LOS ANGELES — A single dose of the novel monoclonal antibody eptinezumab (Alder Pharmaceuticals), which targets calcitonin gene-related peptide (CGRP), is effective in the prevention of chronic migraine for up to 3 months, a large phase 3 trial suggests.
The Prevention of Migraine via Intravenous Eptinezumab Safety and Efficacy 2 (PROMISE-2) trial, which included more than 1000 participants, showed that a 100-mg or 300-mg dose of the study drug at baseline significantly reduced monthly migraine days (MMDs) over weeks 1 to 12 compared with placebo (the primary endpoint).
Significantly more members of both dosing groups also showed at least a 75% reduction in MMDs over weeks 1 to 12, as well as migraine reduction on the first day post-infusion, than members of the placebo group.
The findings were presented here at the American Academy of Neurology (AAN) 2018 Annual Meeting.
"We saw that the probability of having a migraine attack the very next day after treatment was reduced by 52%, which reflects the very rapid onset of benefit from eptinezumab at the population level," principal investigator Richard B. Lipton, MD, director of the Montefiore Headache Center and professor of neurology at the Albert Einstein College of Medicine, New York City, said to meeting attendees.
He later told Medscape Medical News that two results in particular exceeded his expectations.
"One was the rapidity of onset of the treatment effect, which I think is unparalleled in migraine prevention," said Lipton. "The other was that a full third of people achieved the very high bar of 75% or greater reduction in monthly migraine days."
Race to Market
In May, the CGRP-targeting therapy erenumab (Aimovig, Amgen and Novartis) received US Food and Drug Administration (FDA) approval for the prevention of migraine in adults — making it first-in-class to be given the thumbs up for this indication.
Along with eptinezumab and erenumab, two other CGRP antagonists have been racing each other to market. Galcanezumab (Eli Lilly and Co) and fremanezumab (Teva Pharmaceuticals) are under review by the FDA, with the latter having a Prescription Drug User Fee Act action date of September 16.
In PROMISE-2, investigators enrolled 1072 patients aged 18 to 65 years with chronic migraine. All were randomly assigned to receive an infusion of 100 mg (n = 356; 86% women; mean age, 41.0 years) or 300 mg eptinezumab (n = 350; 90% women; mean age, 41.0 years) or matching placebo (n = 366; 89% women; mean age, 39.6 years).
At baseline, mean MMDs were 16.1, 16.1, and 16.2 for the three groups, respectively. Over weeks 1 to 12, both study drug groups had significantly greater reductions in baseline MMDs (change, –7.7 and –8.2) than the placebo group (–5.6; both comparisons, P < .0001).
The eptinezumab groups also met several secondary outcomes, including significantly more (compared with the placebo group) achieving at least a 50% and at least a 75% reduction in MMDs between baseline and week 12 and a reduction in migraine on the first day after receipt of the infusion (all comparisons, P ≤ .0001).
Table. Key Secondary Outcomes Among Treatment Groups
|Outcome||Eptinezumab 100 mg (% of Group)||Eptinezumab 300 mg (% of Group)||Placebo (% of Group)|
|≥75% reduction in MMDs||26.7||33.1||15.0|
|≥50% reduction in MMDs||57.6||61.4||39.3|
|Migraine reduction on day 1 after infusion||51.0||51.6||27.1|
In addition, more members of both dosing groups experienced at least a 75% reduction in MMDs by week 4 vs the placebo group (both dosing groups, P < .0001).
"This was one of the key protocol secondary outcomes and was significant," reported Lipton. "But the point is that the benefits of eptinezumab occur very rapidly. The population's levels of improvement reached their full potential at 1 to 4 weeks, which is a relatively rapid onset of action."
Three serious treatment-emergent adverse events (AEs) were reported in each of the three study groups. There were also two, eight, and two reports of any AE leading to drug withdrawal in the 100-mg, 300-mg, and placebo groups, respectively.
The most frequently reported AEs were nasopharyngitis (4%, 6%, and 4%, respectively), upper respiratory tract infection (3%, 4%, and 4%), nausea (2%, 3%, and 2%), urinary tract infection (2%, 3%, and 2%), and dizziness (1%, 3%, and 1%).
"The safety profile was consistent with previous eptinezumab studies," noted Lipton.
After Lipton's presentation, session co-moderator Natalia S. Rost, MD, MPH, director of the Acute Stroke Service at Massachusetts General Hospital and associate professor of neurology at Harvard Medical School, Boston, asked whether there were any data on long-term use of the drug, including any AEs from long-term exposure.
Rost, who was chair of the meeting's scientific committee, also asked whether there were any plans for head-to-head trials instead of just those that compared with placebo.
"With the explosion of calcitonin gene-related peptide therapies in the past several years, there's a lot of interest in regard to long-term use of these medications. For many patients, this becomes a life-long treatment," she said. "Also, will we ever see head-to-head trials with other migraine-preventative drugs?"
"Regarding long-term data, obviously with new molecular entities, you don't know what you don't know," answered Lipton.
All of the companies developing medications in this class "are conducting long-term safety studies. And my sense of the data I've seen so far is that the safety and the tolerability of CGRP-targeting therapies look really excellent," he said.
"So far, there's been no evidence of complications related to vascular disease in the data that are available," Lipton added. "But we'll have to wait for the long-term safety data to see where that leaves us."
As for upcoming comparisons, he noted that the commonly used oral medication topiramate "has definitely made life better for many of my patients, and I've very grateful for it. But when you look at medical claims data, it turns out that only 25% of people who get a prescription for it remain on it after 6 months and only 15% remain on it after a year," said Lipton.
He said that intolerability issues were commonly cited by the patients as reason for discontinuing the medication.
"I would guess that the monoclonal antibodies would have an edge in efficacy but they would certainly have an edge in tolerability. And if you looked at long-term results, my guess is they would favor monoclonal antibodies — depending on what you did with the people who discontinued the studies," he said.
"I hope those studies are done. I doubt the sponsors who make these drugs would do the studies, but I think doing so would certainly help us move towards a better foundation of evidence-based medicine and preventive treatment of chronic migraine," Lipton concluded.
After the session, Rost noted that a difference from other CGRP-targeting therapies is that this medication has 100% bioavailability after intravenous administration.
"That's what they say, although I haven't seen the results yet of the pharmacokinetics study. This is important because as most drugs pass through the body before reaching full capacity in the blood flow, they basically lose strength," she told Medscape Medical News.
But 100% bioavailability means the entire proportion of the drug enters circulation and delivers an active effect. "Bioavailability is good because they should be able to deliver smaller doses and do so more efficiently than what so far subcutaneous drugs have been doing," she said.
Still, she reiterated her concerns over what safety data may reveal for patients receiving recurrent injections over, potentially, their lifetime. "It's not clear whether any other prophylactic medications that are being used right now are, in comparison, more effective," said Rost.
For clinicians, "our focus is our patients. First, you try what's already out there, that which is already tested and tried, has an acceptable cost, and is something they can tolerate. But if that doesn't work, you escalate. I don't think this is going to be a first-line medication for a long time," she said.
Additional findings from PROMISE-2, as well as from the PROMISE-1 trial, will be presented at late-breaking, platform, and poster sessions at the upcoming American Headache Society (AHS) annual meeting, which will begin June 28, Alder announced in a statement released yesterday.
This will include quality-of-life and efficacy data after participants received two quarterly infusions in PROMISE 2, and new 1-year data from patients with episodic migraine who received eptinezumab in PROMISE 1.
Medscape Medical News will be onsite at the AHS meeting and providing coverage of the top studies presented.
PROMISE-2 was funded by Alder BioPharmaceuticals. Lipton reports having received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder, Allergan, the American Headache Society, Amgen, Autonomic Technologies, Avanir, Boston Scientific, Bristol-Myers Squibb, Colucid, Dr Reddys, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Novartis, Pfizer, Supernus, Teva, Trigemina, Vector, and Vedanta. He also holds stock options in eNeura, "a company without commercial products," he reported. Rost has received personal compensation for consulting, serving on a scientific board, speaking, or other activities from Broadview Ventures, Covance Inc, Merck and Co, Omniox, and Sanofi Genzyme and has received personal compensation in an editorial capacity for UpToDate and Current Treatment Options in Cardiovascular Medicine.
American Academy of Neurology (AAN) 2018 Annual Meeting. Clinical Trials Plenary Session, presentation 8. Presented April 24, 2018.
Medscape Medical News © 2018
Cite this: Eptinezumab Safe, Effective for Migraine Prevention - Medscape - Jun 21, 2018.