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.govNCT03744910. Registered on November 19, 2018.

Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade

“…14,45 Thus, IMAGINE is a prognostic biomarker-enriched (HLA-DSA + AMR with cg >0, ie, caAMR) RCT linked to an RLSE (slope of eGFR decline at 1 y) for accelerated approval. 7,44 Furthermore, the eGFR effect size with clazakizumab in phase 2 is consistent with and supports the surrogate eGFR endpoint for the IMAGINE study. 42 Table 1 lists the inclusion and exclusion criteria and Table 2, the primary and secondary endpoints.…”

“…Importantly, the FDA has agreed to consider an RLSE for accelerated approval, enabling the study to be both informative and feasible. 47 Finally, we have a manufacturer and sponsor (CSL Behring 44 ) committed to completing the study. 7 The partnership between the government, academia, FIGURE 1.…”

Early Versus Late Acute AMR in Kidney Transplant Recipients—A Comparison of Treatment Approaches and Outcomes From the ANZDATA Registry

“…The complement inhibitor eculizumab, which initially evoked enthusiasm on the basis of nonrandomized study, results in preventing AMR but it failed to demonstrate efficacy in this context in a randomized placebo-controlled trial. 18,36,37 The anti-interleukin-6 antibody, Clazakizumab (clinicaltrials.gov ID NCT03380962, NCT03744910), 43,44 which also has promising results from preliminary case series, is currently under investigation in a randomized placebo-controlled trial. 40 Another promising agent IgG-degrading enzyme of Streptococcus pyogenes is undergoing assessment in the prevention and treatment of early AMR (clinicaltrials.gov ID NCT02475551).…”

New treatment for antibody-mediated rejection: interleukin-6 inhibitors

“…Notably, the decision to halt the study was not due to safety concerns. Clearly, a continued need exists to seek effective treatments for transplant recipients at risk of allograft failure, and this must be done in a robust manner that facilitates clear decision-making [ 20 , 22 ].…”