COMMENTARY

Novel Treatments Are Reshaping Migraine Treatment, Prevention

Hans-Christoph Diener, MD, PhD

Disclosures

December 24, 2019

This transcript has been edited for clarity.

Dear colleagues, I'm Christoph Diener, a neurologist from the University of Duisburg-Essen in Germany. This month I'd like to talk about recent developments in the treatment of acute migraine attacks and migraine prevention.

Moving Beyond Triptans in the Treatment of Acute Migraine Attacks

Until about 30 years ago, when it came to the treatment of acute migraine attacks, we only had analgesics like aspirin or acetaminophen, or nonsteroidal anti-inflammatory drugs and ergotamine. This changed with the introduction of the triptans, which were clearly more effective than analgesics, worked in patients who did not respond to analgesics, and had a very good side-effect profile.

At that time, there was a concern that triptans could perhaps induce vasoconstriction. They were therefore contraindicated in vascular diseases, like in those with a history of myocardial infarction or ischemic stroke. But we also have to remember that during this time there was a totally different understanding of the pathophysiology of acute coronary syndrome than there is today. Many physicians once thought that vasoconstriction plays a role in acute myocardial infarction, whereas now we know that the key contributors are ruptured plaques and local thrombin generation.

Beyond their contraindications, triptans were also limited by the fact that not all patients responded to them, which created a need to develop new treatments. There are now two new classes of drugs to treat acute migraine attacks. The first are the so-called ditans, such as the recently approved lasmiditan. This drug works on the serotonin 5-HT1F receptor, which is present not only on blood vessels and neurons but also in the central nervous system. Lasmiditan has no vasoconstrictive properties.

In randomized phase 3 trials, lasmiditan was clearly superior to placebo and, in indirect comparisons, as effective as a triptan. Lasmiditan's side-effect profile shows that the drug works centrally, with dizziness, tiredness, and somnolence among the most commonly observed side effects. At the moment, we don't know whether this drug is comparable to triptans or whether it works in people who do not respond to a triptan.

The second class of drugs are small-molecule antagonists of the calcitonin gene-related peptide (CGRP) receptor. CGRP antagonists studied in the treatment of acute migraine attacks include rimegepant, ubrogepant, and atogepant. Although these have proven superior to placebo, indirect comparisons seem to indicate that they are less effective than triptans. They can, however, be given to patients who have contraindications for triptans. Two of these drugs have been studied in the treatment of acute migraine attacks, and two others have been studied as daily intake for the prevention of migraine, although we don't yet know whether they are effective in this indication.

Monoclonal Antibodies Provide Migraine Prophylaxis With Limited Safety Issues

In the prevention of migraine attacks, we had a number of drugs that were effective, but unfortunately, they also had unpleasant adverse events that resulted in a not very good rate of compliance. This was particularly true for topiramate, which is effective but has many side effects.

This unmet need led to the development of monoclonal antibodies against the CGRP receptor or ligand. At the moment, we have four such monoclonal antibodies: erenumab, galcanezumab, fremanezumab, and eptinezumab. All have shown efficacy in episodic and chronic migraine above that obtained with placebo. The response rate (≥ 50% decrease of monthly migraine days from baseline) is somewhere between 30% and 60% for monoclonal antibodies, compared with somewhere between 15% and 40% for placebo.The biggest advantage of these new monoclonal antibodies is that they have almost no side effects and are extremely well tolerated.

What do we know about these monoclonal antibodies at the moment? We know that they work in people who do not respond or cannot tolerate the traditional migraine-preventive drugs like beta-blockers, flunarizine, topiramate, valproic acid, or onabotulinumtoxinA.

They are injected either subcutaneously once a month or every 3 months, or they are given intravenously. I think the question of whether these should be given once a month or every 3 months depends on what the patient wants. I would definitely use once-monthly administration in women who can get pregnant.

The onset of activity is very quick, so that in most patients it's possible to say after 4-8 weeks whether a CGRP monoclonal antibody is effective or not.

They work in combination with traditional migraine-preventive drugs. They also reduce the intake of acute medication, which is why they work in patients with medication-overuse headache.

The tolerability profile is excellent. Less than around 5% of all patients terminate the treatment because of adverse events.

Conversely, what we don't know at the moment is the safety of using monoclonal antibodies in patient subgroups where CGRP might play a role, such as those at a high risk for ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, angina pectoris, or acute coronary syndrome. I would also be very reluctant to give this drug to people with inflammatory bowel disease, chronic obstructive pulmonary disease, or preliminary hypertension. And definitely, women who are pregnant, can get pregnant, or are breastfeeding should not yet get these antibodies.

In summary, we have very interesting new drugs for the treatment of acute migraine attacks. Whether they are superior or equivalent to triptans, we don't know.

We now also have new treatments for the prevention of migraine. They have an excellent adverse-event profile but, unfortunately, they are very expensive. This is why their use is restricted in most healthcare systems to migraine patients who failed all other drugs, couldn't tolerate them, or had contraindications.

Ladies and gentlemen, I am Christoph Diener from the University of Duisburg-Essen in Germany. Thank you very much for listening.

Dr Diener is an expert in the treatment of stroke and headache, and chairs the German Headache Consortium and the German Stroke Data Bank.

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