New understanding of migraine causes reveals new drug targets

We could be on the cusp of a new wave of migraine therapies. Re-examining a neurological pathway long dismissed for the treatment of a painful condition has yielded promising results. By understanding the various mechanisms behind migraine that it affects more than 1 billion people worldwidewe could provide relief to the 1 in 3 people with this condition who do not respond to current treatment.

Failed drug trials over the past few decades have meant that many have dismissed this avenue as irrelevant in our efforts to prevent and treat migraines. But now, a placebo-controlled study is questioning whether that was too hasty.

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

Last year, scientists showed it infusions of substance P resulted in headaches in 71 percent of people who don’t have migraines, along with enlargement of the superficial temporal artery that does were associated with the condition. They have now found a similarly large effect when given to people who suffer from migraines, which supports the involvement of substance P.

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

Ashin’s team wondered if these failures were due to these drugs acting on only one of the substance P 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 act directly on sensory neurons to amplify pain signals.

“After trials of drugs targeting the NK1 receptor failed, there were no serious efforts to explain the failure,” he says Michael Moskowitz at Harvard, who discovered the role of the trigeminal nerve in migraine. “They likely missed blocking a wide range of effects of substance P. With new knowledge comes new treatment options, and based on new and existing knowledge, it seems timely and prudent to reevaluate strategies that target substance P.”

Now it should be more straightforward because we can make monoclonal antibodies that directly block the molecules. They have already been shown to antagonize calcitonin gene-related peptide (CGRP), the target of our most effective migraine therapies, and are being investigated for a third migraine-related neuropeptide: pituitary adenylate cyclase-activating polypeptide (PACAP).

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

Shifting focus to the causes of migraine could reduce our reliance on CGRP inhibitors. Since 2018, when the first CGRP inhibitor was approved in the US, this treatment has revolutionized how we manage migraines – cutting the number of migraine days per month in half and shortening the duration of any remaining attacks. But they they don’t work for up to 40 percent of people.

“CGRP drugs work very well for some people, but not for everyone,” he says Peter Goadsby at King’s College Hospital in London, which discovered the role of CGRP in migration in the 1990s alongside Edvinsson. “Finding the next thing to 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 actual effects of blocking these problematic peptides. “We should be optimistic because substance P, CGRP, and PACAP act on the meningeal vessel wall and their respective receptor systems, but they do so in different ways,” says Moskowitz. Blocking multiple pathways in combination may be the key to reducing non-responders, he suggests.

But drugs that target substance P and PACAP may not have as much of an impact as those that block CGRP, which is released in much greater amounts in the trigeminal nerve. “I don’t think so.” [these targets] they replace CGRP,” says Edvinsson. “I think they’re more like sprinkles on ice cream.”

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