CoLucid Hopes Lasmiditan Can Offer New, Safer Migraine Drug Class

Prospects that CoLucid Pharmaceuticals’ lead asset might offer a viable new class of migraine treatment are brighter following the release of positive Phase III data showing lasmiditan helps twice as many patients to be headache-free after two hours versus a placebo.

CoLucid Pharmaceuticals Inc.'s share price surged after the Cambridge, Mass.-based company announced positive topline results from the SAMURAI Phase III study, the first of two pivotal studies evaluating oral lasmiditan, its lead asset, as an acute treatment for migraines.

The stock opened 83% higher Sept. 6, the day the data were announced, at $19.50.

CoLucid is developing oral lasmiditan as a first-line therapy for migraine sufferers who are contraindicated from using triptans, the current standard-of-care, due to cardiovascular conditions or risk factors.

While the data from the first Phase III trial appear promising, CoLucid will face growing competition in the migraine market if lasmiditan is approved. A new class of biologics are in late-stage development for migraine called calcitonin gene-related peptide (CGRP) inhibitors by Amgen Inc., Teva Pharmaceutical Industries Ltd., Eli Lilly & Co. and Alder BioPharmaceuticals Inc. Meanwhile, Allergan PLC is developing an oral CGRP inhibitor.

Promising Trial Results

In the trial involving 2,231 patients, treatment with either a 100 mg or a 200 mg dose of lasmiditan led to a statistically significant increase in the proportion of migraine sufferers reporting pain freedom at two hours relative to placebo, the trial’s primary endpoint. It showed 32.2% of those given the 200 mg dose of lasmiditan reported they were headache-free after two hours, compared to 15.3% who took the placebo. And 40.7% of those patients said they no longer felt the associated symptom of their migraine that they found most bothersome, which could be nausea, fear of noise or of light. Only 29.5% of the patients on placebo said they were free of such symptoms after two hours.

CoLucid, which floated on NASDAQ in May 2015, is developing a new mechanism of action for the treatment of migraines. Lasmiditan selectively targets 5-HT1F receptors in the trigeminal pathway, making up a new drug class called “ditan,” which distinguishes it from other drug classes, including triptans, which carry a warning for patients with cardiovascular risk factors or diseases.

CoLucid hopes lasmiditan will avoid that issue as, unlike triptans, the drug doesn’t cause vasoconstriction, the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels. The biotech claims that lasmiditan represents the first new mechanism of action to emerge for migraine to in the last 20 years.

“Lasmiditan works through a novel mechanism of action. We are highly CNS penetrant and we are highly selective for a receptor called 5-HT1F which is primarily populated in the CNS on the trigeminal pathway. We are just under 500-fold more selective for 1F than other 5-HT receptors which are found in the periphery, especially the triptan receptors,” CoLucide CEO Thomas Mathers said during an analyst call Sept. 6 in connection with the SAMURAI results.

He said scientists have also demonstrated in nonclinical studies that lasmiditan has no vasoconstrictive properties. “In an in vivo study which will be presented in two weeks in Glasgow, lasmiditan was compared directly to sumatriptan, where sumatriptan showed robust vasoconstriction in clinically relevant doses in a whole-animal in vivo system, lasmiditan, even at four-fold super therapeutic dose, had no vasoconstrictive effects,” he said. Sumatriptan is a synthetic treatment for migraine headaches belonging to the triptan class.

More Phase III Data Coming

SAMURAI was conducted at around 80 US cites. Patients had a mean age of 41.6 years; 83% were females, and 74% were Caucasian, with a mean migraine history of over 19 years. The data also showed a favorable tolerability profile for the drug and found no statistically-significant increase in cardiovascular events in patients taking lasmiditan versus those who took the placebo. That's despite the fact that 82% of patients in the trial had multiple cardiovascular risk factors, such as obesity or hypertension, or else had existing cardiovascular conditions.

CoLucid plans to include data from the SAMURAI study along with that from the ongoing SPARTAN Phase III study – which is expected to read out in the second half of 2017 – in a potential NDA submission for oral lasmiditan. CoLucid is also developing an intravenous formulation of the drug for the hospital setting.

Migraine is a debilitating disease, with attacks lasting from a few hours to a few days. Several factors influence the risk of getting them, including genetics, age, gender, and changes in hormonal status. Current estimates suggest 36 million people in the US suffer from migraines, with 85% of people treated being women and 15% males. Today, most patients with cardiovascular risk go untreated, according to CoLucid.

Triptans represent around 80% of prescribed migraine treatments but more than 40% of patients do not respond to triptans or are unsatisfied with them, according to CoLucid. The class carry serious warnings and contraindications in patients with CV risk factors and disease. Oral triptans have been the backbone of migraine therapy since the 1990s and many are now available as generics. Migraine therapies dihydroergotamines (DHE) and NSAIDs also carry CV warnings.

CEO Mathers told the analysts call that the company is hopeful the SPARTAN trial will be clear cut as well. "Both are very large and well-powered studies, so we are using the same endpoint with SPARTAN and the same statistical powering," he said. "From our standpoint we feel like we have built the right confirmatory trial for lasmiditan."

The difference with SPARTAN is that the firm is rolling subjects into a 50 mg arm as well as a 100 mg and a 200 mg arm, and the trial is running not only in the US but also the UK and Germany.

Asked about the apparently high placebo response rate registered in the SAMURAI trial, Mathers said: “We were expecting a slightly lower placebo response rate in this trial but this response rate is well within the norm of trials have been published more recently."

Some SAMURAI participants were on Botox and others were on beta blockers. Still, FDA guidelines allow enrollment of migraine patients in trials who continue using prophylactic medicines during its course provided they have been on a stable dose three months prior to entering the study and that they maintain that dose during the trial. Such patients are stratified accordingly during studies, the company said.

Asked what the company’s commercialization plans might be for the therapy, the CEO said: “We are focused on developing lasmiditan and emerging as a specialty neurology company with lasmiditan as our core product. We think that lasmiditan could be effectively launched into the United States specialty market, consisting of neurologists and headache specialists, by CoLucid."

Some Analysts Advise Caution

Despite the positive lasmiditan results from the SAMURAI trial, LIFESCI Capital analysts urged caution, and noted CoLucid is a clinical-stage company with no history of commercializing a product and currently has no FDA approved drugs in its portfolio. Migraines meanwhile have a complex pathogenesis that is not fully understood and there are many companies targeting this indication, analysts at LIFESCI Capital said in a reaction note to investors.

“Positive data do not necessarily translate into FDA approval, or the successful commercialization of a product. Regulatory risks remain, as the approval by the FDA and similar regulatory bodies is not guaranteed despite significant time and financial investment. Even if regulatory approval is granted, there is no guarantee that expectations of market penetration and sales will come to fruition,” the analysts said.