OM336 in Sensitized Transplant Candidates

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.

Inclusion criteria

• Biologic male or female, 18 to 70 years of age at the time of informed consent.
• Capable of and willing to provide signed informed consent (ICF); subject must sign ICF indicating that he or she understands the purpose of procedures required for the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the subject's disease.
• Willing and able to comply with the visits, treatments, procedures, laboratory tests, and other requirements according to the current protocol, with a high probability for adherence and completion of the study.
• Presensitized patient

• Deceased kidney donor transplant candidate Broadly sensitized recipient on deceased donor waiting list: inclusion in the AM program (>85% vPRA) for ≥24 months or inclusion in the ETKAS scheme and >95% vPRA for ≥24 months, but not fulfilling the criteria in the AM program (panel reactivity includes specificities that are not acceptable by the local center; e.g. HLA antibodies with an MFI >10.000 but no prior sensitizing event documented).

AND:

A dilution of the baseline serum obtained at screening by 1:100 must lead to a considerable decrease in HLA antibody MFI, with a decrease in vPRA levels by at least 1.0%.

OR

• Living donor kidney transplant candidate Living donor transplant candidate with, according to local policy, unacceptable DSA against the scheduled donor and no option of kidney paired donation (KPD) transplantation, or within a KPD program with no transplant offer after 12 months of listing.

AND:

A dilution of the baseline serum obtained at screening by 1:100 must lead to a negative DSA result or to a considerable decrease in DSA MFI to permissive levels per local lab.

• Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening using a highly sensitive pregnancy test. Women of childbearing potential and fertile men who are sexually active must agree to use a highly effective method of contraception (<1% / year failure rate) during the study and for 150 days after the last dose of study drug. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for 90 days after the last dose of study drug.
• Within 4 weeks prior to inclusion, participants should be up to date on all vaccinations recommended by the local country or regional public health authority, as determined by the Investigator.

Exclusion criteria

• Prior treatment with any therapy that is targeted to BCMA or any other CD3-redirecting drug.
• Treatment with prohibited medications during the timeframes detailed below.
• History of severe allergic reaction (per investigator judgment) or anaphylactic reaction to monoclonal antibody-based therapies or any components of OM336.
• Congenital immunodeficiency with recurrent severe infections over the last 12 months.
• Prior desensitization treatment within 6 months prior to inclusion:

• Apheresis therapy (plasmapheresis or immunoadsorption)
• CD20 mAb, e.g. rituximab or other
• CD38 mAb, e.g. daratumumab or other
• Proteasome inhibitor (bortezomib, carfilzomib)
• Tocilizumab
• Imlifidase
• Any other investigational agent
• WOCBP: Pregnant, or breastfeeding, unwilling to practice adequate contraception.
• Pulmonary compromise requiring chronic supplemental oxygen use to maintain adequate oxygenation.
• Systemic herpes simplex (HSV) or symptomatic herpes zoster virus (HZV) (infection within 3 months prior to screening, or a history of disseminated or ophthalmic or central nervous system (CNS) infection with herpes zoster.
• Active or latent tuberculosis based on a positive QuantiFERON-TB Gold Plus test or equivalent test, medical history, examination, and chest X-ray.
• Active infection with hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV).
• Clinically significant infection (e.g., requiring hospitalization or parenteral antimicrobial therapy) within 3 months prior to screening.
• Any infection requiring oral antimicrobial therapy within 2 weeks prior to inclusion.
• A history of malignancy within the past 5 years (except for successfully treated basal or squamous cell carcinoma of the skin, or successfully treated carcinoma in situ of the cervix, with no evidence of recurrence). Note: low-grade prostate cancer (Gleason score of 6 or less, confined to the prostate and under surveillance/monitoring without need for imminent surgical intervention) is permitted, per judgment of the investigator.
• Live vaccine within 3 months prior to screening.
• Uncontrolled psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status precluding study enrollment according to the judgment of the investigators
• Inadequate liver function at Screening: Total bilirubin >2 × the upper limit of normal (ULN) except if due to Gilbert syndrome; Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) >3 × ULN
• Currently enrolled in or participated in another clinical research study with investigational drug or device within 30 days or 5 drug half-lives of the investigational product (whichever is longer), prior to screening.
• Any clinically significant underlying illness that, in the opinion of the Investigator, may compromise study participation, present a safety risk to the participant, or may confound the interpretation of the study results, including general non-adherence to medication
• Known allergy to dexametasone and its excipients, diphenhydramine and its excipients, acetaminophen and its excipients or to valacyclovir and its excipients.