The triptans, long the workhorses of migraine treatment, have been joined by monoclonal antibodies and small-molecule drugs that block calcitonin gene-related peptide. What’s lacking is a precision approach to treatment based on biomarkers.
The migraine treatment landscape has seen an explosion of new therapies in the recent years and continues to have a robust pipeline, creating a sizable armamentarium of treatment options for the 39 million people in the United States who suffer from the disorder.
Migraine is among the most prevalent illnesses in the world and not only affects quality of life but also productivity, with an estimated 157 million workdays lost each year in the United States. Although there is no cure, there are treatments for both treating migraine at the onset of an attack — known as acute treatment — and for
reducing the frequency, severity and length of the headaches. Frequency is one way migraine diagnoses are categorized. Episodic migraines occur 14 or fewer days per month whereas chronic migraines occur more than 15 days per month. The treatments, though, are the same for both.
According to Richard B. Lipton, M.D., professor and vice chair of neurology at Albert Einstein College of Medicine and director of Montefiore Headache Center, both in New York City, just one drug is approved for chronic migraine that is not also approved for episodic migraine. So the dividing line in treatment choices relates mainly to whether the medication is being used for acute treatment or for prevention. Acute treatment has traditionally involved analgesics, including the common, over-the-counter all-purpose pain relievers, acetaminophen and ibuprofen. The triptans — Imitrex (sumatriptan), Zomig (zolmitriptan), Axert (almotriptan) and others — are prescribed more specifically for acute treatment of migraine (and occasionally cluster headaches).
The causal pathway of migraines is complex and not completely understood. Even so, it is believed that the widening of blood vessels is associated with the attacks and that the triptans are effective as an acute treatment, at least in part, because they narrow blood vessels.
Preventive treatments have also included beta blockers, which relax blood vessels and prevent their overexpansion; antidepressants; and anticonvulsants.
But despite the many and varied treatments, a large number of people with migraines cannot find one that works well for them.
Migraine treatment entered a new era several years ago. For both acute treatment and prevention, there are now several medications available that block a protein called calcitonin gene-related peptide (CGRP). It is believed that CGRP has a role in migraine because it is involved in the transmission of pain signals and neurogenic inflammation that dilates blood vessels.
The FDA has approved four monoclonal antibodies that block CGRP as preventive agents. Amgen and Novartis’ Aimovig (erenumab-aooe), Eli Lilly’s Emgality (galcanezumab-gnlm), and Teva’s Ajovy (fremanezumab-vfrm) are once-a-month injections that patients self-administer. The fourth, H. Lundbeck A/S’s Vyepti (eptinezumab-jjmr), is administered by a physician every three months.
This new class of treatments represents a major step forward in migraine prevention for several reasons, says Lipton: Their benefits kick in very quickly without a lot of dosing adjustment, they have a favorable side effect profile, and they often work in people who do not respond to traditional preventive treatments. “Prior to the approval of the CGRP-targeted monoclonal antibodies, there was a real unmet need in the prevention space,” says Lipton, explaining that medical claims data have shown that 80% of patients who start on a traditional oral preventive treatment discontinue treatment because it doesn’t work for them, the side effects or both.
In early 2020, Biohaven Pharmaceuticals — a small biopharmaceutical company in New Haven, Connecticut — launched its first-ever product, an oral CGRP-targeted treatment called Nurtec ODT (rimegepant). The approval of Nurtec ODT came a year after the FDA approved another oral CGRP-targeted treatment, Allergan’s Ubrelvy (ubrogepant). (Allergan is now part of pharma giant AbbVie.)
Nurtec ODT and Ubrelvy are small-molecule drugs, not monoclonal antibodies, and they are grouped in the gepants class (pronounced GEE-pants). They have their own list of benefits when compared with traditional treatment. For example, the triptans work by narrowing blood vessels, so they may be contraindicated for patients with heart conditions. These newer treatments do not come with the same cardiovascular concerns. They may also be an option for patients who do not respond to triptans or for whom the side effects are too common or serious.
More CGRP-targeted treatments
Biohaven is also making the case for using Nurtec ODT as migraine prevention. In December, a study published in The Lancet detailed the treatment’s effectiveness as a preventive option when taken every other day. The potential approval of Nurtec ODT for prevention of migraine would create the unusual situation for migraine medicine of the same agent being used for prevention and treatment. Meanwhile, Biohaven has been conducting trials that may get zavegepant, another CGRP-blocking agent, approved as both a pill and as a nasal spray.
Biohaven announced the launch of a phase 1 trial of zavegepant last fall and has reported positive results from a phase 2/3 study for the drug as a nasal spray. Delivering a drug intranasally has advantages, explains Lipton. The drug gets into the body faster, so it takes effect sooner. Nausea is a common feature of migraine, so bypassing the digestive system with an intranasal spray might make a drug more effective.
AbbVie’s atogepant may soon be on the market. In July 2020, the company reported positive phase 3 data that showed that it significantly reduced the number of “migraine days” relative to a placebo. An FDA decision was imminent as this issue of Managed Healthcare Executive® went to press.
The FDA approved Eli Lilly’ Reyvow (lasmiditan) for the treatment of acute migraine in 2019. Reyvow is the first approved ditan (pronounced DIE-tan) a class of drugs that target the 5-HT1F receptor.
Another group of migraine medications in development zeroes in on pituitary adenylate cyclase-activating peptide 38 (PACAP-38 ). Amgen’s AMG-301 was the leading PACAP-38 inhibitor, but results from a phase 2a trial showed that it had no benefit relative to a placebo for migraine prevention. But there are other PACAP-38 inhibitor candidates, including Alder BioPharmaceuticals’ ALD1910. The company has completed enrollment of a phase 1 trial that had 96 volunteers. H. Lundbeck, a Danish company, acquired Alder, which is located in suburban Seattle, in 2019.
Physicians and people with migraine have more treatment options than ever before. This abundance perhaps deflects attention away from a fundamental problem: the absence of an approach to treatment that would be informed, at least in part, by genetics and other individual characteristics.
“The challenge is that migraine is almost certainly more than one disease,” explains Lipton. “We know more than 40 genes that contribute to the risk of migraine and what that may mean is that in different people, migraine has a different mechanism.”
With an absence of established biomarkers, physicians are currently left treating patients on a trial-and-error basis. The problem of lumping migraine patients together affects drug development too. Drugs with a particular mechanism of action may fail if too many patients in the trial have a migraine pathophysiology that is not a good fit with the experimental drug’s mechanism of action. Lipton says researchers are working on identifying subgroups of migraine and treatment responses. Several groups are working on finding genetic and other biomarkers for migraines.
Jaime Rosenberg is a freelance writer based in Jersey City, New Jersey.