Clazakizumab in the treatment of chronic active antibody-mediated kidney transplant rejection: Results from the IMAGINE phase 3, randomized, double-blind, placebo-controlled study.

Chronic active antibody-mediated rejection (caAMR) is a leading cause of kidney allograft loss; there are no approved therapies. Clazakizumab binds interleukin-6 and was associated with reduced donor-specific antibodies and stabilized estimated glomerular filtration rate (eGFR) in kidney transplantation (KTx) recipients with caAMR in a phase 2 study. We report the final analysis from the phase 3 Interleukin-6 Blockade Modifying Antibody-mediated Graft Injury and Estimated Glomerular Filtration Rate Decline (IMAGINE) trial, the largest placebo-controlled study in KTx recipients with caAMR. KTx recipients were randomized 1:1 to clazakizumab (12.5 mg subcutaneous every 4 weeks) or placebo. One-year interim analysis of eGFR (N = 115) indicated that the trial was unlikely to meet the primary outcome (time to all-cause allograft loss or irreversible loss of allograft function), resulting in early termination. In the final analysis (N = 191), least-squares mean eGFR change from baseline to week 52 (95% confidence interval) for clazakizumab was -8.0 mL/min/1.73 m2 (-10.2, -5.8) vs -5.2 mL/min/1.73 m2 (-7.4, -3.1) for placebo (P = .959). Allograft loss or irreversible loss of allograft function was experienced by 28.3% and 22.2% of patients treated with clazakizumab and placebo, respectively. Reduced C-reactive protein was observed with treatment. No safety concerns were noted. In conclusion, interleukin-6 blockade with clazakizumab did not translate into improvement in eGFR in KTx recipients with caAMR.