Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist intended for the acute treatment of migraine attacks. Ubrogepant has a chemical structure distinct from previous small-molecule CGRP receptor antagonists that were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report overall and hepatic safety data from two placebo-controlled phase I trials of ubrogepant, spray-dried oral compressed tablet (SD-OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK) trial of single (100-400 mg) and multiple (40-400 mg) ascending doses. Trial B was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported. Ubrogepant was well-tolerated in both trials, with a low incidence of adverse events that did not differ greatly from placebo. Changes in mean ALT levels were minimal and similar to placebo. Over 28 days of treatment, the mean percentage change in ALT from baseline was < 5% at all time points. No participant in either trial demonstrated ALT ≥ 3× upper limit of normal at any time. Ubrogepant SD-OCT demonstrated linear PK appropriate for acute treatment of migraine, with rapid uptake (time of maximum plasma concentration (t max ): 2-3 hours) and no accumulation with daily use. Overall, there was no evidence of ubrogepant-associated hepatotoxicity with daily doses up to 400 mg for 10 days or with daily ubrogepant 150 mg for 28 days. Supratherapeutic dosing is a useful strategy for characterizing hepatic safety in early drug development.Migraine is a highly prevalent neurological disease characterized by recurrent attacks of unilateral and pulsating headaches, which are often accompanied by other debilitating symptoms, including nausea, photophobia, and/or phonophobia. [1][2][3] Migraine is associated with a high personal, familial, and societal burden. [4][5][6][7][8] During migraine attacks, activation of the trigeminovascular system leads to increased release of vasoactive neuropeptides, including calcitonin gene-related peptide (CGRP) and substance P, as well as nitric oxide, resulting in meningeal blood vessel vasodilation. 3 The principal goals of acute treatment for migraine attacks are to provide rapid and durable relief of headache pain and associated symptoms while preventing recurring attacks and restoring the ability to function. 2,9 However, despite the widespread availability of acute treatment options for migraine, treatment optimization remains difficult or impossible for many individuals due to limited effectiveness, poor tolerability,

Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations, which were used to inform the phase III dose-selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one phase II trial. A population pharmacokinetic model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from phase II to phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the phase III clinical trials. Migraine is a highly prevalent, disabling, and complex neurologic disorder characterized by debilitating headaches in conjunction with gastrointestinal and sensory alterations. 1-3 Calcitonin gene-related peptide (CGRP) is the most abundant neuropeptide in the trigeminal nerve and plays a key role in migraine pathogenesis. 3-5 Proof-of-concept for CGRP receptor antagonists (CGRP-RA) as potentially effective migraine treatment has been demonstrated with several compounds, including olcegepant (BIBN 4096), telcagepant (MK-0974), and MK-3207. 6-8 However, clinical development of both telcagepant and MK-3207 was stopped due to elevations in liver transaminase levels in a small number of patients. In a phase II clinical trial, ubrogepant (MK-1602), an oral, chemically distinct CGRP-RA, demonstrated efficacy without evidence of drug-induced liver injury when administered as a single dose. 9 The efficacy of ubrogepant was subsequently confirmed in two phase III trials (ACHIEVE I and ACHIEVE II), where clinical doses of 25, 50, and 100 mg were associated with improved efficacy compared with placebo. 10-12 Although clinical dose selection represents a challenge for any drug-development program, clinical dose selection for ubrogepant was further complicated by: (i) difficulty in