P4371 - Mirikizumab Pharmacokinetics and Exposure-Response Relationships in Patients With Moderately to Severely Active Crohn’s Disease in Phase 2 and 3 Studies

Laiyi Chua, , Yuki Otani, , Stuart Friedrich, , Frederick Durand, , Xin Zhang,
Eli Lilly and Company, Indianapolis, IN

Introduction: Mirikizumab (MIRI) is approved for ulcerative colitis (UC) and showed efficacy for Crohn’s disease (CD) in Phase 2 (AMAG) and Phase 3 (VIVID-1) trials. This analysis characterized MIRI pharmacokinetic (PK) properties and exposure-response (ER) relationships in adults with moderately to severely active CD using data from 2 trials.

Methods: Patients received 12-week MIRI induction (200/600/1000 mg [AMAG] or 900 mg [VIVID-1] intravenously [IV] every 4 weeks [Q4W]), followed by MIRI maintenance (200/600/1000 mg IV [AMAG], or 300 mg administered subcutaneously (SC) [AMAG and VIVID-1] Q4W) up to Week (W)52. PK parameters were estimated by non-linear mixed-effects modeling. Covariate effects on MIRI exposure were evaluated using simulation-based estimations. The exposure efficacy model included data from participants who had model-predicted average drug concentration during multiple dosing. Clinical efficacy at W12 was compared with AMAG graphically and models were conducted on primary endpoints. ER for patients achieving endoscopic response by Simple Endoscopic Score for CD (SES-CD) at W12 and W52 were assessed using logistic regression models.

Results: MIRI PK was best described by a linear two-compartment model with first-order absorption. Population (PopPK) model-estimated parameters were consistent across both trials (Table). AMAG indicated a near-maximal efficacy for doses between 600 and 1000 mg IV for endoscopic response by SES-CD at W12, suggesting that 900 mg IV in VIVID-1 would produce near-maximal effect for W12 endpoints. Linear relationships between exposure and W12 endoscopic response by SES-CD best described observed data in VIVID-1. In AMAG, model-based analyses of the relationships between exposure and W52 efficacy measures showed no ER trend across MIRI maintenance doses, supporting 300 mg SC Q4W for VIVID-1 Maintenance Period. Linear relationships between exposure and endoscopic response by SES-CD on a logistic scale best described observed data in VIVID-1 at W52. None of the covariates evaluated in PK/ER modelling were considered clinically relevant.

Discussion: The MIRI PK characteristics were consistent with UC studies and typical of monoclonal antibodies. MIRI induction dose of 900 mg IV at W0, W4, and W8 followed by maintenance dose of 300 mg SC Q4W resulted in near-maximal efficacy in VIVID-1. The findings support MIRI dosing regimen proposed for moderately to severely active CD. PK and ER data suggested that no adjustments based on patient factors are warranted.


Disclosures:


Laiyi Chua, , Yuki Otani, , Stuart Friedrich, , Frederick Durand, , Xin Zhang, . P4371 - Mirikizumab Pharmacokinetics and Exposure-Response Relationships in Patients With Moderately to Severely Active Crohn’s Disease in Phase 2 and 3 Studies, ACG 2024 Annual Scientific Meeting Abstracts. Philadelphia, PA: American College of Gastroenterology.