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The calcitonin gene-related peptide (CGRP) blocker galcanezumab bested placebo in a phase IIb trial, meeting its primary endpoint of preventing episodic migraine.

A monthly subcutaneous injected dose of 120 mg of the investigational agent met the study's primary objective: the posterior probability of greater improvement, measured by the mean change from baseline in the number of migraine headache days 9 to 12 weeks after randomization, compared with placebo versus 95% superiority threshold, reported David Dodick, MD, of the Mayo Clinic in Phoenix, and colleagues.

The drug also showed fewer migraine headache days from baseline, with an overall reduction of 4.3 days for patients treated with either 120 or 300 mg of galcanezumab versus 3.4 days for placebo (P=0.02), they wrote online in

"This phase IIb study supported the favorable efficacy and tolerability results of a previous phase II study with galcanezumab, established the lowest effective dose, confirmed the therapeutic value of blocking the CGRP pathway in migraine, and supported phase III trials with galcanezumab for the preventive treatment of episodic and chronic migraine," Dodick told 番茄社区app.

Galcanezumab joins other CGRP blockers fremanezumab, erenumab (Aimovig), and eptinezumab that are being evaluated for migraine prevention. Previous galcanezumab trials have reported benefits over placebo, and manufacturer Eli Lillyon Dec. 11, 2017 that the FDA has accepted the Biologics License Application (BLA) to review the drug.

"The results of this study are consistent with those of other published studies evaluating the CGRP antibodies for prevention of migraine," Elizabeth Loder, MD, MPH, of Brigham and Women's Hospital in Boston told 番茄社区app. "The treatment is clearly more effective than placebo, but the magnitude of the benefit is modest."

"I would like to see a head-to-head trial with currently available preventive drugs," added Loder, who was not involved in the study. "I suspect these new treatments might not prove to be more effective than existing drugs such as topiramate."

Trial Details

In this double-blind trial, researchers enrolled patients, ages 18-65, who had four to 14 migraine headache days per month, and experienced migraine onset prior to age 50. Patients must have stopped botulinum toxin type A and B treatments at least 4 months before baseline.

The study ran from July 7, 2014 to Aug. 19, 2015 in the clinics of 37 licensed physicians and had four periods:

• Period 1 (5-45 days): Initial screening and washout of migraine prevention treatments
• Period 2 (28-38 days): Established baseline for migraine headache days; participants must have experienced at least 2 migraine attacks during this period to continue
• Period 3: Patients randomized to one of five groups to receive subcutaneous injections of 5, 50, 120, or 300 mg of galcanezumab or placebo once monthly for 3 months
• Period 4: 3-month post-treatment period in which patients received none of the tested treatments

The researchers allowed patients to take short-term migraine medications, excluding opioids or barbiturates, as needed. They permitted other preventive treatments only during study period 4, at the discretion of the investigator.

Baseline demographic and clinical characteristics were not statistically significantly different between any treatment groups. The patient population was primarily female (83.0%) and white (75.0%), with an average age of 40.2.

The primary objective was to determine whether at least one dose of galcanezumab was superior to placebo in preventing migraine. To be superior, the posterior probability of greater improvement for any galcanezumab dose group compared with placebo, measured by the mean change from baseline in the number of migraine headache days 9 to 12 weeks after randomization, had to be 95% or more.

For the primary endpoint, 120 mg of galcanezumab significantly reduced migraine headache days compared with placebo (99.6% posterior probability −4.8 days, 90% Bayesian credible interval −5.4 to −4.2 vs 95% superiority threshold −3.7 days, 90% BCI −4.1 to −3.2).

The overall change from baseline in the number of migraine headache days during study period 3 also was statistically significantly different for patients treated with both 120 mg (−4.3 migraine headache days; 95% CI −4.9 to −3.7, P=0.02) and 300 mg (−4.3 migraine headache days, 95% CI, −4.9 to −3.7, P=0.02) of galcanezumab, compared with placebo (−3.4 migraine headache days, 95% CI −3.8 to −2.9).

Adverse events that were reported by 5% or more of patients in at least one galcanezumab group, and more frequently than placebo, included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea.

"The very low discontinuation rate due to adverse events in this study reinforces the favorable tolerability profile of galcanezumab that will hopefully translate into improved patient adherence, compared to currently approved preventive options for episodic migraine, and long-term patient outcomes," Dodick said.

Study limitations included its short duration, although the authors noted that a 3-month double-blind period is routine in migraine prevention trials. The 28-day baseline period, although standard, also may not have been long enough to establish an accurate baseline of headache frequency.

Finally, the researchers did not correct secondary endpoints for multiple comparisons; these should be interpreted with caution and viewed as preliminary, they wrote.

Concern for Pregnant Women

Galcanezumab's 28-day half-life also may improve adherence since patients don't need to take it daily, but could be a disadvantage if side effects occur, Loder noted.

"I particularly worry about this because we do not have good information on the safety of these antibody treatments in pregnancy, yet childbearing women are most severely affected by migraine and most likely to be using these treatments," she said. "Roughly half of pregnancies are unintended, and if unintended pregnancy occurs shortly after taking an injection of this treatment, first trimester exposure will occur."

"CGRP is a potent vasodilator and is widely distributed in the body, so it is likely that it plays an important role in many processes," she added. "Galcanezumab appears to be well tolerated, although there are quite a number of respiratory and GI infections or inflammatory conditions, such as Crohn's exacerbation, appendicitis, sinusitis, etc. That will be something to look for in future trials."

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