Study for Desensitization of Chronic Kidney Disease in Adult Patients in Need of a Kidney Transplant Who Are Highly Sensitized to Human Leukocyte Antigen

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study is to assess the safety and tolerability of REGN5459 (Part A) or REGN5458 (Part B) as monotherapy in patients with chronic kidney disease (CKD) who need kidney transplantation and are highly sensitized to human leukocyte antigen (HLA). The secondary objectives of the study are to determine/assess the following for REGN5459 (Part A) or REGN5458 (Part B): Dose regimen(s) that result in a clinically meaningful reduction of anti-HLA alloantibody levels Effect on calculated panel-reactive antibody (cPRA) levels Time to maximal and clinically meaningful reduction in anti-HLA alloantibody levels Duration of the effect of study drug on the reduction of anti-HLA alloantibodies Effect on circulating immunoglobulin (Ig) classes (isotypes) Pharmacokinetics (PK) properties Immunogenicity

Official Title
-----------------
A Dose Escalation and Proof-of-Concept Study of REGN5459 or REGN5458 (BCMA × CD3 Bispecific Antibodies) for Desensitization of Chronic Kidney Disease Patients in Need of Kidney Transplantation Who Are Highly Sensitized to Human Leukocyte Antigen

Conditions
-----------------
Chronic Kidney Disease (CKD)

Intervention / Treatment
-----------------
* Drug: REGN5459
* Drug: REGN5458


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Has Chronic Kidney Disease (CKD) requiring hemodialysis, and awaiting kidney transplant on the United Network for Organ Sharing (UNOS), with a cPRA ≥99.9%, or those with a cPRA >98% (98.1% to 99.8%) who have spent 5 years or longer on the waitlist Adequate hematologic and adequate hepatic function as defined in the protocol Willing and able to comply with clinic visits and study-related procedures Key Exclusion Criteria: Current or active malignancy not in remission for at least 1 year Central nervous system (CNS) pathology or history of CNS neurodegenerative or movement disorders Patients who have had their spleen removed, including patients with functional asplenia Patients who have received a stem cell transplantation within 5 years Use of investigational agents within 8 weeks or 5 half-lives of study drug administration (whichever is larger) Hypogammaglobulinemia, defined as total plasma IgG <300 mg/dL at screening Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone (or anti-inflammatory equivalent) within 72 hours of start of study drug administration Received a calcineurin inhibitor (eg, tacrolimus, cyclosporine) within 30 days of study drug administration Received cyclophosphamide, rituximab, obinutuzumab, other anti-CD20 or B cell-depleting agents, or proteasome inhibitors or anti-CD38 therapies (eg, isatuximab, daratumumab) within 6 months of study drug administration Prior treatment with any anti-BCMA antibody (including antibody drug conjugate or bsAb) or BCMA-directed CAR-T cell therapy Has received a COVID-19 vaccination within 1 week of planned start of study drug, or for which the planned COVID-19 vaccination would not be completed 1 week before start of study drug Note: Other protocol defined inclusion / exclusion criteria apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REGN5459<br>REGN5459 escalating dose | Drug: REGN5459<br>* Administered by intravenous (IV) infusion<br>* Other names: BCMAxCD3;|
| Experimental: REGN5458<br>REGN5458 escalating dose | Drug: REGN5458<br>* Administered by intravenous (IV) infusion<br>* Other names: linvoseltamab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse event(s) of interest (AEI) from the first dose through end of the safety observation period |  | Up to approximately 4 weeks | 
| Incidence and severity of treatment-emergent adverse events (TEAE)s from the first study drug dose up to the end of the study | TEAEs include adverse events of special interest (AESI) and serious adverse events (SAEs) | Up to 30 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants with a clinically meaningful reduction in anti-HLA alloantibodies | Clinically meaningful reduction in anti-HLA alloantibodies are defined as either: Reduction in Calculated panel-reactive antibody (cPRA) from baseline, or Reduction in the peak (immunodominant) anti-HLA mean fluorescence intensity (MFI) to <5,000, or by ≥50% by Single antigen bead (SAB) assay | Up to 30 weeks | 
| Maximum reduction in the peak (immunodominant) MFI of anti-HLA alloantibodies from baseline |  | Up to 30 weeks | 
| Percent change from baseline in the peak (immunodominant) MFI |  | Up to 30 weeks | 
| Percent change from baseline in the sum of MFI of anti-HLA alloantibodies using the SAB assay |  | Up to 30 weeks | 
| Time to first clinically meaningful reduction in anti-HLA alloantibody levels by SAB assay | Defined as peak anti-HLA alloantibody MFI <5,000 or ≥50% reduction | Up to 30 weeks | 
| Time to maximal reduction in anti-HLA alloantibody levels by SAB assay | Defined as peak anti-HLA alloantibody MFI <5,000 or ≥50% reduction | Up to 30 weeks | 
| Maximum reduction in cPRA from baseline |  | Up to 30 weeks | 
| Time to first clinically meaningful reduction in cPRA |  | Up to 30 weeks | 
| Time to maximal reduction in cPRA from baseline |  | Up to 30 weeks | 
| Duration of a reduction in peak anti-HLA alloantibody to MFI <5,000 or by ≥50% by SAB assay |  | Up to 30 weeks | 
| Duration of maximal reduction in anti-HLA alloantibody MFI by SAB assay |  | Up to 30 weeks | 
| Duration of maximal reduction in cPRA by SAB assay |  | Up to 30 weeks | 
| Serum concentration of Immunoglobulin(Ig) classes over time |  | Up to 30 weeks | 
| Percent change from baseline of serum concentration of Ig classes |  | Up to 30 weeks | 
| Concentration of REGN5458 in serum over time |  | Up to 30 weeks | 
| Concentration of REGN5459 in serum over time |  | Up to 30 weeks | 
| Incidence of treatment-emergent REGN5458 anti-drug antibodies (ADA) over time |  | Up to 30 weeks | 
| Incidence of treatment-emergent REGN5459 ADA over time |  | Up to 30 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
kidney transplant, hemodialysis, desensitization