Clazakizumab for Kidney Transplant Rejection

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stanley Jordan, MD

Must not be taking: Live vaccines, Investigational agents

Disqualifiers: HIV, HBV, HCV, TB, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot participate if you have used investigational agents within 4 weeks of the trial or if you have had a recent infection requiring antibiotics.

What data supports the effectiveness of the drug Clazakizumab for kidney transplant rejection?

Clazakizumab has shown promise in early studies for kidney transplant rejection by reducing harmful antibodies and stabilizing kidney function. In a pilot study, it helped highly sensitized patients receive transplants by lowering antibody levels, suggesting it could be effective in managing rejection. ^{1 2 3 4 5}

How is the drug clazakizumab different from other treatments for kidney transplant rejection?

Clazakizumab is unique because it is a monoclonal antibody that specifically targets interleukin-6, reducing inflammation and donor-specific antibodies, which are key factors in chronic active antibody-mediated rejection. Unlike other treatments, it offers a novel approach by directly modulating the immune response, and there are currently no approved drugs for this condition, highlighting its potential as a new therapeutic option. ^{1 2 4 6 7}

What is the purpose of this trial?

Patients who have had a previous allograft failure represent a major problem for transplant centers as they are highly-human leukocyte antigen (HLA) sensitized and unlikely to receive another transplant without significant desensitization. This single center, phase I/II, open label single-arm exploratory study focuses on enrolling twenty patients (ages 15-75) who will begin desensitization therapy to achieve HLA incompatible (HLAi) renal transplantation. Patients who qualify will receive up to 6 doses of clazakizumab 25 mg monthly pre-transplantation. If patients receive an HLAi transplant during the study, the participants will continue to receive another 6 monthly doses of clazakizumab 25 mg, followed by a 6 month protocol biopsy. Patients will continue another 6 doses over 6 months if improvements are seen after the 6th dose of clazakizumab. Patients who develop evidence of persistent allograft dysfunction may have non-protocol biopsies for cause. Patients who receive 12 doses of clazakizumab post-transplant will receive a 12M protocol biopsy.

Research Team

Stanley Jordan, MD

Principal Investigator

Cedars-Sinai Medical Center Comprehensive Transplant Center

Eligibility Criteria

This trial is for highly-HLA sensitized patients aged 15-75 awaiting a kidney transplant, who have had previous allograft failure, pregnancies, transfusions or transplants. They must be on the UNOS list with a cPRA≥50%, vaccinated against pneumococcus and TB-free. It excludes those intolerant to IL-6 inhibitors, pregnant or lactating women, HIV/HBV/HCV positive individuals, recent live vaccine recipients and those with certain infections or malignancies.

Inclusion Criteria

I am a highly sensitized patient waiting for a kidney transplant.

I am between 15 and 75 years old.

I have had pregnancies, blood transfusions, or a kidney transplant.

Exclusion Criteria

I cannot tolerate clazakizumab or similar medications.

I have tested positive for hepatitis B or C.

I have an active CMV or EBV infection confirmed by blood tests.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Desensitization Treatment

Participants receive up to 6 doses of clazakizumab 25 mg monthly pre-transplantation for desensitization

6 months

6 visits (in-person)

Post-Transplant Treatment

Participants who receive an HLAi transplant continue to receive 6 doses of clazakizumab monthly post-transplantation

6 months

6 visits (in-person)

Extended Treatment

Participants may continue to receive another 6 doses of clazakizumab if improvements are seen after the 6th dose post-transplant

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including protocol biopsies at 6 and 12 months post-transplant

12 months

Treatment Details

Interventions

• Clazakizumab

Trial Overview The study tests Clazakizumab in patients needing desensitization before a kidney transplant. Participants will receive up to six monthly pre-transplant doses of Clazakizumab (25 mg), continuing post-transplant if successful. The treatment aims to improve chances of receiving an HLA incompatible renal transplant and reduce rejection.

Participant Groups

Group I: Clazakizumab Experimental Treatment 1 Intervention

All twenty patients will receive clazakizumab monthly. Patients will receive up to 6 doses pre-transplantation. If patients are transplanted during the study, they will then receive 6 doses of clazakizumab (monthly) and a 6 month protocol biopsy will be performed. Based on the biopsy results and clinical labs PI will determine if patients should continue monthly doses for up to another 6 doses and day 330 post-transplantation. Patients who received 12 post-transplant doses of clazakizumab will then undergo a 12 month protocol biopsy.

Who Is Running the Clinical Trial?

Stanley Jordan, MD

Lead Sponsor

Trials

4

Recruited

90+

Findings from Research

The Phase 3 IMAGINE study is the first large-scale trial evaluating clazakizumab, a monoclonal antibody targeting interleukin-6, for treating chronic active antibody-mediated rejection (AMR) in approximately 350 kidney transplant recipients.

Clazakizumab aims to reduce donor-specific antibody production and stabilize kidney function, with the trial using the eGFR slope as a key measure to predict graft loss, potentially leading to faster approval of new treatments for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design. Nickerson, PW., Böhmig, GA., Chadban, S., et al.[2022]

Clazakizumab, an anti-IL-6 treatment, was well tolerated in a pilot study of 20 highly HLA-sensitized patients, leading to significant reductions in HLA alloantibodies and enabling 18 out of 20 patients to successfully receive transplants without a rebound of donor-specific antibodies.

The treatment was associated with an increase in regulatory immune cells post-transplant, although antibody-mediated rejection occurred in three patients, indicating that while clazakizumab shows promise for desensitization, further randomized controlled trials are needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clazakizumab for desensitization in highly sensitized patients awaiting transplantation. Vo, AA., Huang, E., Ammerman, N., et al.[2023]

In a study of 27 kidney transplant patients with severe, steroid-resistant rejection, treatment with rituximab led to significant improvements in kidney function, as indicated by a decrease in serum creatinine levels from 5.6 mg/dL to 0.95 mg/dL at discharge.

Only three patients experienced graft loss not related to patient death during a follow-up period of about 605 days, suggesting that rituximab may effectively help reverse rejection episodes and improve transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab as treatment for refractory kidney transplant rejection. Becker, YT., Becker, BN., Pirsch, JD., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design. [2022]

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

Clazakizumab for desensitization in highly sensitized patients awaiting transplantation. [2023]

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

Regimen of tacrolimus-based immunosuppression with basiliximab, mycophenolate mofetil, and low-dose steroid reduces acute rejection in kidney transplants. [2018]

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

Rituximab as treatment for refractory kidney transplant rejection. [2023]

5. Spain pubmed.ncbi.nlm.nih.gov

[Immunosuppression and surgical complications after renal transplantation]. [2021]

6. Turkey pubmed.ncbi.nlm.nih.gov

Anti-Interleukin 6 Therapeutics for Chronic Antibody-Mediated Rejection In Kidney Transplant Recipients. [2022]

7. Turkey pubmed.ncbi.nlm.nih.gov

Treatment of antibody-mediated rejection in kidney transplant recipients: a single-center experience with a bortezomib-based regimen. [2019]