Why pharma isn’t done tackling migraines

In the days long before migraine drugs, those with the condition were willing to try almost anything to get rid of the pain. They wrapped their heads in potato slices, rubbed their temples with a pungent salve of cow manure and molasses, and stuck bloodsucking leeches to their forehead.

It’s a desperation migraine sufferers understand. Chronic migraine, which affects more than 10% of people worldwide, isn’t just headaches but a neurological condition that triggers throbbing head pain that can last for days and can sometimes cause visual disturbances, brain fog, nausea and extreme sensitivity to light and sounds. The condition is a leading cause of disability in the U.S., particularly for women, who are disproportionately affected. In fact, three out of every four migraine sufferers are women.

Treatment options have come a long way since the days of folk remedies. The first migraine treatment, ergotamine came along in the 1920s, and a trickle of other drugs followed. However, the FDA approved the real game-changer in the early 1990s — GSK’s sumatriptan, sold under the brand-name Imitrex. It was the first in a crop of triptan drugs that provide rapid relief by tamping down nerve inflammation and constricting dilated blood vessels.

“Everything changed because of these,” said Dr. Seth Lederman, CEO of Tonix Pharmaceuticals, a company working in the migraine space.

Even today, sumatriptan remains the gold standard, he said. But the field took another leap forward in 2018 with the arrival of groundbreaking injectable or intravenous migraine prevention drugs called calcitonin gene-related peptide (CGRP) monoclonal antibodies. This category includes drugs such as Amgen’s Aimovig and Eli Lilly and Co.’s Emgality, which prevent headaches by reducing levels of CGRP, a protein that drives migraine symptoms.

A subcategory of related small molecule drugs called gepants followed. Most gepants, such as Pfizer’s blockbuster Nurtec, are pills approved to both prevent and treat migraine pain. However, the newest addition, Zavzpret, is a nasal spray that Pfizer acquired from Biohaven Pharmaceuticals  along with Nurtec in a transaction that was worth $11.6 billion. The FDA signed off on the drug in March for acute relief, but it’s still in phase 2/3 for migraine prevention.

These new drugs have advantages over existing migraine meds.

“The standard of care treatment options for migraine, while effective, do have many limitations, including tolerability issues, contraindications for cardiovascular disease, the need for repeat dosing and the risk of developing medication overuse headache, which exacerbates migraine and increases the frequency and severity of attacks,” a Pfizer spokesperson said.

CGRP and gepants can work where other drugs have failed and help those who can’t take other migraine treatments. These options carry a lower risk of rebound headaches and other side effects and have a solid safety profile, which has helped them fuel a global migraine market expected to reach $15.6 billion by 2029.

However, while CGRP drugs have offered new options, they’re not a panacea. They typically reduce the average number of monthly headache days from around 15 to 12, leaving room for improvement, Lederman said.

“Even with the CGRP blockers and now the gepants, migraine is not solved,” he said.

Several companies are working on novel treatments and trying new takes on old treatments to bring more relief.

Examining the pipeline

In 2022, PhRMA listed 13 migraine medications in development. Since then, at least two have failed, including a phase 2 Eli Lilly drug, LY3451838, for treatment-resistant migraine and a transdermal patch from Zosano Pharmaceuticals, which declared bankruptcy and sold its technology to Emergex Vaccines.

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“Even with the CGRP blockers and now the gepants, migraine is not solved.”

Dr. Seth Lederman

CEO, Tonix Pharmaceuticals

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Of those that remain, there are a few testing novel mechanisms, including Tonix’s TNX-1900, an oxytocin-based drug now in phase 2 as a migraine preventative, and Lundbeck’s monoclonal antibody Lu AG09222 targeting a neuropeptide called pituitary adenylate cyclase-activating polypeptide, which also plays a role in migraine, Lederman said. Others are a mix of CGRP drugs and new combinations and formulations of existing drugs.