NCT02028065.

Suvorexant is a dual orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia at a maximum dose of 20 mg. This randomized double-blind crossover study evaluated the abuse potential of suvorexant in 36 healthy recreational polydrug users with a history of sedative and psychedelic drug use. Single doses of suvorexant (40, 80, and 150 mg: 2-7.5 × maximum dose), zolpidem (15 and 30 mg: 1.5-3 × maximum dose), and placebo were administered, with a 10-day washout between treatments. Subjective and objective measures, including visual analog scales (VASs), Addiction Research Center Inventory, and cognitive/psychomotor tests, were evaluated for 24-hour postdose. Suvorexant had significantly greater peak effects on "drug liking" VAS (primary endpoint) than placebo. Although effects of suvorexant on abuse potential measures were generally similar to zolpidem, they remained constant across doses, whereas zolpidem often had greater effects at higher doses. Suvorexant (all doses) had significantly fewer effects than zolpidem 30 mg on secondary measures, such as "high" VAS, Bowdle VAS, and Addiction Research Center Inventory morphine-benzedrine group. The overall incidence of abuse-related adverse events, such as euphoric mood and hallucination, was numerically lower with suvorexant than zolpidem. In agreement with its classification as a schedule IV drug, suvorexant demonstrated abuse potential, compared with placebo. The abuse potential was similar to zolpidem using certain measures, but with a reduced incidence of abuse-related adverse events. Although this suggests that the overall abuse liability of suvorexant may be lower than zolpidem, the actual abuse rates will be assessed with the postmarketing experience.

A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervous system efficacy in epilepsy and tremor models, as well as significant effects on rat active wake as measured by electrocorticogram.

Atogepant is a potent, selective, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once‐daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double‐blind, placebo‐controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty‐four participants aged 23–55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well‐tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half‐life of ~ 11 hours, and no evidence of accumulation after once‐daily dosing. Overall, atogepant at a high oral dose is safe and well‐tolerated in healthy participants with no clinically meaningful elevations in ALT.

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,