Article In Brief
Researchers reported that a monthly 300 mg dose of galcanezumab decreased the weekly frequency of cluster headache.
Galcanezumab, a humanized monoclonal antibody, may be effective as a preventive treatment for episodic cluster headache, a multicenter trial in Europe and North America found.
A 300 mg monthly dose, administered subcutaneously, decreased the weekly frequency of headache attacks across weeks one through three after the initial injection, as compared with placebo.
Results of the randomized, blinded trial—conducted at 35 international sites—were published online July 11 in The New England Journal of Medicine.
“For neurologists, the paper offers an evidenced-based treatment for episodic cluster headache aimed at reducing attack frequency during the bout,” Peter Goadsby, MD, PhD, FAHS, the study's lead author told Neurology Today.
In early June, the Food and Drug Administration approved galcanezumab as the first and only medication for the treatment of episodic cluster headache. In binding selectively to calcitonin gene–related peptide (CGRP) and suppressing its activity, galcanezumab previously had been shown to prevent migraine.
“There are no other positive trials in cluster headache with such agents,” said Dr. Goadsby, a neurologist and director of the NIHR Wellcome Trust at the King's College Clinical Research Facility in London, and professor of neurology at the University of California, San Francisco.
“Cluster headache attacks are widely regarded as the most severe pains humans experience,” he said. As a result, “it is challenging to have such patients enter a placebo-controlled trial,” said Dr. Goadsby. “Moreover, one needs to wait until they cycle into a bout, which can take a year.”
The prevalence of cluster headache is much lower than that of migraine. Nonetheless, it is a disabling primary headache disorder marked by severe attacks on one side of the head. Associated with agitation or restlessness, it also brings on cranial autonomic symptoms, such as lacrimation, conjunctival injection, and nasal congestion.
Without treatment, attacks span 15 to 180 minutes, striking once or several times per day during cluster headache periods that may last anywhere from weeks to months. In between bouts, patients experience attackfree remissions of variable duration, based on whether they have episodic cluster headache or chronic cluster headache.
Among the typically prescribed treatments are highflow oxygen and triptans—selective agonists of serotonin (5hydroxytryptamine [HT]) receptors that activate 5HT1B and 5HT1D (5HT1B/1D) receptors, such as sumatriptan, administered either subcutaneously, or intranasally, and zolmitriptan, administered intranasally.
Offlabel options include highdose verapamil and lithium, each of which has been adversely linked with side effects. The severity of attacks in some patients has spurred the development of invasive treatments such as deepbrain stimulation, trigeminal nerveroot section, and occipitalnerve stimulation.
Study Design, Findings
The trial enrolled participants ranging from 18 to 65 years of age and with a history of episodic cluster headache as defined according to the International Classification of Headache Disorders, 3rd edition (beta version). Cluster headache attacks had to be distinguishable from other headache disorders, such as migraine.
Other eligibility criteria were a cluster headache attack frequency of at least one attack every other day, a minimum of four total attacks, and no more than eight attacks per day during the seven consecutive days of the prospective baseline period. To lessen the possibility of early spontaneous remission due to the disorder's natural course, patients also were required to have experienced a cluster headache period lasting at least six weeks.
To treat cluster headache attacks, patients were permitted to use only subcutaneous, intranasal, or oral triptans; highflow oxygen; acetaminophen (paracetamol); and nonsteroidal anti-inflammatory drugs. Concurrent preventive treatments for cluster headache were prohibited.
Too few volunteers met the eligibility criteria, so recruitment was terminated before accrual of at least 162 participants, which had been the planned sample size.
Of the 106 enrolled patients, 49 were randomized to the galcanezumab group (at a 300 mg dose) and 57 to the placebo arm, administered subcutaneously at baseline and at one month.
The primary end point was the mean change from baseline in weekly frequency of cluster headache attacks across weeks one through three after administration of the initial dose. The key secondary end point was the percentage of individuals who had at least a 50 percent reduction in weekly frequency of cluster headache attacks at week three compared to baseline.
During the baseline period, the mean number of cluster headache attacks per week was 17.8±10.1 in patients who received galcanezumab and 17.3±10.1 in those given the placebo.
The mean reduction in weekly frequency of cluster headache attacks across weeks one through three was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; p= 0.04).
At week three, 71 percent of patients in the galcanezumab group and 53 percent in the placebo arm had at least a 50 percent decrease in headache frequency.
Investigators found no significant between group variations of adverse events, although 8 percent of patients in the galcanezumab group had pain at the injection site.
Eli Lilly funded the galcanezumab trial, provided the medication, and performed the analyses.
Neurologists interviewed by Neurology Today credited the investigators with tackling a rare disorder that is complicated to evaluate in a clinical trial and to treat in a physician practice.
The attacks can occur spontaneously and then remit, with patients experiencing improvement after a study begins and confounding whether their pain subsided due to the investigational drug or relented on its own, said Andrew Blumenfeld, MD, FAAN, FAHS, a neurologist and director of the Headache Center of Southern California in San Diego.
“Given the positive findings in the well-designed study showing separation between the galcanezumab and control groups, the medication should become a first-line treatment for cluster headache” Dr. Blumenfeld said.
Amid very limited treatment options, the drug “should make a big difference for our patients,” he explained, by shortening the cycle of headache attacks for those who suffer intense stabbing sensations, typically behind the eye on the same side. Some patients engage in restless activities, such as stair sprinting, “to bring the attacks to an end because the pain is so severe.”
“Not only are there few treatments, but there is also such heterogeneity in terms of responses among cluster patients that it's welcoming to have another option for this rare disease state, with a prevalence of one in 1,000 individuals,” said Paul G. Mathew, MD, FAAN, FAHS, assistant professor of neurology at Harvard Medical School and a headache specialist at Brigham and Women's Hospital.
Recruitment for double-blind, placebo-controlled trials for cluster headache can be challenging, because the thought of taking placebo for weeks to months, and not have their excruciating pain under control is not something many patients are willing to endure,” Dr. Mathew said. In addition, with an estimated prevalence of one in 1,000 individuals, cluster is much less common than migraine, although he suspects the actual prevalence is higher.
For two consecutive months, Dr. Mathew prescribed the 300 mg dose of galcanezumab to a patient with refractory cluster headache that was incompletely responsive to nerve blocks and steroid tapers. It shortened “the bout of disabling pain” from about six weeks to a couple of weeks. Cluster attacks are typically seasonal, with early spring and early fall being “prime time” for many patients, he said.
Prescribing caution in patients older than 65 would be warranted. The safety and efficacy of galcanezumab were not evaluated in this group, said Jessica Ailani, MD, FAHS, associate professor of neurology and director of Medstar Georgetown Headache Center at Medstar Georgetown University Hospital.
The drug is contraindicated in pregnant or lactating women, or a woman attempting to conceive, as well as individuals with known coronary artery disease. “This class of drugs has not been studied in patients who have had a stroke or myocardial infarction,” Dr. Ailani said.
“It is unclear if the medication would be more effective the longer it is used—something we are seeing often with this class of medication,” she added. “We also don't know if more side effects or adverse events would occur with longer use, though based on safety in migraine, it is less likely.”
Unlike in migraine, there were not consistent benefits across studies with monoclonal antibodies targeting CGRP for cluster headache. Galcanezumab was not effective for chronic cluster headache, and fremanezumab was not effective for neither episodic nor chronic cluster headache, said Matthew Robbins, MD, FAAN, FAHS, assistant professor of neurology and director of the neurology residency program at Weill Cornell Medicine in New York.
Before galcanezumab, neurologists “were faced with too few treatments with very limited evidence” in formulating the American Headache Society's guidelines in 2016. “The most effective drug in clinical practice, verapamil, was given a Level C rating, mainly because of the lack of studies,” Dr. Robbins said.
Although it would be challenging to determine if galcanezumab can replace verapamil as a first-line preventive measure, a shorter treatment latency could be one advantage. “Galcanezumab may render the need for simultaneous short-term preventive treatments, such as oral steroids or greater occipital-nerve injection with steroids, unnecessary,” he said. “Cost and access are likely to be major factors as well. Comparative studies are certainly needed.”
Dr. Ailana has consulted for Allergan, Alder, Amgen, Lily, Teva, Impel, Satsuma, Promius, Gammacore, Biohaven, Supernus; she has received fees for speaking for Allergan, Alder, Amgen, Lily, Teva, Promius, and Gammacore. Dr. Mathew has received consulting fees from Lilly, Amgen, Allergan, Biohaven, Promius, Revance, Satsuma, Stealth BioTherapeutics, Supernus, and Takeda. Dr. Robbins had no disclosures. Dr. Blumenfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder, Allergan, Amgen, Avanir, Depomed, Eli Lilly, Novartis, Pernix, Promius, Supernus, and Teva.