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A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection
Katharina A Mayer1, Eva Schrezenmeier1, Matthias Diebold1
1From the Departments of Medicine III (K.A.M., M.D., M.S., S.H., A.K., F.E., K.D., G.A.B.), Clinical Pathology (H.R., N.K., J.K.), and Clinical Pharmacology (S.S., C.F., B.J.) and the Center of Virology (E.P.-S., H.V.), Medical University of Vienna, Vienna; the Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland (M.D.); the Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin (E.S., S.K., A.A., B.O., F.H., K.B.), MorphoSys, Planegg (R.B.), the Department of Pathology, University of Erlangen-Nürnberg, Erlangen (K.A.), and Chronix Biomedical, Göttingen (E.S., J.B.) - all in Germany; the Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, Heritage Medical Research Centre, University of Alberta, Edmonton, AB, Canada (P.F.H.); and Human Immunology Biosciences, South San Francisco, CA (U.D.P., J.S.D., H.N.G.).
Background:
Antibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option.
Methods:
In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period. The primary outcome was the safety and side-effect profile of felzartamab. Key secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels.
Results:
A total of 22 patients underwent randomization (11 to receive felzartamab and 11 to receive placebo). The median time from transplantation until trial inclusion was 9 years. Mild or moderate infusion reactions occurred in 8 patients in the felzartamab group. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group; graft loss occurred in 1 patient in the placebo group. At week 24, resolution of morphologic antibody-mediated rejection was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]), for 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). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5), for a mean difference of -1.95 (95% CI, -2.97 to -0.92). Also lower was a molecular score reflecting the probability of antibody-mediated rejection (0.17 vs. 0.77) and the level of donor-derived cell-free DNA (0.31% vs. 0.82%). At week 52, the recurrence of antibody-mediated rejection was reported in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels.
Conclusions:
Felzartamab had acceptable safety and side-effect profiles in patients with antibody-mediated rejection. (Funded by MorphoSys and Human Immunology Biosciences; ClinicalTrials.gov number, NCT05021484; and EUDRACT number, 2021-000545-40.).
