When Eli Lilly and Co. took over Colucid Pharmaceuticals Inc. for nearly $1 billion in early 2017, it brought then-migraine candidate Reyvow (lasmiditan) back to its founder and now to its FDA approval for the acute treatment of migraine, with or without aura, in adults. Its unusual mechanism puts it outside many other approved migraine treatments, which could hinder its market penetration.
Reyvow is the first FDA-approved medicine in a new class of acute migraine treatment (serotonin (5-HT)1F receptor agonists) that binds to 5-HT1F receptors. However, Lilly cautioned that Reyvow's therapeutic effects are "presumably mediated by agonist effects at this receptor; however, the precise mechanism is unknown."
It expands Lilly's existing migraine franchise, which includes recently approved Emgality (galcanezumab-gnlm) solution (300 mg) for injection for treating episodic cluster headache in adults. The June approval makes it the first and only calcitonin gene-related peptide (CGRP) inhibitor that reduces the frequency of these attacks. That nod followed Emgality's September 2018 approval for migraine treatment in adults. (See BioWorld, June 6, 2019, and Oct. 1, 2018.)
Also in September 2018, the FDA approved, as preventive treatments of migraine, Teva Pharmaceutical Industries Ltd.'s Ajovy (fremanezumab-vfrm) and, in May 2018, Novartis AG and Amgen Inc.'s Aimovig (erenumab-aooe). Ajovy is a 225-mg/1.5-mL single-dose injection in a prefilled syringe with two dosing options: 225 mg monthly, administered as one subcutaneous injection, or 675 mg every three months, administered as three subcutaneous injections. Aimovig is also self-administered and is labeled for 70-mg or 140-mg once-monthly dosing.
In March, the FDA accepted Allergan plc's NDA for its oral CGRP inhibitor, ubrogepant, for acute treatment in migraine in adults. A 10-month review was assigned, with the PDUFA before year's end. Following a similar small-molecule strategy is Biohaven Pharmaceuticals Inc., which is due to report top-line data from a phase II/III trial of its second oral CGRP inhibitor, vazegepant, in development for prevention and for acute treatment, before year's end.
SBV Leerink analysts noted the mechanism of Reyvow's 5-HT1F agonist could restrict it to a cameo in migraine prevention as "many physicians view this product as a viable add-on agent to the CGRPs ... as they remain concerned about 'over-blocking' the CGRP with multiple CGRP agents."
There are warnings and precautions associated with Reyvow, such as the single 50-mg, 100-mg or 200-mg doses that caused significant driving impairment in a recent study. Compared to placebo, more sleepiness was reported at eight hours. Patients are advised not to engage in hazardous activities requiring complete mental alertness, such as driving, for at least eight hours after each dose.
The FDA still has work to do, as Reyvow is being reviewed by the DEA for a controlled substance classification. The DEA is expected to wrap up within the next 90 days, most likely making the drug available to patients in retail pharmacies.
The Leerink analysts lauded Reyvow's "solid efficacy" for acute migraine "but we believe its side effects and burdensome label (driving impairment warning, DEA scheduling) will probably limit usage in the primary care space, resulting in this product becoming no more than a niche product with <$500M peak sales."
Reyvow's NDA approval was based on two phase III studies, with both meeting the efficacy endpoints of pain freedom and freedom from migraine's most bothersome symptoms, such as nausea, sensitivity to light or to sound two hours following its administration, compared to placebo. Then came the successful phase III Gladiator trial, involving the more than 20,000 migraine attacks of more than 4,000 patients.
The oral 5-HT1F agonist's approval boosted the sagging Lilly stock last week. The shares are down 6.4% this year but closed up 1.27% on Friday. On Monday, though, the price per share slipped .42% from its Friday close.
Nearly four years ago, Indianapolis-based Lilly paid $46.50 per share for Colucid, about a 40% premium, in an all-cash deal that put then-candidate lasmiditan back in the hands of Lilly, where it was discovered. Lasmiditan was out-licensed to Colucid in 2005. Lilly didn't list pain high on its priorities back then, but research efforts since have been configured differently. (See BioWorld, Jan. 19, 2017.)