Kidney allograft failure is most commonly associated with antibody-mediated rejection (AMR). Banff classification describes diagnosis of AMR based on serologic, morphologic, and molecular criteria. To date, there are no approved therapies for the treatment of AMR.
Targeting CD38, a transmembrane glycoprotein expressed by immune and hematopoietic cells, to inhibit graft injury caused by alloantibodies and natural killer (NK) cells, may offer a therapeutic option. Felzartamab, an investigational fully human IgG1 monoclonal CD38 antibody, depletes target cells through antibody-dependent cellular cytotoxicity and phagocytosis.
Katharina A. Mayer, MD, and colleagues conducted a phase 2, randomized, double-blind, placebo-controlled trial designed to evaluate the safety, side effect profile, and preliminary efficacy of felzartamab in the treatment of AMR occurring at least 180 days following kidney transplantation. Results were reported in the New England Journal of Medicine.
The primary outcome of interest was the safety and side effect profile of felzartamab. Secondary outcomes included renal biopsy results at 23 and 52 weeks, donor-specific antibody levels, peripheral NK cell counts, and donor-derived cell-free DNA (cfDNA) levels.
The study was conducted from October 2021 to March 2023. The study population included 22 patients with AMR occurring at least 180 days following transplantation. Of those 22 patients, 11 were randomly assigned to receive felzartamab and 11 were assigned to receive placebo. One patient in the placebo group had graft loss caused by rejection at week 14 of the trial; 21 patients completed the trial treatment. Following completion of the last scheduled patient visit, the database was locked and unblinded on March 7, 2024.
Median time until trial inclusion was 9 years following transplantation. The two groups were generally well balanced in baseline characteristics, with the exception of median age (patients in the placebo group were older: 33 years of age in the felzartamab group vs 46 years of age in the placebo group). In addition, median estimated glomerular filtration rate (eGFR) was higher in the felzartamab group than in the placebo group (60 mL/min/1.73 m2 vs 36 mL/min/1.73 m2, respectively).
In the total study population, 32% (n=7/22) of patients had active AMR, and 68% (n=15/22) had chronic active AMR. In 59% (n=13/22), the presence of human leukocyte antigen class II donor-specific antibody was observed. In 36% (n=8/22), a mean fluorescence intensity of donor-specific antibody of more than 10,000 was observed. Median eGFR was 37 mL/min/1.73 m2. The median ratio of spot urine protein-to-creatinine was 993, with urinary protein measured in milligrams and creatinine measured in grams. Most patients had fully developed AMR as revealed on molecular analysis. In 18 of the 22 patients, triple immunosuppression was being administered.
In safety analyses, all patients experienced adverse events (AEs), all of which were reported as predominantly mildly or moderately severe. Patients in the felzartamab group reported a greater incidence of AEs compared with those in the placebo group (119 vs 81 events). The incidence of AEs the trial investigators deemed to be related to felzartamab was also greater in the felzartamab group than in the placebo group (27 vs 11 events). There were no fatal AEs, and no patients discontinued treatment due to AEs. The frequency of serious AEs (primarily infection-related events) was lower in the felzartamab group than in the placebo group (one patient vs four patients, respectively).
Infections were the most frequent AEs (n=17/22 patients; 77%) and were more frequent in the felzartamab group than in the placebo group (10 patients [91%] vs seven patients [64%]). Eight patients in the felzartamab group reported infusion-related reactions, compared with zero in the placebo group, during the first infusion. The frequency of nasopharyngitis was greater in the felzartamab group than in the placebo group (nine patients vs three patients, respectively), as was the frequency of COVID-19 (seven patients vs three patients, respectively).
Biopsy procedures were performed at 24 weeks and 52 weeks in 11 patients in the felzartamab group and 10 in the placebo group. Resolution of morphologic AMR (including either chronic [inactive] rejection or no rejection) at week 24 was more frequent in the felzartamab group (82%; n=9/11 patients) compared with the placebo group (20%; n=2/10 patients). The between-group difference was 62 percentage points (95% CI, 19-100) and a risk ratio of 0.23 (95% CI, 0.06-0.83).
The median microvascular inflammation score was lower in the felzartamab group than in the placebo group at 24 weeks (0.0 vs 2.5; mean difference, –1.95; 95% CI, –2.97 to –0.92). The molecular score reflecting the probability of AMR was also lower in the felzartamab group than in the placebo group (0.17 vs 0.77; mean difference, –0.39; 95% CI, –0.64 to –0.14), as was the level of donor-derived cfDNA (0.31% vs 0.82%).
At 52 weeks, survival in both groups was 100%. One patient in the placebo group experienced graft loss due to persistent chronic active AMRs. The one-year eGFR slope in the felzartamab group was –0.39 mL/min/1.73 m2 compared with –4.53 mL/min/1.73 m2 in the placebo group. In both groups, there was no change in spot urinary protein-to-creatinine ratio over time.
The small sample size and short duration were cited by the authors as limitations to the study findings, as was the possibility that the results in this predominantly White European transplant population may not be generalizable to transplant populations in other regions, including North America.
In conclusion, the researchers said, “The results of this trial suggest that felzartamab may have the potential to effectively and safely reverse ongoing [AMRs], which underscores the potential of felzartamab as a therapeutic option warranting further investigation in the context of late or even early rejection after organ transplantation.
“The present pilot trial showed that felzartamab met its primary outcome of apparent safety and an acceptable side effect profile.”
Source: New England Journal of Medicine
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