A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection
Mayer, K. A., et al.New England Journal of Medicine 2024 [record in progress].
Aims
They aim to assess the safety of CD38 monoclonal antibody therapy, felzartamab in the treatment of AMBR in kidney transplantation.
Interventions
Participants received either felzartamab (9 IV doses of 16mg over 20 weeks) or placebo.
Participants
22 adult kidney recipients with AMBR at least 180 days after transplantation and a eGFR >20ml/min/1.73m2.
Outcomes
Primary outcome was ther safety and side effect profiles of felzartamab. Secondary outcomes included: resolution of ABMR, level of microvascular inflammation, classifier score of ABMR, DSA assessment, NK-cell count, donor cfDNA & eGFR slope.
Follow-up
52 Weeks
CET Conclusions
The investigators present a blinded, placebo-controlled RCT for the safety of potentially exciting therapy for ABMR, felzartamab. They find an effective early response during the treatment window of the first 24 weeks, with resolution to chronic (inactive) rejection or no rejection in 9 of the 11 (82%) who received the anti-CD38, with only 2 of 10 (20%) having resolution in the placebo group. This was accompanied by reduction in the microvascular inflammation scores for those who received felzartamab compared to placebo. In the 6-month observation period following treatment the differences between the groups begins to wane, with 3 of those who had inactivity on biopsy at 6 months having activity at 12 months. Within the placebo group there is still only 2 of 10 with no activity on biopsy at 12 months, but these are 2 different participants from those at 6 months, who have become active. Along with this, the differences in microvascular injury score and probability score for AMBR have become narrower. The relevant clinical manifestation of this was the 1-year eGFR slope was shallower with felzartamab at -0.39 ml/min/1.73m2, compared with -4.53 ml/min/1.73m2 in placebo. It appears likely that during the treatment period there is an effect of the anti-CD38 on activity, but that without regular dosing, or additional treatments titrated to biopsy results this effect diminishes over time. With NK-cell depletion, the key safety considerations is infections, which were unsurprisingly numerically higher, but not significant in the felzartamab group, 91% compared with 64% in the control. The inherent limitation of small sample size within this safety RCT means commenting on efficacy or the risk benefit with adverse infection is not possible, but they have performed a robustly designed study demonstrating safety of felzartamab with convincing preliminary evidence for a larger multi-centre/multi-national efficacy study for the treatment for a condition which to date has no approved therapies.
Data analysis
Strict intention-to-treat analysis
Trial registration
ClinicalTrials.gov - NCT05021484; EudraCT-2021-000545-40