A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection
In a phase 2 randomized trial, the anti-CD38 antibody felzartamab had an acceptable safety profile and resolved morphologic antibody-mediated rejection in most treated patients at 24 weeks, though rejection activity frequently recurred after treatment was stopped.
Background
Antibody-mediated rejection is a leading cause of kidney-transplant failure, and no approved effective therapy exists, particularly for late rejection. Targeting CD38, which is highly expressed on plasma cells and natural killer cells, may inhibit graft injury caused by alloantibodies and NK cells, providing a rationale for the CD38 monoclonal antibody felzartamab.
Study design
This double-blind, randomized, placebo-controlled phase 2 trial enrolled 22 patients with antibody-mediated rejection occurring at least 180 days after transplantation (median time from transplantation, 9 years), assigning 11 to felzartamab (16 mg per kilogram) and 11 to placebo for nine infusions over 6 months, followed by a 6-month observation period. The primary outcome was safety and side-effect profile, with secondary outcomes including biopsy results, donor-specific antibody levels, NK-cell counts, and donor-derived cell-free DNA.
Key findings
Mild or moderate infusion reactions occurred in 8 felzartamab patients; serious adverse events occurred in 1 felzartamab versus 4 placebo patients, with 1 graft loss in the placebo group. At week 24, resolution of morphologic antibody-mediated rejection occurred in 9 of 11 felzartamab patients (82%) versus 2 of 10 placebo patients (20%). Felzartamab also lowered the median microvascular inflammation score, the molecular rejection probability score, and donor-derived cell-free DNA. By week 52, rejection recurred in 3 of 9 felzartamab responders, with biomarkers trending back toward baseline.
Clinical implications
Felzartamab showed acceptable safety and promising efficacy in suppressing both morphologic and molecular antibody-mediated rejection, supporting CD38-directed therapy as a candidate strategy. The frequent recurrence after treatment cessation suggests the effect is transient and that longer or maintenance dosing, now under investigation in a phase 3 trial, may be required.
Category
Transplant
Source
The New England Journal of Medicine
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