The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

Abstract

More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT 1F receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50-400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient.

Effects of Lasmiditan on Cardiovascular Parameters and Pharmacokinetics in Healthy Subjects Receiving Oral Doses of Propranolol

“…Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT 1F receptor agonist that exerts therapeutic effects in the acute treatment of migraine by decreasing neuropeptide release and inhibiting pain pathways. [1][2][3][4] Lasmiditan has demonstrated efficacy in acute treatment of migraine in phase 3 studies. [5][6][7][8] Data from nonclinical studies 9 suggest that lasmiditan does not induce vasoconstriction, unlike triptans which are commonly prescribed for migraine.…”

“…[5][6][7][8] Data from nonclinical studies 9 suggest that lasmiditan does not induce vasoconstriction, unlike triptans which are commonly prescribed for migraine. [1][2][3][10][11][12][13][14] Inconsistent changes in blood pressure were observed following lasmiditan dosing across the individual studies in the clinical pharmacology program, with increases in systolic blood pressure (SBP) and diastolic blood pressure (DBP) observed in some but not all studies (data on file).…”

The Therapeutic Impact of New Migraine Discoveries

“…Oral administration in a dose of 400 mg showed higher therapeutic gain compared to the intravenous dose of 20 mg [57]. The studies show rapid absorption and a bioavailability of 40% in the case of oral administration [58]. Two ongoing phase 3 and a long-term open-label trial were started in 2015 to test lasmiditan in episodic, disabling migraine [55].…”

“…Due to its different chemical structure and the selective action on the 5-HT 1F receptor, the side effects of lasmiditan are completely different from those of triptans. Dizziness, paresthesia, and vertigo were the most common adverse events reported, predominantly attributable to the presence of 5-HT 1F receptors in the cerebellum and the vestibular nuclei, and also because of the high BBB penetration of lasmiditan [55,58]. On the basis of these, CNS-related side effects can be anticipated following a long-term use of lasmiditan, which might limit its clinical use and delay further studies [59].…”

Trajectory of migraine-related disability following long-term treatment with lasmiditan: results of the GLADIATOR study

“…Lasmiditan is centrally penetrant and evidence suggests that lasmiditan exerts its therapeutic effects in the treatment of migraine by decreasing neuropeptide release and inhibiting pain pathways, potentially including both the trigeminal nerve innervation of the meningeal artery and in the trigeminocervical complex [6]. Lasmiditan lacks the vasoconstrictor activity which arises from the 5-HT 1B effects of triptans [6][7][8][9][10].…”