ARTICLE IN BRIEF

THE NEUROTRANSMITTER calcitonin-gene-related peptide (CGRP) is present throughout the body and brain, and spikes during migraines. CGRP antibodies and antagonists act by reducing CGRP levels or blocking the actions of CGRP, although it is not clear where they have their effect. While the exact pathophysiological role of CGRP in migraine remains unknown, it is clear that its elevation and interaction with its receptor directly contributes to migraine intensity, through enhancing both peripheral and central nociception pathways, possibly through increasing mast cell degranulation, neurogenic inflammation, and vasodilation. CGRP antibodies are thought to be peripherally restricted, whereas CGRP antagonists may have central actions.

In large clinical trials, researchers reported that four calcintonin-gene related peptide antibodies — three that bind to the peptide itself, and one that binds to the receptor — were safe and effective for reducing migraine days.

BOSTON—The mood at the American Headache Society (AHS) annual scientific meeting here in June was decidedly upbeat, with experts in the field declaring a “paradigm shift” and “the start of a new era in the treatment of migraine.” The excitement was generated by announcements of positive trial results across the board for four antibodies, from four competing companies, targeting the calcitonin gene-related peptide (CGRP) or its receptor.

Three agents — eptinezumab from Alder Biosciences, fremanezumab from Teva, and galcanezumab from Lilly — bind to the peptide itself, while erenumab, from Amgen, binds to the receptor. While not all the companies have submitted data for final regulatory review, all have completed large-scale trials, and all, according to results presented at the meeting, met their primary and secondary endpoints — rapid, significant, and long-lasting relief of migraine — with adverse-effect profiles identical or close to placebo.

DR. DAVID W. DODICK said the monoclonals are likely to greatly improve adherence over current migraine preventives. “This is going to be changing the way neurologists practice.”

“We are about to enter an era where we have preventive treatments specifically for migraine. We are standing at the edge of an incredible development,” predicted Peter Goadsby, MD, PhD, FAHS, professor of neurology at Kings College London and chair of the AHS science program committee.

CGRP MECHANISMS

CGRP was discovered in the early 1980s as an alternatively-spliced transcript of the calcitonin gene. Soon thereafter it was found to be abundantly produced by trigeminal nerve endings, and was elevated during migraine attacks. While the exact pathophysiological role of CGRP in migraine remains unknown, it is clear that its elevation and interaction with its receptor directly contributes to migraine intensity, through enhancing both peripheral and central nociception pathways, possibly through increasing mast cell degranulation, neurogenic inflammation, and vasodilation.

Small-molecule CGRP antagonists were developed early on, but have been limited by concerns over adverse effects, including liver toxicity. That set the stage for development of monoclonal antibodies targeting either the peptide of its receptor.

None of the four monoclonal antibodies against the CGRP system are immunomodulatory, since their target is not the immune system. A small percentage of patients, ranging from 1 percent to 14 percent, depending on the drug and the study, do carry antibodies against the monoclonal antibody, but so far none has been shown to affect the ability of the treatment to reduce migraine.

The clinical programs for the four agents have proceeded rapidly, culminating in the recently completed phase 3 trials announced at the AHS meeting.

EPTINEZUMAB

A single dose of eptinezumab reduced migraine days by 75 percent after three months in a third of patients with chronic migraine, according to the results of a phase 2B trial presented here. The trial enrolled 616 patients who had 15 to 28 headache days per month, at least eight of which were migraine. As in each of the other studies presented at the meeting with monoclonals targeting the CGRP system, patients were primarily female, with a history of migraine often of a decade or more.

Patients received a single intravenous dose of eptinezumab (300 mg, 100 mg, 30 mg, or 10 mg) or placebo. The primary endpoint was the percentage of patients with a 75% or greater reduction in migraine days over three months.

At baseline, patients had 16 migraine days per month. The primary endpoint was achieved by 33 percent of patients in the 300-mg dose group and 31 percent of those in the 100-mg group, versus 21 percent receiving placebo (both comparisons p<0.05).

Neither of the low-dose groups were different from placebo. In a post-hoc analysis, there was a dose-dependent reduction in the severity of migraine compared to placebo as well, and the separation from placebo for frequency began to appear within the first 24 hours of treatment.

“It might not just be frequency that is affected,” said Jeffrey Smith, MD, lead author and senior vice president at Alder. “This is an exploratory endpoint, but it may be important as well.” In addition, he noted, migraine reduction was extremely rapid, with a separation from placebo beginning to appear within the first 24 hours of treatment.

Eptinezumab is now in phase 3 trials, with the final results expected in early 2018.

GALCANEZUMAB

Sheena Aurora, MD, a medical fellow and global launch leader at Eli Lilly Company, reported that monthly injections with galcanezumab reduced headache days by an average of four days per month for six months, compared to two days for placebo, according to results from a phase 3 trial that enrolled more than 900 patients. Participants were randomized 2:1:1 to placebo or galcanezumab at 120 mg or 240 mg, delivered by subcutaneous injection once monthly for six months. At baseline, patients had about nine migraine headache days per month.

After six months, patients on placebo had a decline in mean migraine headache days of 2.25 days, while those on galcanezumab declined by 4.29 days at 120 mg and 4.18 days at 240 mg. Both were significant compared to placebo at p<0.001. Both doses outperformed placebo at each monthly assessment.

In a secondary analysis, there were significantly more patients on active treatment who achieved a 50 percent or more reduction in the number of migraine headache days — 36 percent of those on placebo compared with 59 percent for those taking 120 mg and 56 percent, 240 mg — as well as a 75 percent or more reduction (18 percent of those on placebo; 33 percent on 120 mg, and 34 on 240 mg. Injection-site reactions were more common in active treatment than placebo. Eli Lilly, which is developing the drug, is planning to submit data for approval to the US Food and Drug Administration (FDA) later this year.

FREMANEZUMAB

Patients receiving a single injection of fremanezumab began to experience relief within one week of administration, and continued to experience significant reduction in migraine for up to three months compared to placebo, according to data from a phase 3 trial presented here.

The trial included three arms: placebo injections once a month for three months; a single 675 mg subcutaneous injection of fremanezumab, followed by two monthly placebo injections (designed to test the efficacy of quarterly injections); and one 675 mg injection of fremanezumab followed by two monthly injections of 225 mg fremanezumab.

DR. KATHLEEN B. DIGRE: “Typically weve needed to wait four to eight weeks to see a response, whereas each of the CGRP antibodies appear to show some kind of signal by one week. Thats remarkable.”

The primary endpoint was the change from baseline in the number of monthly headache days of at least moderate severity over three months: 1,130 patients were randomized 1:1:1 to each of the three treatment arms.

Placebo-treated patients experienced an average of 2.5 fewer headache days per month during the study. Monthly headache days declined by 4.6 days in patients receiving monthly fremanezumab, and by 4.3 days in those receiving the single dose (both results p<0.001 versus placebo). Injection-site effects were similar in placebo and active-treatment groups.

Active treatment was associated with at least a 50% reduction in headache days in 41% of those on monthly treatment and 38% of those on quarterly treatment, versus 18% on placebo (both results p<0.001 versus placebo). Benefits emerged within one week of initial treatment.

ERENUMAB

In patients with chronic migraine, erenumab reduced monthly migraine days by 6.6 days, versus 4.2 days for placebo, according to a phase 3 study presented here. Successful phase 3 trials of erenumab for episodic migraine have been previously presented.

DR. STEPHEN D. SILBERSTEIN: “Absent head-to-head studies, it is difficult to determine what nuances there may be between these drugs. Instead, the global message from these trials is that we have a new series of drugs that are powerful and effective, and have a side-effect profile similar to placebo. For one of the most disabling of disorders, which affects millions of people in their most productive years, this allows hope.”

To test its potential in chronic migraine, defined as headache for 15 or more days per month, and migraine for eight or more days per month, investigators enrolled 667 patients, randomized 3:2:2 to monthly placebo, erenumab 70 mg or erenumab 140 mg, administered subcutaneously. The primary endpoint was the change from baseline in monthly migraine days over three months of treatment, a measure meant to account for expected month-to-month fluctuations in severity.

The researchers used the mean of the three months, rather than the reduction in the final month, because experience has shown that the response rate fluctuates somewhat from month to month, said the lead investigator, Stewart J. Tepper, MD, FAHS, professor of neurology at the Geisel School of Medicine at Dartmouth in Hanover, NH.

At baseline, patients in each group had a mean of 18 monthly migraine days. Both doses of erenumab reduced that by a mean of 6.6 days, versus 4.2 days for placebo (p<0.001 for both). Active treatment was also associated with a greater response rate, with 40 percent and 41 percent in the low- and high-dose groups experiencing a 50 percent or greater reduction in monthly migraine days, versus 23 percent for placebo (p< 0.001 for both).

Adverse event profiles were similar for active treatment and placebo, except for a small increase in injection-site pain in those receiving erenumab. The results of the trial were published recently in June in Lancet Neurology. The company has submitted data to the FDA for an indication for both episodic and chronic migraine.

EXPERTS COMMENT

“The results reported for these drugs are very exciting,” commented Kathleen B.Digre, MD, FAAN, professor of neurology and ophthalmology and director of the division of headache and neuro-ophthalmology at the University of Utah in Salt Lake City. The safety profile looks very promising, compared to current preventive treatments, and the speed of response “is extraordinary,” she said. “Typically we've needed to wait four to eight weeks to see a response, whereas each of the CGRP antibodies appear to show some kind of signal by one week. That's remarkable.”

David W. Dodick, MD, FAAN, professor of neurology at the Mayo Clinic in Scottsdale, AZ, said that, because of their ease of administration and tolerability, the monoclonals are likely to greatly improve adherence over current migraine preventives. “This is going to be changing the way neurologists practice.”

Stephen D. Silberstein, MD, FAAN, professor of neurology and director of the Headache Center at Jefferson University Hospital at Thomas Jefferson University in Philadelphia, said, “I would look at them all as a group. They are all effective, and they all look safe and tolerable.”