What the Migraine Field Knows in the 2 Years Since Launch of CGRPs

The advent of calcitonin gene-related peptide (CGRP) blockers kicked off a revolution in migraine therapy when the class began launching 2 years ago.

“I don't think, at least certainly not in my career time, has been a more exciting time in the migraine field, given the plethora of new therapies that we’ve had over the past 2 years,” said David W. Dodick, MD, FRCP (C), FACP, professor of neurology at the Mayo Clinic College of Medicine, during his presentation at the Migraine Trust International Symposium. His lecture focused on both the knowledge gained through controlled clinical trials as well as real-world experiences.

Pivotal trials of the monoclonal antibodies have all been positive, he said. The therapies have a good responder rate, high tolerability, and have been successful in reducing medication overuse headaches as well as helping patients who previously failed other treatments, he said.

Across the 4 products available in the United States, there is about a 50% responder rate for both chronic and episodic migraine; moreover, the proportion of patients with a greater than 75% reduction in migraine days is about a third, which he called “quite significant.”

Tolerability is “one of the areas where this class of drugs stands out,” he said. The overall serious adverse events rate is about 2.5%, and the overall withdrawal rate from clinical trials due to adverse events was also around 2.5%, he said. Older prophylactic medications have much higher withdrawal rates in clinical trials due to adverse events, he said.

Since launch, Dodick said, he has learned that the CGRP blockers are effective in those who are overusing medications. The majority of the patients in the clinical trials were chronic migraine sufferers who were using overusing acute medications, but notably, “they were just told to carry on as usual with their acute treatments. So there was no discontinuation, detoxification, or withdrawal from acute medications.”

Regarding prior treatment failures, Dodick said most of the biologics are effective in patients who have failed at least 1 and often 2 to 4 preventive medications; in addition, they take effect quickly. In a post hoc analyses, all were effective in 1 week.

He also reviewed 5-year data on erenumab, which was the first of the CGRP drugs to launch. Thus far, it appears that the effects are cumulative for patients who stay on them long term, with no new safety issues.

Another noteworthy item is additional knowledge about where CGRPs work, and this has treatment implications, he said. He pointed to a 2019 article in the Journal of Headache, which described how immunohistochemistry methods unveiled a “close relationship” between 2 different neurons (the CGRP containing C-fibers and the Aδ-fibers containing the CGRP-receptor elements) in the trigeminal system.

"There may be a point of axon-axon interaction for the released CGRP and a site of action for gepants and the novel mAbs to alleviate migraine," according to the authors of the paper.

In other words, this may create a synergistic effect between a blockade of CGRP and a treatment like onabotulinumtoxinA, Dodick said.

In real-world settings, Dodick noted several studies have reviewed vascular concerns, severe constipation, and the possibility of anaphylaxis, which all biologics carry.

In clinical trials, concerns about hypertension did not arise in clinical trials, but practitioners will now see a warning label on erenumab for hypertension based on postmarketing surveillance. “We clearly need to learn a lot about who’s at risk for hypertensive response, and how best to monitor for this response,” he said.

As a result of the postmarketing surveillance, erenumab had its labeling changed to note the possibility of hypersensitivity reactions as well as constipation severe enough to require hospitalization.