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SAN FRANCISCO -- The calcitonin gene-related peptide (CGRP) inhibitor galcanezumab provided relief for episodic cluster headache and continued to show good efficacy against migraine, according to a pair of research reports presented here.

A phase III trial showed that monthly injections of galcanezumab -- a humanized monoclonal antibody recently given the brand name Emgality -- led to a significant reduction in the frequency of cluster headache attacks.

"This is one of the first placebo-controlled studies performed in cluster headache," which has no approved prophylactic treatment, according to Sheena Aurora, MD, of Eli Lilly, the developer of galcanezumab. "This is really uncharted territory."

These findings were presented at the American Headache Society annual meeting. Researchers also presented further analyses of previously reported phase III studies showing that galcanezumab provides rapid-onset relief of migraine and reduces the number of headache days in people not helped by onabotulinumtoxinA (Botox).

Vascular dysfunction is thought to play a key role in migraine. CGRP is a potent vasodilator, and blocking the peptide or its receptors has been shown to prevent migraine, but without the cardiovascular side effects often seen with triptans. The mechanisms underlying cluster headache, which involves recurrent attacks of intense pain on one side of the head, are not well understood, but here too, vascular dysfunction is believed to be involved.

Several CGRP inhibitors -- both monoclonal antibodies and small molecules -- are in the late stages of development. The first of these, erenumab (Aimovig), received FDA approval for migraine prevention in May. A Biologics License Application for galcanezumab for migraine is now under review.

Episodic Cluster Headaches

The CGAL study compared galcanezumab versus placebo for prevention of episodic cluster headaches. Up to 90% of cluster headaches are episodic, separated by pain-free remission periods lasting longer than 3 months, while about 10% are chronic.

"Cluster headache is not terribly common if you compare it to migraine, but it's much more devastating. These patients are overrepresented among the people in headache clinics for whom we often are really not able to offer effective treatment," session moderator Elizabeth Loder, MD, MPH, of Brigham and Women's Hospital in Boston, told 名媛直播.

Aurora presented results from the 8-week double-blind treatment portion of the trial. The analysis included 106 patients. More than 80% were men -- a reversal of the gender distribution for migraine -- and the mean age was 46 years. They had experienced cluster headaches for about 17 years on average and more than 10% had considered suicide.

Participants first began recording their headache attacks in an electronic diary. After 10 to 15 days, they were randomly assigned to receive monthly self-administered injections of 300 mg galcanezumab (higher than the doses used for migraine) or placebo. Diaries showed that they had an average of 17.5 weekly cluster headache attacks during the baseline period.

During the first 3 weeks after starting treatment, weekly cluster headache attack frequency fell by 8.7 in the galcanezumab arm -- that is, by about half -- and by 5.2 in the placebo arm (P=0.036), Aurora reported. At Week 3, 76% of participants in the galcanezumab group and 57% in the placebo group reported at least a 50% reduction in headache attack frequency (P=0.04).

At Week 4, about 70% of galcanezumab recipients and about 45% of placebo recipients said their cluster headache condition was "much better" or "very much better" since they started treatment (P=0.016). By Week 8, however, the improvement rate in the placebo arm rose to about 65% while the rate in the galcanezumab arm stayed the same, so the difference was no longer statistically significant (P=0.58).

Treatment was generally safe and well tolerated, with an adverse event profile similar to those previously observed in studies of galcanezumab for migraine. Four patients (8%) in the galcanezumab arm and 12 (21%) in the placebo arm discontinued treatment during the double-blind period; two galcanezumab recipients and one placebo recipient did so due to adverse events. Aurora said that there were "no clinically meaningful differences" in safety or tolerability between the two treatment groups, except for more injection site pain in the galcanezumab arm (8.2% versus 0%, respectively).

Aurora also reported that another phase III study called CGAM, looking at chronic cluster headache, did not see a significant difference in the reduction in headache frequency over 3 months in the galcanezumab and placebo groups (-5.4 versus -4.6, respectively; P=0.33).

"It's disappointing that galcanezumab didn't meet its primary endpoint in the chronic cluster headache trial," Loder told 名媛直播. "I think the company deserves a huge amount of credit for pushing ahead with trials for this devastating illness."

Galcanezumab for Migraine

Aurora also presented findings from an unplanned post hoc analysis of data from phase III studies of galcanezumab for preventing episodic migraine, looking at the time to onset of effect.

As reported last year, once-monthly galcanezumab reduced headache frequency more than placebo among patients with episodic migraine in the EVOLVE-1 and EVOLVE-2 trials, and among those with chronic migraine in the REGAIN trial. In EVOLVE-1, the reduction in monthly migraine headache days was 4.7 days with a 120 mg dose of galcanezumab and 4.6 days with a 240 mg dose, versus 2.8 days with placebo.

EVOLVE-1 included 858 participants in the U.S. and EVOLVE-2 included 916 patients in the U.S., Europe, and Asia. In both trials, more than 80% were women, the average age was about 41 years, they had experienced migraine for a mean of 20 years, and they had a mean of 9.1 migraine headache days per month.

At the AHS meeting, Aurora reported that a statistical separation between galcanezumab and placebo was seen starting around 1 week after the first injection, with galcanezumab providing a greater reduction in weekly headache days. Current oral therapies, she noted, often do not produce results for 2 to 3 months.

"For patients who have had migraine for 20 years on average, seeing a reduction in migraine headache days as early as week 1 is gratifying," she said.

Separately, a poster presented at the meeting described a post hoc analysis of EVOLVE and REGAIN trial data involving patients who previously failed onabotulinumtoxinA due to lack of efficacy or tolerability issues.

In this subgroup, patients treated with either 120 mg or 240 mg galcanezumab had a significantly greater reduction in the average number of monthly migraine headache days compared with placebo recipients, and more of them saw at least a 50% reduction in migraine days.

In addition to galcanezumab, the AHS industry-submitted oral abstract session also included data on Amgen's erenumab, Alder's eptinezumab, and Teva's fremanezumab.

Summarizing the monoclonal antibody studies, Loder told 名媛直播, "To me, the fascinating thing is they all look quite similar. I'm sure the individual companies would disagree, but to me we're seeing pretty much across the board the same statistically significant -- but let's face it, modest -- reductions in number of headache days."

"I think the message with this class of medications is that they're very well tolerated," she added. However, she noted that long-term safety remains uncertain, and safety during pregnancy is still a concern.