Phase III Immunotherapy Trial for Migraine Shows Positive Results

An antibody therapy against a key inflammatory molecule involved in migraines reduces the number of headaches that chronic migraine patients experience per month in a phase III trial.

A new study of fremanezumab, an immunotherapy that counteracts one of the molecules released during migraine, was found successful in reducing the number of days that chronic migraine sufferers experienced headaches. The results of the phase III clinical trial were published November 29, 2017 in the New England Journal of Medicine.

The World Health Organization estimates that between 127 and 300 million people around the world experience chronic migraine, defined as 15 or more headaches per month for at least three months. The disease can be debilitating and although a number of interventions exist, many only work for a certain time before they fail to prevent or relieve pain.

“This therapeutic approach offers new hope for people whose migraines cannot be treated with existing medicine,” says Stephen D. Silberstein, M.D., principal investigator of the HALO CM trial, Professor of Neurology and Director of the Jefferson Headache Center at the Vickie & Jack Farber Institute for Neuroscience at Thomas Jefferson University Hospital. “Our worldwide effort to evaluate this novel therapeutic approach has shown positive results and was safe in patients.”

Fremanezumab, a monoclonal antibody developed by Teva Pharmaceuticals, is a biological agent that binds to and blocks the action of a migraine-associated protein called calcitonin gene-related peptide (CGRP). Mounting evidence of its importance in migraines has made CGRP a focal point of research and drug development. The peptide is released at high levels during migraine in response to inflammation, and triggers a cascade effect that stimulates more CGRP release. This results in increasing sensitivity of the brain to pain. By blocking this peptide, doctors hope to break the cycle of increasing inflammation and increased pain sensitivity that contributes to migraine headaches.

Researchers from 132 sites across nine countries enrolled 1130 patients and randomly assigned them to one of three groups: one that received quarterly treatments, a group that received one treatment per month, and one that received placebo injections. The trial lasted for 16 weeks, with a 12-week treatment window.

The results of the trial show that treatment with fremanezumab reduced the number of days patients experience headache by an average of 4.3 days with quarterly treatment and 4.6 days with monthly treatment. “We saw some patients with 100 percent reduction in migraine, others with 75 percent reduction,” says Dr. Silberstein. The level of response varied between patients.

The researchers also looked at how well the therapy worked relative to each patient’s headache burden. They calculated the percent of patients who had more than a 50 percent reduction in the number of days they experienced either a severe or moderate headache per month. Using this measure, the researchers saw that 37.6 percent of patients on the monthly regimen, and 40.8 percent on the quarterly regimen had at least a 50 percent reduction in the number of moderate headaches per month, compared to 18.1 percent in the placebo group.

The therapy had a favorable safety profile with the most common adverse event reported as irritation at injection site, which was reported in the placebo group as well.

“If approved, this treatment would provide physicians with an important new tool to help prevent migraine, reduce a patient’s migraine load, and potentially help patients return to normal” says Dr. Silberstein.

Brain Scans Show Dopamine Levels Fall During Migraine Attacks

Using PET scans of the brain, University of Michigan researchers showed that dopamine falls and fluctuates at different times during a migraine headache.

This could help scientists better understand dopamine-based therapies for migraines as well as a patient’s behavior during an attack.

The connection between dopamine and migraines has long been a poorly understood therapeutic and research area, says Alex DaSilva, assistant professor at the U-M School of Dentistry and Center for Human Growth and Development at the University of Michigan.

Dopamine—sometimes called the brain’s feel-good neurotransmitter—helps regulate emotion, motivation and sensory perception.

Physicians and emergency rooms often give migraine patients dopamine antagonists, drugs that block overactive dopamine receptors, to level off wild dopamine fluctuations and ease migraine attacks.

DaSilva and colleagues took various measurements of brain activity and dopamine levels of eight migraine sufferers and eight healthy patients during migraine attacks and between headaches. They compared study participants to each other with and without headaches, and also migraineurs to healthy patients.

When migraine patients were between headaches, their dopamine levels were as stable and even as the healthy patients, DaSilva said. But during an attack, the migraine patients’ dopamine levels fell significantly.

“Dopamine is one of the main neurotransmitters controlling sensory sensitivity,” said study co-author Kenneth Casey, U-M professor emeritus of neurology. “Therefore, a drop in dopamine could produce increased sensory sensitivity so that normally painless or imperceptible sensory signals from skin, muscle and blood vessels could become painful.”

This supports the hypothesis held by some researchers that migraines are a periodic disorder characterized by sensory hypersensitivity during which light, sound and odors may become abnormally intense, Casey says.

DaSilva says he was surprised when patients who were resting during their migraine attacks experienced a small dopamine spike and worsening symptoms when researchers applied warmth to their foreheads.

This condition in chronic pain patients is called allodynia—when a stimulus that normally wouldn’t cause pain does. DaSilva says the sudden small spike in dopamine was probably an aversive reaction to environmental stimulation.

This small fluctuation was only a partial recovery of dopamine, but it made the suffering worse because the dopamine receptors were highly sensitive by then, and even a small recovery would induce more nausea, vomiting and other symptoms related to migraine, he says.

In addition to the pain of migraines, DaSilva says the fall in dopamine in general could also explain some of the isolation and withdrawal that migraineurs exhibit during an attack.

“This dopamine reduction and fluctuation during the migraine attack is your brain telling you that something is not going well internally, and that you need time to heal by forcing you to slow down, go to a dark room and avoid any kind of stimulation,” he said.

Montefiore and Einstein Researchers Leverage Social Media to Uncover New Data on Migraine Sensory Experiences

A highly trafficked social media forum is yielding new findings on migraine symptoms, according to clinical researchers from the Montefiore Headache Center and Albert Einstein College of Medicine. A new report, “Special sensory experiences in migraine: a social media study,” reveals important disease epidemiology on migraine experiences like olfactory hallucinations, which may not be uncovered during traditional doctor/patient communications. Data from this study will be presented at the 58th Annual Meeting of the American Headache Society (AHS) being held June 9 – June 12 in San Diego.

Migraine ranks in the top 20 of the world’s most disabling medical illnesses, yet is underreported. While hallucinations around certain odors, noises and tastes have been known to occur during a migraine, these symptoms are not included in the International Headache Society classification. To garner more insights into these manifestations, researchers at Montefiore and Einstein tapped The Daily Migraine, a consumer-facing online forum to query 678 respondents through Facebook, Instagram and Twitter three times over three weeks, revealing new insights about experiences with certain tastes, sounds or smells in association with migraine attacks. Queries around olfactory hallucinations, most notably unpleasant smells like cigarette smoke and animal scents were what those with migraine most searched online. Queries also revealed ringing as the predominant migraine-associated sound. Unpleasant tastes, specifically a metallic taste, were also commonly searched.

“As researchers we have only scratched the surface of the depth of patient experience and disease information we can glean from social media channels,” said Matthew S. Robbins, M.D., FAHS, study author and director, Inpatient Services, Montefiore Headache Center, chief of Neurology, Jack D. Weiler Hospital and associate professor of Clinical Neurology, Einstein. “Using social media as a research tool, we learned more about migraine symptoms and what should be included during intake evaluations.”

The magnitude of migraine disability on everyday life causes missed work days, missed opportunities and events spent among family and friends, and can undermine the emotional, social and financial fabric of a family. A recent report published in Mayo Clinic Proceedings, from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study, found that approximately 41% of people with migraine and 23% of spouses stated that they believed those impacted by migraine would be better parents if they did not have migraine, which consequently led to half of migraineurs missing at least one family activity in the past month.

“Given the onerous physical and emotional impact of migraine, an online forum is a unique resource to the professional headache community to help us improve how we diagnose, care for and treat headache and facial pain syndromes,” said Cynthia Armand, M.D., study author and chief resident, Department of Neurology, Montefiore and Einstein. “For individuals affected by these neurological diseases, an online site may provide more anonymity and a community, making it a safe place to be open and honest without fear of being judged or marginalized.”