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

Abstract

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.gov NCT03744910 . Registered on November 19, 2018.

Keywords: Chronic active antibody-mediated rejection; Clazakizumab; Estimated glomerular filtration rate; Kidney transplantation.

Fig. 1

IMAGINE study design. BL, baseline; cAMR, chronic active antibody-mediated rejection; EOS, end of study; eGFR, estimated glomerular filtration rate; Q4W, once every 4 weeks; SC, subcutaneous

Fig. 2

IMAGINE study schedule of events for year 1. ^aAEs occurring during the Screening Period are to be recorded as Medical History. Any AE that meets the definition of a SAE must also be reported to CSL Behring (or its delegate: e.g., CRO) within 24 h of site awareness. AE, adverse event; BKV, polyoma BK virus; BL, baseline; CBC, complete blood count; CMV, cytomegalovirus; CNI, calcineurin inhibitor; DSA, donor-specific antibodies; EBV, Epstein–Barr virus; ECG, electrocardiogram; eGFR, estimated glomerular fibrillation rate; EOT, end of treatment; EQ-5D-5L, EuroQOL-5 dimensions, 5 levels questionnaire; FACIT, Functional Assessment of Chronic Illness Therapy; hsCRP, high-sensitivity C-reactive protein; IgG, immunoglobulin G; IL-6, interleukin-6; KDQoL-36, Kidney Disease Quality of Life 36-Item Short-Form Survey; MFI, mean fluorescence intensity; MMF, mycophenolate mofetil; MPA, mycophenolic acid; PCR, polymerase chain reaction; Q4W; once every 4 weeks; SAE, serious AE; SC, subcutaneous; UACR, urine albumin-to-creatinine ratio; wk, week