OM336 in Sensitized Transplant Candidates

Overview

This investigator-initiated, single-arm, open-label Phase IIa pilot study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of OM336 in highly HLA-sensitized adults with chronic kidney disease awaiting kidney transplantation. The study will enroll 12 participants who have either a very low likelihood of receiving a compatible deceased donor kidney because of broad HLA sensitization or unacceptable donor-specific antibodies against a potential living donor. Participants will receive one 4-week course of subcutaneous OM336, with the option of a second 4-week course based on the change in virtual panel-reactive antibody (vPRA) levels after the initial treatment period. Participants will subsequently be followed for up to 24 months and, if transplantation occurs, for at least 12 months after transplantation. The primary objectives are to evaluate the safety and tolerability of OM336 through Week 24 and (co-primary endpoint) its effect on HLA sensitization, assessed by changes in vPRA levels at Week 24. Secondary and exploratory objectives include assessment of the durability of changes in vPRA and donor-specific antibodies, the number of potential compatible donors, transplantation rates, OM336 pharmacokinetics and immunogenicity, and effects on B-cell and plasma-cell immunity and antibody characteristics. An optional substudy will assess B-cell immunity in bone marrow and lymph-node samples.

This investigator-initiated, prospective, single-arm, open-label Phase IIa pilot trial will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary immunologic effects of OM336 in highly sensitized adults with chronic kidney disease who are awaiting kidney transplantation. The study will characterize the effects of treatment on HLA sensitization and on cellular components of humoral immunity over a follow-up period of up to 24 months. The study addresses the substantial barriers to transplantation associated with HLA sensitization. Highly sensitized kidney transplant candidates may have prolonged waiting times because of a restricted pool of immunologically compatible donors, while candidates with a potential living donor may have donor-specific antibodies (DSA) that preclude transplantation because of the associated risk of antibody-mediated rejection. Existing desensitization approaches, including antibody removal and therapies targeting B cells or plasma cells, may provide incomplete or transient reductions in alloantibody levels. A therapeutic approach capable of reducing the cellular sources responsible for persistent alloantibody production could therefore potentially increase access to transplantation. OM336 is an investigational, humanized IgG4 (κ/λ) bispecific T-cell engager directed against B-cell maturation antigen (BCMA) and CD3. BCMA is expressed on plasmablasts and plasma cells, with lower expression on memory and naïve B-cell subsets. OM336 is designed to simultaneously bind BCMA-expressing cells and CD3-positive T cells, promoting T-cell-dependent cellular cytotoxicity and depletion of BCMA-expressing target cells independently of conventional antigen presentation. Mutations in the Fc domain are intended to prevent antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement deposition, while retaining FcRn binding to support a prolonged serum half-life. The study will investigate whether this mechanism can reduce alloantibody-producing plasma-cell populations and thereby decrease the level and breadth of HLA sensitization. Twelve participants will be enrolled at two European kidney transplant centers. Participants will be broadly sensitized deceased-donor kidney transplant candidates with persistently high virtual panel-reactive antibody (vPRA) levels or living-donor candidates with unacceptable DSA against the intended donor, according to the study-specific eligibility criteria. The trial is exploratory and is not designed to provide confirmatory evidence of efficacy. OM336 will be administered by weekly subcutaneous injections using a fractionated dosing regimen during a 4-week treatment course, consisting of two step-up doses followed by three weekly 40-mg doses through Day 28. The initial treatment course will be followed by a 5-month observation period. At Month 6, HLA antibody profiles will be reassessed and vPRA recalculated. Participants with a vPRA reduction of less than 5 percentage points may receive a second 4-week treatment course with step-up dosing and weekly administration through approximately Week 30. Participants will subsequently be followed through Month 24. If transplantation occurs during the study, additional post-transplantation safety follow-up will be performed for at least 12 months. The primary assessment will focus on the safety and tolerability of OM336 (number and percentage of participants experiencing treatment-emergent adverse events through Week 24;. AE will summarized by system organ class and preferred term \[MedDRA\]) and the change in virtual panel reactive antibody (vPRA) from baseline through Week 24. Additional assessments will characterize the magnitude and durability of changes in HLA sensitization, including vPRA, donor frequency, donor-specific antibody (DSA) levels for living-donor candidates, the number of potentially delistable unacceptable antigens, and HLA antibody characteristics such as binding intensity and complement-fixing capability. Additional serologic assessments include ABO blood group- and xenoantigen-reactive antibodies. OM336 PK will be characterized using plasma concentration-time data, including maximum concentration, time to maximum concentration, and area under the concentration-time curve, with additional parameters such as half-life, clearance, and volume of distribution calculated as appropriate. Immunogenicity will be assessed by measurement of anti-drug antibodies. Pharmacodynamic and exploratory translational assessments will evaluate components of B-cell and plasma-cell immunity in peripheral blood. In an optional substudy, bone marrow aspiration and lymph-node sampling obtained during transplantation may be used to further characterize treatment-related changes in B-cell and plasma-cell populations. Because this is a small, uncontrolled pilot study with limited prior information regarding the effect of BCMA-directed T-cell engagement on HLA sensitization, no formal confirmatory sample-size calculation or hypothesis-testing framework is planned. The sample size of 12 participants is intended to permit an initial systematic assessment of safety, tolerability, PK, PD, immunogenicity, and preliminary immunologic activity while limiting exposure to investigational treatment in this vulnerable population. Safety analyses will include treatment-emergent adverse events, serious adverse events, adverse events of special interest, and relevant laboratory abnormalities. Immunologic results will primarily be interpreted using descriptive statistics and estimation of the magnitude and variability of changes in vPRA, DSA, antibody characteristics, and cellular immune measures. The study is not intended to provide definitive evidence of efficacy. The study will provide initial clinical data on the feasibility, safety, and potential biologic activity of BCMA-directed T-cell engagement as a desensitization strategy in kidney transplant candidates. The findings are intended to inform the design of subsequent clinical studies evaluating OM336 and related approaches for reducing HLA sensitization and potentially increasing access to kidney transplantation.