Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

Abstract

Background Antibody-mediated rejection (ABMR) is a cardinal cause of renal allograft loss. This rejection type, which may occur at any time after transplantation, commonly presents as a continuum of microvascular inflammation (MVI) culminating in chronic tissue injury. While the clinical relevance of ABMR is well recognized, its treatment, particularly a long time after transplantation, has remained a big challenge. A promising strategy to counteract ABMR may be the use of CD38-directed treatment to deplete alloantibody-producing plasma cells (PC) and natural killer (NK) cells. Methods This investigator-initiated trial is planned as a randomized, placebo-controlled, double-blind, parallel-group, multi-center phase 2 trial designed to assess the safety and tolerability (primary endpoint), pharmacokinetics, immunogenicity, and efficacy of the fully human CD38 monoclonal antibody felzartamab (MOR202) in late ABMR. The trial will include 20 anti-HLA donor-specific antibody (DSA)-positive renal allograft recipients diagnosed with active or chronic active ABMR ≥ 180 days post-transplantation. Subjects will be randomized 1:1 to receive felzartamab (16 mg/kg per infusion) or placebo for a period of 6 months (intravenous administration on day 0, and after 1, 2, 3, 4, 8, 12, 16, and 20 weeks). Two follow-up allograft biopsies will be performed at weeks 24 and 52. Secondary endpoints (preliminary assessment) will include morphologic and molecular rejection activity in renal biopsies, immunologic biomarkers in the blood and urine, and surrogate parameters predicting the progression to allograft failure (slope of renal function; iBOX prediction score). Discussion Based on the hypothesis that felzartamab is able to halt the progression of ABMR via targeting antibody-producing PC and NK cells, we believe that our trial could potentially provide the first proof of concept of a new treatment in ABMR based on a prospective randomized clinical trial. Trial registration EU Clinical Trials Register (EudraCT) 2021-000545-40. Registered on 23 June 2021. ClinicalTrials.gov NCT05021484. Registered on 25 August 2021

Primary membranous nephropathy combined with ALECT-2 renal amyloidosis：a case report

“…Furthermore, CD38 is an excellent target for the therapy of AL amyloidosis [36]. A team of researchers from the United States and Belgium published a new study on fezatuzumab, demonstrating that it can effectively reduce anti-PLA2R antibody titres in MN patients and that fezatuzumab, as an anti-CD38 monoclonal antibody, has promising therapeutic potential for the treatment of light chain amyloidosis [37]. This could open up new therapy options for people with PMN and AL amyloid nephropathy.…”

The Clinical Utility of Post-Transplant Monitoring of Donor-Specific Antibodies in Stable Renal Transplant Recipients: A Consensus Report With Guideline Statements for Clinical Practice

“…In addition, a small phase II prospective randomized trial with an IL-6 inhibitor has shown some promising results in chronic active ABMR (caABMR), and is currently being studied in a large multicenter phase III RCT [ 171 , 172 ]. Additional evidence is emerging on the effectiveness of costimulation blockade, as discussed above, and anti-CD38 therapy in patients with aABMR and caABMR, the latter of which is currently being investigated in a phase II RCT in the form of felzartamab [ 149 , 173 ]. In light of emerging data one may conclude that (early) acute ABMR with dnDSA (but without transplant glomerulopathy) could be more responsive to maintenance treatment optimization as well as PP and IVIG and eventually novel treatment regimens than patients with caABMR or cABMR, albeit all the treatment options have a low amount of supporting evidence.…”

Harnessing the B Cell Response in Kidney Transplantation – Current State and Future Directions

“…Felzartamab, a recombinant fully human monoclonal anti-CD38 monoclonal antibody, will be evaluated for safety and tolerability in a multi-center 12-month randomized placebo-controlled parallel-group trial (NCT05021484) ( 146 ). The study hypothesis is that felzartamab will deplete DSA-producing plasma cells thus reducing alloantibody production.…”