REGN5459 + REGN5458 for Transplant-Ready Chronic Kidney Disease

Recruiting at 17 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Regeneron Pharmaceuticals

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

Disqualifiers: Malignancy, CNS disorders, Asplenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 78 weeks

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called vonsetamig (also known as REGN5459) for people with chronic kidney disease awaiting a transplant. The researchers aim to determine if vonsetamig can safely lower specific antibodies that hinder finding a matching kidney. The trial will also assess any side effects and how the drug behaves in the body. Suitable participants include those on dialysis, on the kidney transplant waitlist, and with high levels of certain antibodies (cPRA ≥99.9% or cPRA >98% with a 5-year wait). As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking medical advancements.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that vonsetamig, a combination of the drugs REGN5459 and REGN5458, is being tested for safety in individuals needing kidney transplants. This treatment aims to reduce high levels of antibodies against HLA, which can pose challenges for transplant patients. Studies have found that REGN5459 has manageable side effects and promising results in patients with multiple myeloma, a type of blood cancer. Similarly, REGN5458 has been tested for safety in patients with the same condition, showing good outcomes and response rates.

The trials for vonsetamig are in the early stages. While some evidence suggests it is safe, more research is needed to confirm this. Early findings indicate that the treatment is generally well-tolerated, though participants may still experience some side effects. Further studies will help clarify the safety of vonsetamig for those awaiting kidney transplants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about REGN5458 and REGN5459 for chronic kidney disease because they represent a novel approach to treatment. Unlike current therapies, which often manage symptoms or slow progression with medications like ACE inhibitors or ARBs, these new treatments target specific pathways involved in the disease process. REGN5458 and REGN5459 are designed to modulate immune responses more precisely, potentially offering better protection for kidney function and preparing patients for transplants more effectively. This targeted action could mean improved outcomes and fewer side effects, making these treatments a promising advancement in chronic kidney disease care.

What evidence suggests that vonsetamig could be an effective treatment for chronic kidney disease?

Research has shown that the drugs REGN5459 and REGN5458 might help lower certain antibodies in patients needing a kidney transplant. In this trial, participants will receive a combination of REGN5459 and REGN5458. Earlier studies found that REGN5459 can quickly and effectively reduce these antibodies, while REGN5458 helped 75% of patients achieve positive results. These treatments target specific proteins that produce antibodies, potentially enabling kidney transplants for patients previously considered too risky. Early results are promising, but further research is needed to confirm the long-term effectiveness of these treatments. ^{1 4 6 7 8}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• REGN5458
• REGN5459

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

Antibody-mediated rejection (ABMR), primarily driven by B cells, is a major cause of chronic kidney transplant failures, highlighting the need for better treatment strategies.

Currently, there are no FDA-approved therapies specifically for ABMR, but ongoing clinical trials are exploring new regimens to improve outcomes for kidney transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harnessing the B Cell Response in Kidney Transplantation - Current State and Future Directions. Anwar, IJ., DeLaura, IF., Gao, Q., et al.[2023]

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]

A new anti-CD3 antibody was discovered that shows significantly lower cytokine release while still effectively killing tumor cells, which could reduce toxic side effects in patients.

This antibody can be used in a next-generation T-cell-recruiting bispecific antibody (T-BsAb) platform, allowing for potent tumor targeting without the high cytokine release typically associated with these therapies, potentially improving their safety and efficacy in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies. Trinklein, ND., Pham, D., Schellenberger, U., et al.[2020]

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]

The fully human bispecific antibody REGN5458, which targets B-cell maturation antigen (BCMA) and CD3, effectively induces T-cell killing of multiple myeloma cells and shows strong antitumor activity in mouse models, demonstrating its potential as a rapid therapeutic option.

In head-to-head comparisons, REGN5458 cleared tumors more quickly than anti-BCMA CAR T cells, suggesting that bispecific antibodies can engage existing T cells at the tumor site for immediate action, while CAR T cells require time to activate and expand before they can attack the tumor.

NCBI (Pubmed)

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. DiLillo, DJ., Olson, K., Mohrs, K., et al.[2021]

Citations

1. withpower.com withpower.com/clinical-trials/for-kidney-transplant?page=2

Top Kidney Transplant Clinical Trials | Power REGN5459 + REGN5458 for Transplant-Ready Chronic Kidney Disease. Minneapolis ... The drug already has data showing both safety and effectiveness. As a ...

2. investor.regeneron.com investor.regeneron.com/news-releases/news-release-details/new-regn5458-bcmaxcd3-phase-1-data-show-75-response-rate-highest/

New REGN5458 (BCMAxCD3) Phase 1 Data Show 75% ... In results presented at ASH today, 73 patients were treated with REGN5458 doses ranging from 3-800 mg for up to 21 months at the time of data cutoff. Patients ...

3. experts.umn.edu experts.umn.edu/en/projects/a-dose-escalation-and-proof-of-concept-study-of-regn5459-or-regn5

A DOSE ESCALATION AND PROOF-OF-CONCEPT ... A DOSE ESCALATION AND PROOF-OF-CONCEPT STUDY OF REGN5459 OR REGN5458 (BCMA ? CD3 BISPECIFIC ANTIBODIES) FOR DESENSITIZATION OF CHRONIC KIDNEY DISEASE PATIENTS ...

4. aging.networkofcare.org aging.networkofcare.org/riverside/CommunityResources/ClinicalTrials?keyword=%22Chronic%20Kidney%20Disease%20%28CKD%29%22

Riverside Clinical Trials KNOW-CKD (KoreaN cohort study for Outcome in patients With Chronic Kidney Disease) is a nation-wide, ten-year longitudinal cohort study, launched in 2011.

5. withpower.com withpower.com/trial/phase-2-kidney-diseases-2022-5a8fc

REGN5459 + REGN5458 for Transplant-Ready Chronic ... 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.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05092347

NCT05092347 | A Study to Learn How Safe and Tolerable ... The purpose of this study is to determine whether vonsetamig will safely decrease anti-HLA antibodies to allow for kidney transplantation.

7. researchgate.net researchgate.net/publication/365812932_Updated_Safety_and_Efficacy_of_REGN5458_a_BCMAxCD3_Bispecific_Antibody_Treatment_for_RelapsedRefractory_Multiple_Myeloma_A_Phase_12_First-in-Human_Study

Updated Safety and Efficacy of REGN5458, a BCMAxCD3 ... Updated Safety and Efficacy of REGN5458, a BCMAxCD3 Bispecific Antibody, Treatment for Relapsed/Refractory Multiple Myeloma: A Phase 1/2 First-in-Human Study.

8. myeloma.org myeloma.org/videos/early-deep-durable-responses-regn5458-first-human-study-patients-rrmm

Early, Deep, and Durable Responses with REGN5458, in a ... Updated safety, overall response and response durability in patients treated with REGN5458 in the Phase 1 portion of this ongoing trial are ...