REGN5459 + REGN5458 for Transplant-Ready Chronic Kidney Disease

Recruiting in Palo Alto (17 mi)

+15 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Regeneron Pharmaceuticals

Must not be taking: Corticosteroids, Calcineurin inhibitors, Anti-CD20

Disqualifiers: Malignancy, CNS disorders, Asplenia, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests the safety of two experimental drugs, REGN5459 and REGN5458, in kidney disease patients who need a transplant but have high antibody levels that make finding a donor difficult. The drugs work by lowering these antibodies to improve donor compatibility.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. Specifically, you must not have used investigational agents within 8 weeks, calcineurin inhibitors within 30 days, or certain other treatments like cyclophosphamide or rituximab within 12 months before starting the study drug.

Is the BCMAxCD3 bispecific antibody (REGN5458) safe for humans?

In studies with monkeys, the BCMAxCD3 bispecific antibody (REGN5458) was generally well tolerated, causing only mild inflammatory responses like temporary increases in certain proteins and cytokines (small proteins important in cell signaling). ^{1 2 3 4 5}

What makes the drug REGN5459 + REGN5458 unique for treating transplant-ready chronic kidney disease?

REGN5459 + REGN5458 is unique because it involves a bispecific antibody that targets BCMA (B-cell maturation antigen) and CD3, potentially offering a novel mechanism to modulate the immune response in kidney transplantation, which is different from traditional immunosuppressive drugs that primarily target T cells. ^{6 7 8 9 10}

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

This trial is for adults with chronic kidney disease who need a kidney transplant and are highly sensitized to human leukocyte antigen (HLA). They must be on hemodialysis, have been waiting for a transplant with a cPRA ≥99.9%, or have a cPRA >98% if they've been on the waitlist for over 5 years. Participants should not have active cancer, history of certain treatments, recent vaccinations, or specific medical conditions.

Inclusion Criteria

I have severe CKD, need dialysis, am on the UNOS waitlist for a kidney, and have a high cPRA score.

My blood and liver tests meet the study's requirements.

Willing and able to comply with clinic visits and study-related procedures

Exclusion Criteria

I have not had treatments targeting BCMA for my cancer.

Your blood test shows very low levels of a specific protein called IgG.

I have no history of brain disorders or movement issues.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive vonsetamig to decrease anti-HLA antibodies for kidney transplantation

78 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• REGN5458 (Monoclonal Antibodies)
• REGN5459 (Monoclonal Antibodies)

Trial Overview The study tests REGN5459 (Part A) and REGN5458 (Part B) as potential treatments to reduce anti-HLA alloantibody levels in patients awaiting kidney transplants. It aims to find effective doses, understand how long the drugs work, their impact on immune system proteins, and overall safety.

Participant Groups

Group I: Vonsetamig Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Findings from Research

A novel platform was developed to create tetravalent bispecific antibodies (BsAbs) that effectively target CD5 and HLA-DR, showing good specificity and affinity, which is crucial for targeted cancer therapies.

The best-performing bispecific antibody, CD5xDR-CR3, demonstrated significant therapeutic activity in a human leukemia xenograft model, indicating its potential for effective treatment in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies. Golay, J., Choblet, S., Iwaszkiewicz, J., et al.[2016]

Patients with CRLF2-rearranged B-ALL show high levels of TSLPR expression, making it a promising target for therapy alongside CD19.

The novel bispecific antibody 1B7/CD3 effectively activates T cells and induces tumor remission in preclinical models, demonstrating a favorable safety profile with a maximum tolerated dose of ≤1 mg/kg in cynomolgus monkeys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL. Tian, Z., Shi, C., Yang, G., et al.[2023]

The bispecific F(ab')2, combining anti-CD3 and anti-P-glycoprotein antibodies, significantly enhanced the ability of human immune cells (PBMCs) to kill P-glycoprotein-positive kidney cancer cells, indicating its potential as a targeted cancer therapy.

This bispecific approach did not affect the immune response against P-glycoprotein-negative cancer cells, suggesting a specific mechanism of action that could be beneficial for treating multidrug-resistant cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmentation by bispecific F(ab')2 reactive with P-glycoprotein and CD3 of cytotoxicity of human effector cells on P-glycoprotein positive human renal cancer cells. Heike, Y., Okumura, K., Tsuruo, T.[2019]

Research into spontaneously tolerant kidney transplant recipients has revealed potential biomarkers related to B-cell subsets that could help personalize immunosuppressive therapy, reducing side effects and costs.

These findings suggest that understanding the regulatory mechanisms of B cells in tolerance could lead to new therapies that improve long-term outcomes for kidney transplant patients, but further large-scale studies are needed to confirm these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. Baron, D., Giral, M., Brouard, S.[2021]

Kidney transplant recipients treated with belatacept showed better kidney function and lower rates of donor-specific anti-HLA immunization compared to those treated with traditional calcineurin inhibitors (CNI), based on Phase III clinical studies.

In a study of 13 belatacept-treated patients, there was a significant increase in transitional and naïve B cells, along with lower levels of B cell activating factor (BAFF), suggesting that belatacept may promote a more favorable B cell environment that could help reduce alloimmunization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kidney transplant recipients treated with belatacept exhibit increased naïve and transitional B cells. Leibler, C., Matignon, M., Pilon, C., et al.[2023]

Recent advancements in antibody detection and elimination techniques, along with therapeutic agents like bortezomib and eculizumab, have improved management options for highly sensitized kidney transplant patients.

Despite these advancements, the increasing number of human leukocyte antigen-mismatched transplants and the ongoing challenge of controlling donor-specific antibody production mean that sensitization remains a significant issue in kidney transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current approaches to the management of highly sensitized kidney transplant patients. Süsal, C., Morath, C.[2011]

In a multicenter study of kidney transplant patients, 25-30% were predicted to be tolerant at any given time, with 13.7% consistently showing a B cell receptor 'signature' associated with tolerance over a 2-year period.

Patients with this tolerance 'signature' experienced significant improvements in kidney function, as measured by estimated glomerular filtration rate, suggesting that B cells may play a crucial role in the survival and function of transplanted kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function. Asare, A., Kanaparthi, S., Lim, N., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies. [2016]

2. United States pubmed.ncbi.nlm.nih.gov

Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL. [2023]

4. Japan pubmed.ncbi.nlm.nih.gov

Augmentation by bispecific F(ab')2 reactive with P-glycoprotein and CD3 of cytotoxicity of human effector cells on P-glycoprotein positive human renal cancer cells. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

A BCMAxCD3 bispecific T cell-engaging antibody demonstrates robust antitumor efficacy similar to that of anti-BCMA CAR T cells. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Kidney transplant recipients treated with belatacept exhibit increased naïve and transitional B cells. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Current approaches to the management of highly sensitized kidney transplant patients. [2011]

9. United States pubmed.ncbi.nlm.nih.gov

B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Harnessing the B Cell Response in Kidney Transplantation - Current State and Future Directions. [2023]