentially important pathophysiological insight. Everybody now says IgA is what causes IgA nephropathy, but I'm not certain about that. And the study is yet another piece of evidence to nurture that doubt.”

PREVAIL, the ongoing 104-week phase 3 multicenter, randomized, double-blind, placebo-controlled trial, evaluates the efficacy and safety of felzartamab in adults with IgAN and consists of a 24-week treatment period where patients are randomly assigned to receive felzartamab or placebo, followed by an 80-week off-medication study.

The primary endpoint is the percent change in 24-hour UPCR at week 36, with a key secondary endpoint of change in eGFR at week 104. Further secondary endpoints included the percentage of participants achieving complete remission, safety, AEs, pharmacokinetics, and immunogenicity.

PREVAIL began enrollment in June 2025, recruiting 454 participants with biopsy-confirmed IgAN, with eGFR of ≥30mL/min/1.732, proteinuria of ≥1.0 g/day or UPCR ≥0.8 g/g.

“The question I am asked all the time is which drug for which patient. The drugs of the future are anti-APRIL, APRIL/BAFF inhibitors, or CD38 antibodies. Which one is better? I honestly don’t know. They have clear differences: anti-APRIL and APRIL/BAFF inhibitors require continuous administration, while CD38 therapies allow treatment pauses,” said Foegle. “In terms of clinical efficacy, they appear broadly similar. Hopefully, this competition will help reduce costs, which is a major concern. Another unresolved question is how to manage non-responders. Can you switch from one therapy to the other? I don’t think combination therapy makes sense, but if a patient fails anti-APRIL, could a CD38 antibody work, or vice versa? We will have to find out. There is still so much to learn.”

With 10 drugs in late-phase clinical development showing similar proteinuria reductions, there are new opportunities for patient and clinician's treatment choice. Further investigation into the long-lasting safety and efficacy of felzartamab for patients with IgAN will continue with phase 3 PREVAIL.

Editor’s Note: Floege reports relevant disclosures with AstraZeneca, Bayer, Biogen, and others.

References

1. Floege, J, Perkovic, V, Barratt, J, et al. PREVAIL: A Phase 3 Trial of Felzartamab in Adults With IgA Nephropathy. Presented at: ASN Kidney Week 2025; November 5–9, 2025; Houston, TX.

2. Rovin BH, Barratt J, Heerspink HJ L, et al. DUPRO Steering Committee and PROTECT Investigators. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2‑year results from a randomised, active‑controlled, phase 3 trial. Lancet. 2023;402(10417):2077‑2090. doi:10.1016/S0140‑6736(23)02302‑4. pubmed.ncbi.nlm.nih.gov