FDA Grants Breakthrough Therapy Designation to Biogen’s Felzartamab for Late Antibody-Mediated Rejection in Kidney Transplants

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The FDA has granted Breakthrough Therapy Designation (BTD) to Biogen’s felzartanab, an investigational anti-CD38 monoclonal antibody for late antibody-mediated rejection (AMR) in kidney transplant recipients. Supporting data were published in The New England Journal of Medicine and presented at the 61st European Renal Association Congress in Stockholm this past May.¹

"Antibody-mediated rejection is a major reason why kidney transplants fail, and currently patients suffering from AMR have tremendous unmet medical need,” said Travis Murdoch, head HI-Bio, Biogen, in a press release. “We are focused on tackling this important challenge, and the breakthrough therapy designation will enable us to work efficiently with the FDA to accelerate development of felzartamab in AMR.”

The study, published in The New England Journal of Medicine, was a Phase II, double-blind, randomized, placebo-controlled trial. Twenty-two patients with AMR that had occurred at least 180 days after transplantation were randomly assigned to receive nine infusions of felzartamab or placebo for six months, followed by a six-month observation period. The primary endpoint of the study was the safety and adverse effect (AE) profile of felzartamab, with secondary endpoints including renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels.

Results found that by week 24, AMR resolution was 82% in the felzartamab group, significantly higher than the AMR in the placebo group, which was 20%. Additionally, the felzartamab group showed a significantly lower median microvascular inflammation score of zero compared to 2.5, reduced molecular markers of rejection, and decreased levels of donor-derived cell-free DNA. Despite these results, three out of nine patients who initially responded to felzartamab showed recurrence of AMR, with increases in molecular activity and biomarkers approaching baseline levels.

Mild or moderate infusion reactions were reported in eight patients in the felzartamab group, while serious AEs were reported in one patient in the felzartamab group and four patients in the placebo group. Overall, the treatment was found to demonstrate an acceptable safety and efficacy profile.²

According to a study published in the American Journal of Transplantation, AMR occurs in approximately 1% to 10% of patients who receive kidney transplants. Despite the implementation of desensitization protocols, up to one-third of highly sensitized recipients may develop acute AMR following transplantation. In first-time transplant recipients, nearly 5% experience AMR, with some cases representing an anamnestic response from cryptic sensitization, in which human leukocyte antigens-specific memory B cells are present but soluble antibody is not being produced or is not detectable.³

Previously, felzartamab was given BTD and Orphan Drug Designation (ODD) by the FDA as a treatment for primary membranous nephropathy, while also receiving ODD for the treatment of AMR in kidney transplant recipients. Currently, Phase II studies have been completed in AMR, primary membranous nephropathy, and IgA nephropathy, with plans to initiate Phase III trials across the same indications next year.¹

Reference

1. Biogen Receives U.S. FDA Breakthrough Therapy Designation for Felzartamab for the Treatment of Antibody-Mediated Rejection in Kidney Transplant Recipients. Biogen. October 9, 2024. Accessed October 9, 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-receives-us-fda-breakthrough-therapy-designation

2. A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection. The New England Journal of Medicine. May 25, 2024. Accessed October 9, 2024. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2400763

3. Antibody-mediated rejection: New approaches in prevention and management. Science Direct. Accessed October 9, 2024. https://www.sciencedirect.com/science/article/pii/S1600613522098410#:~:text=1.,10%25%20of%20kidney%20transplant%20recipients.