Felzartamab Shows Potential Therapeutic Benefit, Acceptable Safety for Late Antibody-Mediated Rejection

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Felzartamab demonstrated a potential therapeutic benefit and an acceptable safety and adverse event (AE) profile in patients with antibody-mediated rejection occurring at least 180 days following a kidney transplant procedure, according to the results of a Phase II trial (NCT05021484) published by The New England Journal of Medicine.^1,2

Felzartamab, a fully human anti-CD38 monoclonal antibody, has previously been granted Breakthrough Therapy Designation and Orphan Drug Designation (ODD) by the FDA for the treatment of primary membranous nephropathy, as well as ODD for antibody-mediated rejection in patients who received a kidney transplant. Biogen gained rights to the drug when it acquired Human Immunology Biosciences in May 2024.³

The study authors noted that antibody-mediated rejection is the primary cause of kidney allograft failure. To date, no therapies have been approved by the FDA to treat antibody-mediated rejection.

“CD38 has emerged as a promising therapeutic target in antibody-mediated rejection, given the potential for its use as a target for the depletion of the plasma cells that produce donor-specific antibodies and NK cells, which are presumed to be critical for microvascular inflammation,” the study authors wrote. “Clinical evidence from anecdotal reports has suggested that the targeting of CD38 could prevent or reverse antibody-mediated rejection.”¹

The double-blind, randomized, placebo-controlled trial randomly assigned 22 patients with antibody-mediated rejection occurring at least 180 days following transplantation to receive nine infusions of felzartamab at a dose of 16 mg per kilogram of body weight or placebo for six months, which was followed by a six-month observation period. The median time from kidney transplant to trial inclusion was nine years. The trial’s primary outcome was the safety and AE profile of felzartamab, with key secondary outcomes that included renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels.

Eight patients in the felzartamab cohort reported mild or moderate infusion reactions. Serious AEs were observed in one patient in the felzartamab cohort and four patients in the placebo cohort, with graft loss occurring in one patient in the placebo cohort. After 24 weeks, morphologic antibody-mediated rejection resolved more frequently in nine of 11 patients in the felzartamab cohort compared with two of 10 patients in the placebo cohort, which translates to a difference of 62 percentage points (95% confidence interval [CI], 19 to 100) and a risk ratio of 0.23 (95% confidence interval [CI], 0.06 to 0.83).

Median microvascular inflammation score was zero in the felzartamab cohort compared to 2.5 in the placebo cohort, which translates to a mean difference of −1.95 (95% CI, −2.97 to −0.92). A molecular score that reflects the probability of antibody-mediated rejection was 0.17 in the felzartamab cohort compared to 0.77 in the placebo cohort.

The level of donor-derived cell-free DNA was 0.31% in the felzartamab cohort compared with 0.82% in the placebo cohort. After 52 weeks, recurrence of antibody-mediated rejection was reported in three of nine patients who showed a response to felzartamab, with molecular activity and biomarker levels increasing toward baseline levels.

Investigators concluded that there is no evidence suggesting felzartamab increases the incidence of serious AEs, as no patients discontinued treatment due to an AE.

“Our trial shows greater resolution of antibody-mediated rejection with felzartamab than with placebo (82% vs. 20%) at week 24, along with decreases in microvascular inflammation and rejection-related transcript scores,” the study authors wrote. “Moreover, plasma levels of donor-derived cell-free DNA, which are used to diagnose graft injury, were lower at weeks 12 and 24 in the felzartamab group, which indicates the clinical relevance of these results. Although this trial was not powered for clinical outcomes, the results suggest a potential stabilization of the eGFR slope, which is a surrogate for long-term allograft survival. Of note, the effect of felzartamab was not durable after treatment discontinuation, as shown by the rejection features that had recurred by week 52, suggesting that continuing treatment would be required for long-term prevention of rejection-related graft loss.”¹

References

1. Mayer K, et al. A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection. N Engl J Med 2024;391:122-132 DOI: 10.1056/NEJMoa2400763. Vol. 391 No. 2.

2. Felzartamab in Late Antibody-Mediated Rejection. ClinicalTrials.gov. April 18, 2024. Accessed July 23, 2024. https://clinicaltrials.gov/study/NCT05021484

3. Biogen Bolsters Late-Stage Pipeline, Expands Immunology Portfolio with Agreement to Acquire Human Immunology Biosciences. News release. Biogen. May 22, 2024. Accessed July 23, 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-bolsters-late-stage-pipeline-expands-immunology-portfolio