New Migraine Drug Targets Could Help 400 Million People

For decades, researchers thought they had hit a dead end with substance P as a migraine treatment. Now they're discovering that earlier failures might have simply been looking at the molecule the wrong way.

More than 1 billion people worldwide experience migraines, and up to 40 percent of them don't get relief from current medications. That's roughly 400 million people still searching for something that works.

Scientists at the University of Copenhagen have breathed new life into research on substance P, a chemical messenger released by the trigeminal nerve. This molecule triggers pain by dilating blood vessels, causing inflammation around the brain, and amplifying pain signals throughout the nervous system.

Five experimental drugs targeting substance P failed in the 1990s, leading researchers to abandon this approach entirely. But the Danish team discovered why those drugs didn't work: they only blocked one of substance P's three receptors.

The molecule actually binds to three different receptors to cause migraine pain. Those early drugs missed two of them completely.

This discovery comes at a perfect time because we now have the technology to create monoclonal antibodies that can block molecules more completely. These same antibodies already power our most effective migraine medications, which target a different pain molecule called CGRP.

Speaking of new treatments, the pharmaceutical company Lundbeck just announced early results from a trial of bocunebart, a drug targeting yet another migraine molecule called PACAP. According to their announcement, the medication significantly reduced monthly migraine days compared to a placebo.

The Ripple Effect

These multiple pathways to migraine relief could transform treatment from a one-size-fits-all approach to a personalized strategy. Different combinations of drugs might work for different people, dramatically reducing the number of patients left without options.

Michael Moskowitz at Harvard, who first uncovered the trigeminal nerve's role in migraines, believes blocking several pathways together could be the breakthrough millions of patients need. Instead of replacing current treatments, substance P and PACAP inhibitors might work alongside CGRP drugs to catch the cases that slip through.

Peter Goadsby at King's College Hospital, who discovered CGRP's role in migraines during the 1990s, emphasizes the urgency. "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," he says.

The full data from Lundbeck's PACAP trial will be shared at an upcoming medical conference. Researchers are already planning new trials for substance P-blocking drugs using the updated knowledge about all three receptors.

For the first time in decades, people who've tried everything for their migraines without success might finally have new options on the horizon.