Clazakizumab® (Anti-Il-6) for Desensitization of Highly-Hla Sensitized Patients Awaiting Kidney Transplant (Nct03380962)

Vo, Ashley; Ammerman, Noriko; Huang, Edmund; Toyoda, Mieko; Ge, Shili; Peng, Alice; Najjar, Reiad; Williamson, Summer; Myers, C.N.; Sethi, Supreet; Lim, Kathlyn; Choi, Jua; Jordan, Stanley C.

doi:10.1097/01.tp.0000698796.63079.e4

Cited by 9 publications

(8 citation statements)

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“…Clazakizumab has demonstrated an acceptable safety profile when evaluated in other IL-6-related conditions such as rheumatoid arthritis and psoriatic arthritis [ 22 , 23 ]; however, clazakizumab has not yet been approved for any indication. Clazakizumab has recently been investigated in kidney transplant recipients in both the pre-transplant setting as part of a desensitizing regimen [ 9 , 19 , 24 – 26 ] and the post-transplant setting for the treatment of AMR; results from these studies have provided proof-of-concept results supporting further clinical development of clazakizumab [ 27 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

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

Nickerson

Böhmig

Chadban

et al. 2022

Trials

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Background Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. Methods IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. Discussion IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. Trial registration ClinicalTrials.govNCT03744910. Registered on November 19, 2018.

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Section: Introductionmentioning

confidence: 99%

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

Nickerson

Böhmig

Chadban

et al. 2022

Trials

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“…However, upon discontinuation, two of the five transplanted patients developed ABMR, perhaps due to IL‐6 rebound 40 . In contrast, clazakizumab desensitization resulted in similar reduction in DSA without development of ABMR following discontinuation of the drug in phase I/II trial conducted by the same group 41 …”

Section: Discussionmentioning

confidence: 90%

“…40 In contrast, clazakizumab desensitization resulted in similar reduction in DSA without development of ABMR following discontinuation of the drug in phase I/II trial conducted by the same group. 41 Furthermore, clazakizumab-treated patients had higher levels of Tregs following transplant, which may facilitate a robust and longlived protection against ABMR. 42 The induction or lack of suppression of Tregs seen with blockade of the IL-6 pathway may be an advantage over Belatacept, a germinal center-suppressing agent that was paired with CFZ in our group's initial study of dual desensitization therapy.…”

Section: Discussionmentioning

confidence: 99%

Addition of interleukin-6 receptor blockade to carfilzomib-based desensitization in a highly sensitized nonhuman primate model

Anwar

Ezekian

DeLaura

et al. 2022

American Journal of Transplantation

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“…Therefore, the question could arise as to the value of continuing tocilizumab after HLA-incompatible transplantation. To investigate this, a study was conducted using clazakizumab, a monoclonal antibody directed directly against IL-6 and studied in rheumatoid arthritis (not yet marketed) [ 49 ]. Vo et al used clazakizumab as a DES therapy in 10 highly sensitized KTCs receiving IVIg and plasma exchange in parallel.…”

Section: Resultsmentioning

confidence: 99%

Tocilizumab and Desensitization in Kidney Transplant Candidates: Personal Experience and Literature Review

Weinhard

Noble

Jouve

et al. 2021

JCM

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Desensitization (DES) allows kidney transplantation for highly HLA-sensitized subjects. Due to the central role of IL-6 in the immunological response, tocilizumab may improve DES efficacy. Thus, we conducted a PubMed systematic review using the MeSH terms tocilizumab, interleukin-6, kidney transplantation, and desensitization. Tocilizumab (TCZ) was first studied for DES as the second-line treatment after failure of a standard DES protocol (SP) (apheresis, rituximab +/- IVIg). Although TCZ (as a monotherapy) attenuated anti-HLA antibody rates, it did not permit transplantation. However, lymphocyte immuno-phenotyping has shown that TCZ hinders B-cell maturation and thus could improve the long-term efficacy of DES by limiting anti-HLA rebound and so avoid antibody-mediated rejection. This hypothesis is supported by a recent study where clazakizumab, a monoclonal antibody directed against IL-6, was continued after kidney transplantation in association with an SP. Nine out of ten patients were then eligible for transplantation, and there were no donor-specific antibodies at 6 months post-transplantation. In association with an SP, tocilizumab does not seem to significantly improve kidney-allograft access (short-term efficacy) vs. a SP only. However, it could improve the long-term prognosis of HLA-incompatible transplantation by hindering B-cell maturation and, thereby, avoiding donor-specific antibody rebounds post-transplantation.

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Clazakizumab® (Anti-Il-6) for Desensitization of Highly-Hla Sensitized Patients Awaiting Kidney Transplant (Nct03380962)

Cited by 9 publications

References 0 publications

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

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

Addition of interleukin-6 receptor blockade to carfilzomib-based desensitization in a highly sensitized nonhuman primate model

Tocilizumab and Desensitization in Kidney Transplant Candidates: Personal Experience and Literature Review

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