SAN FRANCISCO – , the investigational calcitonin gene-related peptide inhibitor under development as preventive therapy for migraine, looks like a triple threat: Multiple phase 3 randomized trials have not only demonstrated safety and efficacy of the monoclonal antibody for prevention of both episodic and chronic migraine but for prevention of episodic cluster headache as well.
Galcanezumab’s demonstrated preventive benefit in patients with episodic cluster headache, if confirmed, would be a big deal. This type of headache is far less common than migraine, but often characterized as not merely debilitating but devastating. Phase 3 evidence of galcanezumab’s safety and efficacy for prevention of episodic cluster headache constitutes a unique advantage over fremanezumab and eptinezumab, the other two monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) for which new phase 3 data were presented at the. But the latter two novel agents showed advantages of their own.
While the efficacy of the CGRP inhibitors isn’t light-years ahead of the long-standard preventive therapies for migraine, such as topiramate, beta-blockers, antidepressants, and valproate, the new agents offer far greater tolerability and safety – side effect profiles are essentially the same as for placebo except for a modest increase in mild injection site reactions – along with documented substantial quality of life improvements using validated measures. And onset of benefit is far more rapid than with the long-time standard oral preventive medications.
Here are the highlights from the AHS annual meeting:
Sheena K. Aurora, MD, presented the results of the GCAL study, a phase 3 randomized, double-blind, 8-week study of subcutaneous galcanezumab at 300 mg once monthly or placebo administered for 2 months in 106 patients with ongoing episodic cluster headache attacks at baseline.
“This is really uncharted territory. The American Headache Society, in its 2016 cluster headache guidelines, reported that there was no high-quality evidence for prophylactic therapy,” noted Dr. Aurora of Eli Lilly in Indianapolis.
After the GCAL study, that’s no longer true. Study participants were a typical population of episodic cluster headache patients: that is, mostly middle-aged men. They averaged more than 17 cluster headache attacks per week during the baseline period, or 2-3 daily, with roughly a 16-year history of episodic cluster headaches, which typically occur in bursts lasting 6-8 weeks before temporarily fading. Of note, 14 of the 106 patients reported a history of prior suicidal ideation; while disturbing, that’s actually a lower rate than in some epidemiologic studies examining patients with this excruciating form of head pain.
The primary endpoint was the mean change in weekly cluster headache attack frequency during weeks 1-3. The difference was significant: a reduction of 8.7 attacks per week in the galcanezumab group, compared with 5.2 fewer in controls. The key secondary endpoint was the proportion of patients with at least a 50% reduction in weekly cluster attack frequency from baseline at week 3: This was achieved in 76% in the galcanezumab arm, versus 57% for placebo, again a significant difference.
At week 4, 73% of patients on galcanezumab rated themselves as very much or much better on the Patient Global Impression of Improvement, significantly greater than the 46% rate in controls. By week 8, this difference – while trending favorably – was no longer statistically significant, but it must be noted that by then 8 of the original 57 patients randomized to placebo had discontinued treatment because of the lack of efficacy, compared with just 1 of 49 in the galcanezumab group.
Adverse events in the two treatment arms were essentially the same as placebo except for an 8% rate of mild injection site reactions in the active treatment group.
Another double-blind, placebo-controlled phase 3 trial known as the CGAM study was conducted in 237 patients with chronic rather than episodic cluster headache. However, it proved negative for the same endpoints, Dr. Aurora said.
Separately, she presented a new post hoc analysis of the recently published EVOLVE-1 () and EVOLVE-2 ( ) trials. These two mirror-image pivotal phase 3, double-blind, placebo-controlled, 6-month studies of galcanezumab at 120 or 240 mg once monthly included a collective 1,773 episodic migraine patients with a baseline mean of 9.1 migraine headache days per month. Her analysis focused on the rapidity of onset of the humanized monoclonal antibody’s preventive effect.
“As most clinicians are aware, the current oral preventive treatments that we use require titration, and we don’t really see a good effect for maybe 2-3 months,” she observed.
In an ordinal logistic regression analysis, she and her coinvestigators first determined that the galcanezumab group separated from placebo in terms of reduced migraine headache days as early as 1 month in both studies. Next, they drilled down deeper into the participants’ daily headache diaries and determined that the onset of effect was seen at week 1, at which point the odds of a significant reduction in weekly migraine headache days were 2.71-fold greater with galcanezumab than placebo in EVOLVE-1 and 2.88-fold greater in EVOLVE-2.
“Patients would like to know how quickly they might see an effect, so the fact that we start seeing it for patients who’ve had migraine for 20 years with an average of 9.1 migraine headache days per month as early as week 1 is gratifying, even though the absolute numbers who benefit at that point are small,” Dr. Aurora said.