New understanding of the causes of migraine reveals new drug targets

We may be heading for a new wave of migraine treatments. Visiting a long-rejected neurological pathway for treating the painful condition has yielded promising results. By understanding the various mechanisms behind migraine, which affects more than 1 billion people worldwide, we can provide relief for the 1 in 3 people with the condition who do not respond to current treatments.

Failed drug trials in recent decades meant that many dismissed this pathway as unimportant in our quest to prevent and treat migraines. But now a placebo-controlled study has some wondering if this may have been too hasty.

Messoud Ashina at the University of Copenhagen in Denmark and his colleagues looked at a chemical messenger, or neuropeptide, called substance P. This is released by the trigeminal nerve, which has been implicated in migraines for decades. Substance P induces pain by dilating blood vessels, causing inflammation in the meninges (the thin membranes that surround the brain), and by changing the activity of the nervous system to amplify pain signaling.

Last year, researchers showed that infusions of substance P led to headaches in 71 percent of people who don’t get migraines, along with dilation of the superficial temporal artery, which has been linked to the condition. Now they have found an equally large effect when infusing it into people who get migraines, supporting substance P’s involvement.

This comes after substance P was abandoned as a target molecule against migraine in the late 1990s, after five experimental drugs showed that targeting substance P had no advantage over placebo.

Ashina’s team wondered if these failures were due to the drugs acting on only one of substance P’s receptors: the neurokinin-1 receptor (NK1-R). It is now known to bind to a second set of receptors, the MRGPRX2 receptors, which cause inflammation, and to act directly on sensory neurons to increase pain signals.

“After the NK1 receptor-targeting drug trials failed, there was no serious effort to explain the failure,” says Michael Moskowitz at Harvard, who uncovered the role of the trigeminal nerve in migraine. “They probably missed blocking the wide range of substance P effects. With new knowledge comes new treatment options, and based on new and existing knowledge it seems timely and prudent to revise strategies that target substance P.”

This should be easier now that we can produce monoclonal antibodies that block molecules directly. These have already been proven to work against calcitonin gene-related peptide (CGRP), the target of our most potent migraine therapies, and are under investigation for a third migraine-related neuropeptide: pituitary adenylate cyclase-activating polypeptide (PACAP).

Earlier this month, Danish pharmaceutical company Lundbeck announced early results from a randomized controlled trial of its anti-PACAP monoclonal antibody, called bocunebart. According to the announcement, which did not include data, bocunebart infusions significantly reduced monthly migraine days compared to a placebo. “It is of course good news as long as we have hard data,” says Lars Edvinsson of Lund University in Sweden, who was involved in discovering the roles of PACAP and substance P in migraine. Lundbeck says it plans to share full data at an upcoming conference.

A shift in focus on the causes of migraine may reduce our reliance on CGRP inhibitors. Since the first CGRP inhibitor was approved in the US in 2018, these treatments have revolutionized how we manage migraines – halving the number of migraine days per month and shortening the duration of any remaining attacks. But they don’t work for up to 40 percent of people.

“CGRP drugs work very well for some people, but they don’t work for everyone,” says Peter Goadsby of King’s College Hospital in London, who discovered the role of CGRP in migraine in the 1990s, along with Edvinsson. “Finding the next thing that will benefit the hundreds of millions of people who are not well treated by current therapies remains an important challenge.”

We now await further evidence of the real effects of blocking these problematic peptides. “We should be optimistic because substance P, CGRP and PACAP all act on the meningeal vessel wall and their respective receptor systems, but do so in different ways,” says Moskowitz. Blocking multiple pathways in combination may be the key to reducing the number of non-responders, he suggests.

But drugs that target substance P and PACAP may not have as great an effect as those that block CGRP, which is released in far greater amounts in the trigeminal nerve. “I don’t think (these goals) will replace the CGRP,” says Edvinsson. “I think they’re more like the sprinkles on top of the ice cream.”