Eptinezumab, a monoclonal antibody, has shown impressive results in previous clinical trials, giving high hopes for the PROMISE 2 trial.
Richard Lipton, MD
After returning positive results in the PROMISE 1 study, Alder Biopharmaceuticals is undertaking a second phase 3 study to evaluate the use of eptinezumab (ALD403) to prevent migraine.
Dubbed PROMISE 2, the trial will examine the effects of eptinezumab for the treatment of chronic migraine; its predecessor focused on the episodic form of the condition. Chronic migraine, which affects an estimated 1% of the US population, is more ferocious, with most patients experiencing upward of 15 headaches days per month.
“Chronic migraine is really the severe end of the migraine spectrum,” Richard B. Lipton, MD, director of the Montefiore Headache Center and the Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine in the Bronx, New York, told MD Magazine®. “If you compare chronic migraine with, say, epilepsy, which is the second most common neurologic disorder, it’s just as prevalent. Chronic migraine is a really big deal, and it sometimes lives in episodic migraine’s shadow because it’s less common. But it’s still more common than most neurologic diseases—more common than multiple sclerosis, than Parkinson disease in the general population, and, across life span, more common than Alzheimer disease.”
Lipton, a neurologist with more than 3 decades’ experience in the migraine space, stressed the importance of a trial examining a treatment for the chronic condition, noting that those who have it experience not only more frequent attacks but also a lesser quality of life, greater disability levels, and higher medical costs.
The focus of PROMISE 2—eptinezumab—is exciting to Lipton, as well. The monoclonal antibody is 1 of 4 currently in development for migraine that targets calcitonin gene-related peptide (CGRP), a neurotransmitter that is closely related to migraine. (The other 3 therapies are produced by Eli Lilly and Company, Amgen, and Teva Pharmaceuticals.) CGRP levels rise during migraine attacks, and people with chronic migraine experience elevated levels between attacks, “presumably because the nervous system is chronically activated making CGRP,” Lipton said.
While all 4 antibodies have proven successful thus far, the Alder product features a key difference from its peers, which are given by subcutaneous injection. “If you compare eptinezumab with the other antibodies that have been studied in migraine, it is unique because it is the only intravenous [IV] antibody,” Lipton said. “It will only need to be given every 3 months, in contrast with the subcutaneous antibodies, which are generally given on [a] monthly basis.”
PROMISE 2 enrolled 1050 patients with chronic migraine, randomizing them to 1 of 2 doses of eptinezumab or a placebo, investigating the efficacy and safety over the course of 12 weeks. In PROMISE 1, the therapy showed positive results, reducing migraine days by ≥75% after 12 weeks in 29.7% of patients on the 300-mg dose and 22.2% in patients on the 100-mg dose compared with 16.2% with placebo (P = .0007). Perhaps most impressively, however, the therapy showed a ≥50% reduction in the proportion of patients experiencing migraine after 1 day.
“That is really in striking contrast with all the other preventive migraine drugs we have,” Lipton said. “Take the most widely used migraine preventive, topiramate. That’s a drug we start at 25 mg per day for a week, and then gradually escalate the dose through multiple steps. Even once you get to the target dose of 100 mg, you have to give it 6 to 8 weeks before you see if it works. So being able to give an effective dose in the first instance and having a very rapid onset of action is a benefit of this class of drugs, which may be greatest—but we don’t know—with the IV antibody.”
Eptinezumab is a preventive treatment, designed to reduce the frequency and severity of migraine. Lipton told MD Magazine® that these medicines are of higher value compared with their opposite, acute treatments, which are used to restore function in the event of an attack.
In addition, monoclonal antibodies such as eptinezumab have a favorable adverse effect (AE) profile compared with currently available therapies, such as topiramate. Lipton noted that most of the drugs used for migraine prevention act on the brain and were originally developed to treat epilepsy, and they come coupled with many AEs. Topiramate and divalproex sodium are examples of these medicines.
“Side effects are absolutely a big deal, and so having medications that have favorable tolerability profiles is important, and all 4 [monoclonal antibodies] have very favorable side effect profiles. If you look at people who get a topiramate prescription, 1 year later, only 18% stay on the treatment, so it’s tough for people to stay on the medication,” Lipton said.
Currently, onabotulinum toxin A (Botox, Allergan) is the only FDA-approved therapy for chronic migraine. The other treatments—topiramate, divalproex sodium, and beta-blockers—are approved for episodic migraine.
It is expected that the safety data from PROMISE 2 will echo the results from PROMISE 1, which were consistent with previous studies on eptinezumab. As important as the safety profile is, for Lipton, the biggest impact of monoclonal antibodies is their effect on what he calls “super responders.”
“We used to say the goal of preventive therapy was to reduce treatment by 50% or more. If we get a 50% reduction, that’s huge,” Lipton said. “If somebody [is] having 20 headache days a month, they get 10 days a month back. That is a big deal. For eptinezumab, they are looking at 75% responder rates—and there are some people that got the drug who had their headaches completely or nearly completely eliminated. There are super responders to this class of medication, and that is quite exciting.”