Mirikizumab Pharmacokinetics and Exposure-Response in Patients With Moderately-To-Severely Active Crohn's Disease: Results From Two Randomized Studies.

Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody approved for both moderately-to-severely active ulcerative colitis and moderately-to-severely active Crohn's disease (CD). We characterized pharmacokinetics (PK) and exposure-response (ER) of mirikizumab in relation to efficacy and safety in CD using data from randomized phase 2 SERENITY (NCT02891226) and phase 3 VIVID-1 (NCT03926130) trials. Patients received 12-week mirikizumab induction (200, 600, or 1000 mg [SERENITY] or 900 mg [VIVID-1] intravenously [IV]) or placebo, every 4 weeks (Q4W), then maintenance (200, 600, or 1000 mg IV [SERENITY], 300 mg subcutaneously (SC) [SERENITY and VIVID-1], or placebo, Q4W) to Week 52. PK and ER for efficacy were analyzed using population PK and logistic regression models for Weeks 12 and 52 endpoints, respectively, and included analyses of covariate effects. Mirikizumab PK was best described by a two-compartment model, with first-order absorption for SC maintenance doses. Body weight, body mass index, serum albumin concentration, C-reactive protein, and disease severity had statistically significant effects on PK, while body weight and disease severity affected ER; these effects were not considered clinically relevant. Efficacy results of 900 mg mirikizumab in VIVID-1 aligned with SERENITY, which observed near-maximal efficacy at Week 12 with 600-1000 mg mirikizumab IV. Efficacy at Week 52 did not vary markedly with exposure during maintenance. There was no significant association between exposure and adverse events. These results support the selection of 900 mg mirikizumab IV Q4W for induction and 300 mg SC Q4W for maintenance in patients with CD, with no dose adjustment for patient factors required.