Sex Differences in CGRP-Targeted Therapies

By Kayt Sukel | June 6, 2024 | Posted in

A new post-hoc analysis of FDA reviews shows a significant sex difference in the effectiveness of gepants for acute migraine therapy.

For many people living with migraine, drugs that block the signaling of calcitonin gene-related peptide (CGRP), a neuropeptide that contributes to migraine, have been game changers. These drugs include small molecules (gepants) and monoclonal antibodies that target CGRP or its receptor. But whether these medications are equally effective in women and men has remained uncertain.

Now, a new subpopulation analysis of published data from US Food and Drug Administration (FDA) reviews contributes important data on this issue.

The study, from Frank Porreca, University of Arizona, Tucson, US, and colleagues, found that CGRP-targeting antibodies, as well as atogepant, were effective preventive medications in both men and women with chronic migraine. It was unclear whether there were sex differences in the response to those drugs for preventive treatment in patients with episodic migraine. However, notably, the study found that gepants were effective for acute treatment of an ongoing migraine episode only in women, with no proof from the available data that they work in men.

Alan Rapoport, a neurologist from the University of California, Los Angeles David Geffen School of Medicine, US, who was not involved with the study, said this evaluation of data was “extremely important” because it shows something that most headache specialists are “probably unaware of.”

“These data show that gepants work well in women, and not very well at all in men,” he said. “Most headache specialists, due to [differences in disease] prevalence, treat more women than men. But we have plenty of male patients, and we give these same medications to those male patients. And, after seeing these data, I’m going to look very carefully at my male patients and maybe even consider not making gepants my primary medication for acute treatment of migraine for men if I can avoid it.”

The study appeared in the March 2024 issue of Cephalalgia.

The basis of a new study
In an interview with Migraine Science Collaborative, Porreca said he and his colleagues were very curious about whether there might be sex differences in the response rate to CGRP-targeted therapies, considering previous studies suggesting that the cellular and molecular mechanisms underlying pain are sex specific.

“The neurons that produce the signal that the brain ultimate interprets as pain are called nociceptors,” Porreca explained. “Those neurons, whether we look at them in animal models or in postmortem human donors, are different in males and females. They are different in terms of their RNA transcripts, and the proteins that they express, as well as how these neurons respond to the many molecules that activate them. So what we saw as we studied these neurons is that the sensory receptors that ultimately mediate the perception of pain are either male or female. This is a very new concept, but once you start to suggest this is the case, you have to suggest there will be qualitative, including mechanistic, sex differences in headache. Because when you activate the nociceptors, both men and women will feel pain or the headache of migraine. But what drives the pain or the headache may be different in the two sexes.”

Further, preclinical studies on the mechanisms underlying CGRP action suggested the neuropeptide promotes pain in a female-selective manner. Animal studies have also demonstrated that CGRP produces pain behaviors at much, much lower doses in female animals than in males, said Porreca. This, he said, begged the question of whether CGRP-directed therapies might work better in one sex over the other.

“This was the basis of this study: Would the CGRP-based medicines work better in women or in men?” said Porreca.

Making such an investigation possible was the availability of pertinent data.

“Each pharmaceutical company that did a clinical trial to test a CGRP drug filed their data with the FDA and the Center for Drug Evaluation and Research (CDER) for a new drug review. These data are publicly available and, within each report, the data from the trial are broken down by sex, because the FDA asks the companies to do that,” Porreca said.

Identifying sex differences
The researchers began with an analysis of ubrogepant, rimegepant, and zavegepant for acute migraine treatment to look for possible sex differences in response to these gepants.

To assess drug effects, they examined the FDA-mandated co-primary endpoints of two-hour pain freedom and two-hour freedom from most bothersome symptom. Drug effects were determined by subtracting the proportion of patients responding to placebo from the proportion responding to active treatments, for both endpoints.

The researchers also calculated the number needed to treat (NNT) in women and in men. NNT refers to the number of patients that would need to be treated to achieve one positive outcome.

When pooling the data for the three gepants, the researchers found a statistically significant drug effect of 9.5% in women, with an NNT of 11, for the pain freedom outcome. But the drug did not have a statistically significant effect in men, who showed a drug effect of only 2.8% and an NNT of 36. Such a high NNT suggests that even though many women benefit from CGRP-targeted therapies, many don’t – and highlights the need for continued research into new therapies.

“An NNT of 11 shows that 11 women need to be treated before one gets a therapeutic effect,” said Porreca. “This points to there being other mechanisms of migraine and the need for other migraine therapies that target those mechanisms.”

Similarly, only women seemed to benefit in terms of freedom from most bothersome symptom, with a drug effect of 10.2% in women and an NNT of 10, compared to 3.2% in men and an NNT of 32.

“Basically, we found that the drugs were effective in women, but there was no evidence of efficacy in men,” said Porreca. “Now, that doesn’t mean they don’t work in men; there’s just no proof at the moment that they do work in men.” Part of the challenge in finding that proof, he said, was the sample size of male participants who responded to the drugs – just over 200 in total, compared to roughly 1,600 women – making it difficult to detect drug effects in men that would indicate sex differences.

Moving beyond acute treatment, the group next turned to the antibodies erenumab, eptinezumab, galcanezumab, and fremanezumab, which are approved for preventive treatment of episodic and chronic migraine. They also considered atogepant, which is approved for preventive use in episodic migraine.

In contrast to the findings for acute treatment of an ongoing migraine, both men and women benefited from preventive treatment with the antibodies, and from atogepant, for episodic migraine. Here, treatment effects always favored the drug over placebo in both sexes. Consistent with that finding, for chronic migraine treatment, the antibodies showed similar effects in men and women, with the drug again always being favored over placebo.

“When we looked at the more chronic population for prevention, we didn’t see any sex difference,” said Porreca. “That’s important because what it suggests is that, mechanistically, CGRP may play a greater role in migraine as it becomes more chronic. We don’t know yet, and it shows that there is still more research work we need to do in terms of the pathophysiology of migraine to understand how CGRP may contribute as migraine transitions to chronic disease.”

A caveat that should be considered when considering possible sex differences in CGRP therapies for acute treatment of migraine and for migraine prevention is that the criteria for successful intervention are different, said Porreca. For acute migraine, the goal is to achieve the FDA-mandated co-primary endpoints of pain freedom and freedom from most bothersome symptom of an ongoing migraine at two hours after dosing with the drug. The goal is to terminate a migraine that is already underway. In contrast, with preventive therapy, the goal is to stop the migraine from ever starting. Because these two goals are so different, and CGRP’s contribution to the initiation of the migraine compared to the maintenance of an ongoing migraine remains poorly understood, it will be up to new research studies to uncover what role CGRP may play in different types of migraine disease – what sex differences, if any, may exist there.

Next steps
Rapoport said the results were striking, and show that further studies are needed to help determine which drugs might be most effective for male patients who have migraine.

“I’m very interested to see a real-world study – one that prospectively looks at the difference in acute care of migraine with gepants in men versus women,” he said. “These drugs are already being used very heavily. They are being advertised very heavily. And no one is saying anything about them not potentially working in men. So even though only about 25% of people living with migraine are men, it would be helpful to know whom these drugs really work for, how they compare to other classes of drugs, and to whom we should be prescribing them.”

For his part, Porreca said he hopes that clinicians do not automatically stop prescribing gepants to all male patients. He said he is aware that many men have benefited from these drugs, and it is important to remember that migraine therapy is not a one-size-fits-all approach.

“Individual patients are not uniform. That’s something we have to appreciate. Not all men will have migraines that are driven in the same ways as other men,” he said. “Once again, we can’t say that gepants don’t work for men. All we can say is the data from these studies don’t demonstrate that they do.”

In the meantime, Porreca hopes that investigators who are testing future migraine therapies consider sex differences as they design and enroll participants for clinical trials.

“The big implication for me is that, if you do a clinical trial and you have a mechanism in your therapy that works because pain is promoted in a sex-specific manner, you may reach the wrong conclusion if you aren’t careful,” said Porreca. “Eighty-five percent of participants in clinical trials involving migraine are women. That makes sense given the prevalence of migraine in women. Yet if the mechanism of the therapy you are testing is female specific, you may get a positive result because of the number of women in your study. Similarly, if the mechanism is male specific, you might get a negative result. So moving forward, if there is any evidence of sexual dimorphism in the mechanism, it will be important to consider the male-to-female composition of your trial to make sure you aren’t seeing an exaggerated effect or missing out on one.”

Kayt Sukel is a freelance writer based outside Houston, Texas.

Reference
Evaluation of outcomes of calcitonin gene-related peptide (CGRP)-targeting therapies for acute and preventive migraine treatment based on patient sex.
Porreca et al.
Cephalalgia. 2024 Mar;44(3):3331024241238153.

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Kayt Sukel is a passionate traveler and science writer who has no problem tackling interesting (and often taboo) subjects spanning love, sex, science, technology, travel and politics. Her work has appeared in the Atlantic Monthly, New Scientist, USA Today, Pacific Standard, the Washington Post, ISLANDS, Parenting, the Bark, American Baby, National Geographic Traveler, and the AARP Bulletin, among others. She has written stories about out-of-body experiences, artificial intelligence in medicine, new advances in pain treatments, and why one should travel to exotic lands with young children.

She is the author of two books: Dirty Minds: How Our Brains Influence Love, Sex, and Relationships (re-titled as This Is Your Brain on Sex: The Science Behind the Search for Love in paperback) and The Art of Risk: The New Science of Courage, Caution, and Chance.

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