Deborah Brauser

June 20, 2017

BOSTON — The novel serotonin receptor agonist lasmiditan (COL-144, Eli Lilly and Co) is effective and well tolerated for adults with acute migraine, new research suggests.

The phase 3 SAMURAI trial, which included more than 1500 patients, showed that significantly more of those receiving 100 or 200 mg of lasmiditan within 4 hours of a migraine attack had freedom from pain 2 hours after treatment (the primary endpoint) than those who were given matching placebo.

They also had significantly less self-reported "most bothersome symptom" (MBS), such as nausea, phonophobia, or photophobia.

The study drug "selectively targets 5HT-1F receptors in the trigeminal pathway and does not have vasoconstrictive activity, unlike 5-HT (1B/1D) triptan agents," reported Sheena K. Aurora, MD, from Eli Lilly, during her presentation of the results here at the American Headache Society Annual Scientific Meeting (AHS) 2017.

AHS scientific program chair Peter Goadsby, MD, PhD, professor of neurology at King's College London, United Kingdom, and the University of California, San Francisco, noted during a meeting webcast that all physicians will eventually have patients who are not suitable for triptans.

"It's been a question over the past 20 years whether we can develop medicines that didn't constrict blood vessels, and now it looks like that's coming," said Dr Goadsby.

"Lasmiditan doesn't constrict blood vessels, and we're seeing high pain-free rates,” he said. “I think we're soon going to have a new medicine for acute migraine that doesn't have that vascular baggage which has bothered us all."

Headache-Free and Headache Relief

For SAMURAI, the investigators enrolled 1856 patients. The group was 83.6% women; the mean age was 42 years; and 82% had both migraine and at least one cardiovascular (CV) risk factor.

The modified intent-to-treat (mITT) population comprised 1545 patients with a mean Migraine Disability Assessment Score of 31.3, 17.5 mean headache days during the prior 3 months, and mean severity of headache pain rated 7.5 of 10 for the highest level.

The patients in this mITT group were randomly assigned to 100 mg (n = 503) or 200 mg (n = 518) of lasmiditan or to placebo (n = 524). In addition, 35.0%, 28.6%, and 57.8% of the groups, respectively, took a second dose of one of the treatments for rescue.

Not only were patients in both active treatment groups more likely than the placebo group to be headache-pain free (odds ratios [OR], 2.2 and 2.6, respectively) and MBS free (ORs, 1.7 and 1.6) 2 hours after receiving their first dose, but more of them also experienced headache relief, defined as having "mild or no pain."

Table 1. Outcomes After First Dose by Treatment Group

Outcome Lasmiditan 100 mg (%) Lasmiditan 200 mg (%) Placebo (%)
Headache-pain free 28.2 32.2 15.3
MBS free 40.9 40.7 29.5
Headache pain relief 59 59 42.2
All P < .001.

 

"The significant differences between lasmiditan and placebo emerged as early as 1 hour," said Dr Aurora.

Treatment-emergent adverse events (TEAEs) were reported by 36.3%, 42.7%, and 16.4% of the groups, respectively, with most considered to be of mild or moderate severity. In addition, there were no AE-related discontinuations or serious AEs.

The most common TEAEs were dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy.

Table 2. TEAs After First Dose by Treatment Group

TEAE Lasmiditan 100 mg (%) Lasmiditan 200 mg (%) Placebo (%)
Dizziness 12.5 16.3 3.4
Paresthesia 5.7 7.9 2.1
Somnolence 5.7 5.4 2.3
Fatigue 4.1 3.1 0.3
Nausea 3.0 5.3 1.9
Lethargy 1.9 2.5 0.3

 

All but lethargy were also reported after the second dose.

As for CV TEAEs, only palpitations (in 0.3%, 0.7%, and 0 of the groups, respectively) and bradycardia (0.2%, 0, and 0.2%) "were deemed possibly related to the study treatment" after one dose, said Dr Aurora. These incidence rates were similar in the subgroup that had at least 1 CV risk factor.

There were only one report of palpitations, in a patient who took two doses of lasmiditan 100 mg, and one report of tachycardia, in a patient who first took 100 mg of lasmiditan followed by placebo.

Eric Pearlman, MD, PhD, medical lead for headache in the US Medical Affairs Group at Eli Lilly, told Medscape Medical News that this is the first phase 3 trial for this treatment. SPARTAN is looking at 50, 100, and 200 mg of lasmiditan vs placebo, with results expected later this summer; and GLADIATOR is an open-label, long-term safety study that began in December 2015 and is estimated to be completed in 2018.

"We are doing our best to expand the clinician's toolbox, both by medications and in doing our part to help clinicians to understand the huge impact of migraine on patients," said Dr Pearlman.

"Solid Results"

Session moderator Elizabeth Loder, MD, chief of the Division of Headache at Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News that she thought it was interesting that the investigators enrolled some patients who had CV risk factors.

"They mentioned that the most common risk factor was a strong family history of coronary artery disease, and I'd like to know how they defined that. Having a family member with it isn't the same as having a personal cardiovascular risk factor," said Dr Loder.

"But it did look like the medication was well tolerated and separated nicely from placebo" for efficacy, she said. "And they looked at a number of outcomes, including pain free in 2 hours, which matter a lot to patients."

She noted, though, that she was struck by the high placebo rate at 2 hours for pain relief. "That's not the same as pain free, but 40% is high and that seemed interesting to me."

"Overall, I thought these were solid results, although I'm not sure where it will fit into clinical practice," said Dr Loder.

"I know many people think there are a lot of patients for whom triptans may be contraindicated on the basis of cardiovascular risk, but I'm not so sure that's true or that the group that might need this is all that large. But others feel differently," she said.

Still, the investigators showed "solid results for the drug, and it's good to have another option," she added. Also, "this type of research teaches us more about the biology of migraine."

The study was supported by CoLucid Pharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company. Dr Pearlman and Dr Aurora are employees of Eli Lilly. Dr Loder has disclosed no relevant financial relationships.

American Headache Society Annual Scientific Meeting (AHS) 2017. Abstract IOR-11LB. Presented June 10, 2017.

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