Are CGRP Medications Effective Against Migraine in Men?

Most patients with migraine are women, and this observation is reflected in clinical studies. A pharmacologist and a neurologist from the United States argue that the efficacy of calcitonin gene-related peptide (CGRP)-based migraine therapies has been proven in women but not in men and that men should be informed of this.

Tim Jürgens, PhD, MD, president of the German Migraine and Headache Society, is critical of this claim. "That would be scientifically and medically incorrect. The evidence put forward by the US colleagues is not sufficient to deduce that CGRP-based therapy is ineffective in men," Jürgens, who is the chief physician of the Neurology Clinic at the KMG Hospital Güstrow in Germany, told Medscape German Edition.

Raising Questions

In their article, which was published in JAMA Neurology, Frank Porreca, PhD, associate head of pharmacology at the University of Arizona in Tucson, and David W. Dodick, MD, professor emeritus of neurology at the Mayo Clinic Arizona in Phoenix, refer to medication that targets CGRP or its receptors. CGRP is an inflammatory neuropeptide that contributes significantly to the development of migraine attacks.

While antibodies such as fremanezumab, galcanezumab, and eptinezumab attack CGRP directly, erenumab targets the CGRP receptor in the same way as the so-called gepants. The active substances in this class, which was first approved in the European Union in 2022, are small molecules that act as CGRP-receptor antagonists.

Oral rimegepant is indicated for both acute treatment and prophylaxis. In 2023, another drug received approval as a prophylactic against migraines, the oral atogepant. The active substance ubrogepant is also approved in the United States.

Studies of Gepants

Porreca and Dodick base their argument that CGRP-based therapies, especially the new active-substance class of gepants, are less effective in men than in women on preclinical data. These data demonstrated the following points:

In mice, the injection of CGRP directly into the dura mater led to migraine-like headaches. Much lower doses were required for this In female animals than in their male counterparts.
CGRP antibodies alleviate migraine-like pain in female mice considerably better than they do in male mice.

The US authors also drew on the following observations from human studies:

One study with seven women and one man showed that in women, the CGRP level was elevated during a migraine attack and could be normalized again with sumatriptan. In the man, the levels were not elevated, nor could they be reduced through the application of the triptan.
Provocation studies, in which migraine headaches were triggered through an infusion of CGRP to prove its role in the formation of migraines, were conducted almost exclusively in women.
Pooled data on ubrogepant and rimegepant showed no therapeutic benefit in men. While ubrogepant demonstrated a therapeutic benefit, compared with placebo, in 8.3% (freedom from pain) and 12.4% (burdensome symptom after 2 hours) of women, a benefit was only observed in 0.2% or 0.7% of men, compared with placebo. Similar results were seen in studies of rimegepant.

Porreca and Dodick conceded that the therapeutic benefit may be impossible to verify because of the studies' insufficient statistical power. Nevertheless, they write, "The clinical data are consistent with the preclinical studies, and the conclusion is unambiguous. At this point in time, there is little to no evidence of the clinical benefit of these medications in the short-term treatment of migraines in men."

Inefficacy Not Demonstrated?

However, for Jürgens, this limitation does not allow such a conclusion to be drawn. "These investigations were not designed to investigate the effects separately for men and women, they were therefore also not qualified to do so," he said. "That is definitely something that should be investigated in larger cohorts. However, I do not find it conceivable for consequences to be drawn for clinical practice."

The headache specialist is also very critical of the call for male patients with migraine to be informed accordingly. Porreca and Dodick suggest that male patients should be informed that "experimental studies on animals and humans have quite clearly shown that CGRP plays a role with migraines in women and that the evidence from clinical studies supports the efficacy of CGRP receptor antagonists in women — but still not for men."

Nocebo Effect

"It contradicts all scientific principles," said Jürgens. "If you give male patients information such as this — without sufficient evidence to support it — you are eventually encouraging a nocebo effect. It is widely known that the patient's expectation has a major influence on therapy success."

In addition, CGRP antibodies, and even gepants, cause placebo-like side effects. So, it cannot be argued that men are expected to take a large risk for a potentially low efficacy. "In everyday clinical practice, we do not see any difference between men and women in response rates," says the DKMG president. "Nothing of the sort occurred in approval studies either."

Changing Medical Practice

"It is an interesting aspect that may warrant more attention in the future," Jürgens added. He also agreed with the authors' call for clinical studies that will allow efficacy in men to be examined in a targeted manner.

"However, I see no need to change our medical practice right now," Jürgens continued. "If we were to adopt the recommendation by the US colleagues and inform men that the data situation is mediocre, then, on the one hand, this approach would not be indicated by the data, and on the other hand, it would be medically incorrect, since we would potentially induce a nocebo effect — and all this with medications that pose no relevant risk if they are used correctly. Most patients would simply be denied effective therapy."

This article was translated from the Medscape German Edition.

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