Pharmacokinetic and Pharmacodynamic Modeling of LY2951742, a Calcitonin Gene Related Peptide Antibody, in Migraine Patients (P6.091)

Objective: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of LY2951742, a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP), in migraine patients. Background:LY2951742 is being developed for the prevention of migraine. CGRP is implicated in the pathophysiology of migraine and is hypothesized to be involved in the release of inflammatory mediators and the transmission of nociceptive signals. Methods: A phase 2b, randomized, double-blind, placebo-controlled, 12-week treatment phase study of LY2951742 in patients with episodic migraine was conducted at doses of 5 mg, 50 mg, 120 mg and 300 mg given subcutaneously every 28 days. Blood samples were collected to measure LY2951742 and CGRP concentrations. The change from baseline in the number of migraine headache days (MHD) over a 28-day period was assessed in placebo and LY2951742-treated patients. Results: Interim data indicate LY2951742 concentrations increased linearly, but CGRP concentrations increased nonlinearly, with dose. Direct response population PKPD models were developed to characterize the relationship of LY2951742 with CGRP and change in MHD. For PK, LY2951742 apparent clearance of 0.0099 L/h and apparent volume of distribution of 8 L was estimated using a 1-compartment PK model. For PD, baseline CGRP concentration of 0.009 nM, LY2951742 EC50 of 94 nM, CGRP Emax of 1.2 nM and gamma of 0.8 were estimated using a sigmoidal Emax model. Maximum placebo effect of - 3.5 MHD difference from baseline was estimated using an exponential decay model. Baseline MHD (prior to LY2951742 treatment) of 6 days per 28-day period, LY2951742 EC50 of 57 nM and LY2951742 Emax of - 1.25 MHD difference from placebo were estimated using an Emax model. Conclusions: PKPD modeling characterized the relationship of LY2951742 with clinical response on the basis of CGRP (target engagement) and MHD (efficacy) and can be used to aid in dose selection for subsequent clinical trials. Disclosure: Dr. Kielbasa has nothing to disclose. Dr. Quinlan has nothing to disclose. Dr. Bell has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Skljarevski has nothing to disclose.