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N Engl J Med. 2024 Jul 11;391(2):122-132. doi: 10.1056/NEJMoa2400763. Epub 2024 May 25
A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection
PMID: 38804514
Introduction
Antibody-mediated rejection (AMR) remains a leading cause of kidney allograft failure (Sellares et al, Am J Transplant, 2012), yet current treatment options often fall short in addressing the complex immune responses involved. Donor-specific antibodies (DSA) are a marker for AMR, mediating complement dependent-cytotoxicity and antibody-dependent cellular cytotoxicity (Bohmig et al.Transpl Int. 2019).
Image created after Bohmig et al.Transpl Int. 2019
Treatments like anti-CD20 antibodies, proteasome inhibitors and anti-C5 antibodies have had limited success, largely due to heterogeneity of AMR, making difficult to standardize effective treatments.
Trials of treatment options in AMR
Why target CD38 in AMR?
Recent research has targeted specific immune pathways involved in rejection, such as interleukin-6 receptor inhibitors and anti-CD38 monoclonal antibodies. CD38 is viewed as a promising target because of its dual role as a receptor and ectoenzyme (Gozzetti et al, Hum Vaccin Immunother, 2022). In addition to its involvement in plasma cell function (hematopoietic cells, natural killer cells, and plasma cells), CD38 modulates immune responses by hydrolyzing NAD+, influencing leukocyte activations, and shaping the immune microenvironment. It also works with enzymes like 203a and CD73 to convert NAD precursors into adenosine, which can deactivate immune cells. The balance between immune activation and suppression plays an important role in AMR, immune responses driving to graft injury (Rabelink TJ& deVries PJ, Nat Rev Nephrol, 2024).
Figure from Rabelink TJ& deVries PJ, Nat Rev Nephrol, 2024: a- CD38 metabolism and immune modulation. b- Mechanisms of anti-CD38 antibodies
Given high expression of plasma cells, in producing DSA in AMR, targeting CD38 could address one of the main pathophysiological processes. Anti-CD38 antibodies like daratumumab have proven effective in multiple myeloma by inducing cytotoxicity and apoptosis in plasma cells. Same mechanisms are either relevant in AMR, where depleting plasma cells could reduce DSA levels and protect the graft from immune-mediated damage. Although, daratumumab has been explored as rescue therapy for late-refractory AMR in kidney (Spica et al, Case Rep Nephrol Dial, 2019) and heart allografts (Agudo et al, Transplantation, 2021), as well as in desensitization protocols before kidney transplantation (Zhao et al, Transpl Int, 2023), the lack of comprehensive, randomized trials limits our understanding of its potential in AMR.
The Study
This is a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, side effect profile, and efficacy of felzartamab in the treatment of AMR, at least 180 days after kidney transplant. It was conducted at the Medical University of Vienna and at Charité Universitätsmedizin Berlin from October 2021 to March 2023. The patients included in the trial were followed up for 52 weeks.
Methods
The main inclusion and exclusion criteria are mentioned in the infographic below. Notably, patients who had received previous treatment with daratumumab/ tocilizumab or rituximab within 3 months of screening were excluded. Other prohibited treatments were plasma exchange and IV Ig.
Image created from Mayer et al. NEJM. 2024
Randomization and Interventions
Patients were assigned in a 1:1 ratio to receive felzartamab or placebo. Over a 20 weeks period, patients received nine intravenous infusions of felzartamab at a dose of 16 mg/kg body weight (in 250 ml normal saline over 30-90 minutes) or placebo. Doses were administered as weekly infusions for 4 weeks, followed by monthly infusions for 5 months.
Slide from Katharina Meyers’s presentation, A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection, during Late Breaking Clinical Trials, 61st European Renal Association Congress
Premedication, consisting of diphenhydramine (30mg), paracetamol (1000 mg), and prednisolone (100mg) in 100 mL each, was administered 30 minutes before felzartamab infusion. Patients in the placebo group received 3 x 100ml saline.
Baseline immunosupression was optimized before randomization. Patients on calcineurin inhibitors or rapamycin without azathioprine or mycophenolic acid (MPA) were switched to mycophenolate mofetil or enteric-coated MPA to avoid under-immunosupression, with dosages adjusted as tolerated. Tacrolimus, cyclosporine, and rapamycin trough levels were regularly monitored and low dose steroids were reintroduce for patients previously weaned off them.
Primary and secondary outcomes
Being a phase 2 trial, primary outcomes were predominantly safety outcomes. There were secondary outcomes which were surrogate measures of efficcay, as detailed below. Adverse events were graded, focusing on serious events, infusion-related reactions, and infections.
Image created from Mayer et al. NEJM. 2024
Statistical analysis
This was an exploratory trial with a primary safety objective. Thus, no formal power or error calculations were applied. Analysis was done according to the intention-to-treat principle. Standard statistical tests were applied.
Funding
The trial was funded by MorphoSys and Human Immunology Biosciences. 5 of the authors had roles in Human Immunology Biosciences, 4 of them having leadership positions (KB, JD, HG, and UP), while the corresponding author was a consultant (GB) for the same company, and advisory board member for trial design in AMR. One of the authors (RB) is the director of MorphoSys.
Results
Thirty-one adult kidney transplant recipients with a functioning allograft ≥180 days after transplantation were screened for eligibility. Nine recipients did not meet the eligibility criteria and were excluded, and 22 with DSA-positive antibody-mediated rejection were assigned to receive felzartamab or placebo and were followed until week 52. Follow-up biopsies were performed at 24 and 52 weeks. One patient in the placebo arm experienced graft loss, and didn’t undergo further follow-up biopsies.
Figure S2 from Mayer et al, NEJM, 2024
Felzartamab administration happened in the first 20 weeks, its serum levels subsequently decreased between 28 and 36 weeks.
Figure S3 from Mayer et al, NEJM, 2024. Pharmakokinetics of felzartamab.
Baseline characteristics were comparable in both the groups throughout the course of the study. However, at trial entry:
The median recipient age was higher in the placebo group (42 vs 56 years).
The median eGFR was higher in the felzartamab group [60 (35-69) vs 36 (31-43)] ml/min/1.73m2].
Active AMR was noted in 32% of total enrolled patients whereas chronic active AMR was evident in 15 (68%) patients. Thirteen patients (59%) had exclusively human leukocyte antigen (HLA) class II DSA. Mean fluorescent intensity (MFI) of DSA more than 10,000 were noted in 36% patients. 82% of patients were on triple drug immunosuppression prior to enrolment.
Table 1 from Mayer et al, NEJM, 2024
Safety
The study reported a greater incidence of adverse events in the felzartamab group compared to the placebo group (119 vs 81 events). They were primarily mild to moderate in severity and infusion reactions in the felzartamab group. However, the frequency of serious adverse events (infection-related) was lower in the felzartamab group [1 patient (9%) vs 4 patients (36%)]. There were no events of treatment discontinuation owing to adverse events and no fatalities were noted. During the first infusion, 8 patients (73%) in the felzartamab group reported mild/moderate infusion related reactions compared to none in the placebo group. These were managed by slowing the infusion rates and administering steroids and antipyretics and rescheduling the dose where prudent. None of the patients had to miss a dose.
Table 2 from Mayer et al, NEJM, 2024
Infections were the most frequently reported adverse events, occurring more in the felzartamab group (in 10 patients vs. 7 patients).
Table S4 from Mayer et al, NEJM, 2024
Biopsy results
At week 52 biopsy (6 months after treatment completion): 3 out of 9 patients in the felzartamab group who had previously responded to treatment, showed evidence of recurrence of rejection. Also, molecular scores related to rejection and NK cell burden increased toward baseline levels.
Figure created from Mayer et al, NEJM, 2024
Patients in felzartamab group shifted more from active rejection to no rejection compared to placebo. (Fig 1, panel A). Regarding microvascular inflammation scores, at 24 weeks, 7 of 11 felzartamab patients had no inflammation (score of 0), versus 1 of 10 in the placebo group. At 52 weeks, 4 of 11 felzartamab patients maintained this score, while none in the placebo group did. (Fig 1, panel B) In terms of molecular rejection scores, there was a lower likelihood of rejection with felzartamab vs placebo. (Fig 1, panel C)
Figure 1 from Mayer et al, NEJM, 2024. Sankey plots of the dynamics of morphologic antibody mediated rejection (A), microvascular inflammation score (B) and probability of antibody mediated rejection (C)
Biomarkers in peripheral blood
There were reductions in the peripheral blood NK cell count as well as donor-derived cell free DNA (non invasive indicator of allograft rejection) count in the felzartamab group. The salient findings have been given in the figure below:, suggesting that felzartamab may have immunosuppressive effects, reducing both NK cell counts and makers of graft injury like donor-derived cell-free DNA. Lower cfDNA levels, especially at week 12, suggest a possible benfit in limiting graft dammage, athough at 24 weeks the results are not significant
Figure created from Mayer et al, NEJM, 2024
Other notable outcomes were:
The felzartamab group had modestly lower values of mean fluorescence intensity (MFI) of the peak donor specific antibody (DSA), total IgG, and IgM levels.
The numbers of T cells, B cells and CD 138 antibody secreting cells in peripheral blood remained unchanged.
Figure 2 from Mayer et al, NEJM, 2024. A. The percent change in DSA intensity over time. B. Peripheral blood CD16 bright NK-cell counts C. The fraction of donor-derived cell-free DNA. D. Torque teno virus (TTV) levels.
Clinical outcomes
There were no deaths in either group. The 1-year eGFR slope was slower -0.39 ml/minute (95% CI,-5.47 to 4.69) in the felzartamab group versus -4.53 ml/minute (95% CI, -9.83 to 0.77) in the placebo group. The spot urine protein to creatinine ratios were similar in both the groups over time.
Figure S13 from Mayer et al, NEJM, 2024
Discussion
The phase 2 trial of felzartamab demonstrated an acceptable safety profile and promising efficacy for AMR in kidney transplant, occurring after 180 days post-surgery.
Key strengths
Safety: infusion reactions were mild to moderate, without discontinuations due to adverse events
Efficacy: reduction in microvascular inflammation and rejection-related transcript scores, along with decreased donor-derived cell-free DNA levels and stabilized eGFR.
Specific targeting: Unlike other CD38 antibodies, felzartamab did not decreased T-cell mediated rejection, possibly due to its mechanism of action via complement mediated cytotoxicity. (Boxhammer et al, Blood, 2015)
Monitoring rejection: NK cell depletion was observed, targeting antibody-mediated cytotoxicity and rejection, even in the absence of detectable DSA.
New biomarkers (NK cells, cfDNA) were used over traditional DSA monitoring, which can be reliable.
Immunosuppression: no excessive immunosuppression was observed, with normal TTV and immune cell counts maintained.
Key limitations
Comparator: felzartamab was compared to placebo rather than standard anti-rejection drugs (e.g. rituximab), leaving unanswered questions about its superiority over current treatments.
Sustained efficacy: while rejection activity was low at week 24, some patients showed recurrence of rejection by week 52, suggesting the need of sustained administration.
Clinical outcomes: No significant improvements in eGFR slope or proteinuria were noted over time. With the small N, the trial was not really powered for these outcomes.
Adverse events were mild to moderate, especially infusion reactions, more frequent in felzartamab group. CD38 play an important role in defense against viruses and Haemophilus influenzae, and previous studies showed higher infectious risk associated with anti-CD38 administration (Loupy A. & Lefaucheur C, NEJM, 2018). However, even if higher number of infections in felzartamab group, there were not severe episodes.
Study limitations: small sample size, and lack of diversity in the study population limited generalizability. Trial may have a potential risk of bias, because some of the authors have leadership positions in companies which developed felzartamab.
Cost: besides the tested drug, should consider all the diagnostic techniques (dd cfDNA, molecular scores etc.). A more cost-effective trial, would be a basket trial (NephJC summary: Master trial protocol), given the potential role of CD38 in other GNs (Rabelink TJ& deVries PJ, Nat Rev Nephrol, 2024, Rovin BH, et al, KIreports, 2024).
Comparison to other CD38 antibodies
Other CD38 antibodies (daratumumab, isatuximab) have shown limited clinical success in AMR. Concerns exist about anti-CD38 therapy causing cell-mediated rejection due to T-reg depletion and subsequent increase in T-effector cells (Jordan, Transplantation, 2024).
Future outlook
Felzartamab shows potential but requires further studies, including head-to-head trials with existing AMR treatments. It may emerge as a first-line or adjuvant therapy for AMR, but additional data are needed.
Conclusion
The current phase 2 trial suggests that felzartamab is safe to be administered in patients with kidney transplant and AMR. It may even have the potential to effectively and safely reverse AMR pathology, however, the efficacy or non-infeiority should be tested versus standard of care. It would be interesting to see the results of an extensive analysis of Treg cell, NK cells, monocytes, and B cells subsets following the application of this drug in AMR patients.