Set expectations for new migraine treatments

People with chronic migraine may soon be able to choose among multiple novel agents designed specifically for migraine prevention.

In May 2018, FDA announced the regulatory approval of erenumab-aooe for prevention of chronic migraine in adults, and on Sept. 14, fremanezumab-vfrm was approved. These are the first drugs approved specifically for migraine prevention.

“The headache community is excited because in the past, medications used for migraine prevention were initially developed for other conditions, then found to be effective for migraine,” said Mia T. Minen, MD, MPH, a board-certified neurologist and headache specialist at New York University Langone Health in New York City. “This class of drugs was developed for migraine specifically.”

Erenumab and fremanezumab are monoclonal antibodies that belong to a class of large-molecule drugs called calcitonin gene-related peptide (CGRP) inhibitors. CGRP is a neuropeptide distributed throughout the nervous system and is thought to play a role in several processes, including vasodilation, release of inflammatory mediators, and transmission of nociceptive signals to the central nervous system.

“Existing treatments work through other pathways, and, in some cases, we are not certain how they exert their effects [on migraine],” said Elizabeth Loder, MD, MPH, chief of the division of headache at Brigham and Women's Hospital in Boston. “But there are almost certainly some things that we don't yet understand about CGRP inhibitors yet as well.”

Experts like Drs. Minen and Loder plan to use the new treatments for their patients with refractory chronic migraine, a condition estimated to be the sixth-highest cause of years lost to disability worldwide, but note that, as with any new class of drugs, clinicians must start prescribing cautiously.

New players

The new class of CGRP antibodies has been given as injections in clinical trials, and it is anticipated that the drugs will be administered by patients at home using an autoinjector.

Erenumab was approved based on results of three trials. The first was a phase III randomized clinical trial published in the New England Journal of Medicine in 2017. In the trial, 955 patients with episodic migraine were randomly assigned to receive erenumab or placebo for six months. Patients assigned to erenumab had a mean reduction in migraine days per month of between 1 to 2 days compared with placebo. A second study of 577 patients with episodic migraine published in Cephalalgia earlier this year showed a reduction of about 1 migraine day per month over a 3-month period compared with placebo. The third study of 667 patients with chronic migraine published in 2017 in Lancet Neurology showed an average reduction of 2.5 monthly migraine days compared with placebo.

A phase III trial comparing fremanezumab with placebo in 1,130 patients, meanwhile, was published Nov. 30, 2017, by the New England Journal of Medicine and found that both monthly and quarterly injections of the drug reduced headache days per month in patients with chronic migraine. Another phase III trial published May 15 in JAMA that tested both monthly and quarterly dosing for the prevention of episodic migraine in 875 patients found that fremanezumab reduced the mean number of monthly migraine days by 1.3 to 1.5 days over a 12-week period versus placebo. The drug is administered subcutaneously.

Other CGRP antibodies are in development as well, all with small differences in doses or routes of administration. Erenumab and galcanezumab, like fremanezumab, are administered subcutaneously, and eptinezumab is given intravenously.

A recent phase III study of galcanezumab presented at the American Headache Society's 2018 annual meeting met its primary endpoint by reducing weekly cluster headache attacks compared with placebo. This is in addition to three prior phase III studies presented at the society's 2017 annual meeting (EVOLVE-1, EVOLVE-2, and REGAIN) in chronic and episodic migraine that also showed significant reductions in the number of monthly migraine headache days with galcanezumab compared with placebo.

For eptinezumab, results presented at the American Academy of Neurology's annual meeting this year showed that in a phase III trial, the drug decreased the number of monthly migraine days in patients with chronic migraine compared with placebo.

Other drugs are being researched that experts hope will be able to stop migraines in process. These drugs, known as gepants, are oral small-molecule CGRP inhibitors. In April, researchers at the American Academy of Neurology's annual meeting announced positive results from a second phase III trial of ubrogepant, in which a greater percentage of patients assigned to the drug achieved pain freedom at two hours compared with placebo. At the American Headache Society's 2018 annual meeting, researchers presented results of a study of another oral small-molecule CGRP inhibitor, rimegepant, in which 20% of patients assigned to the drug were pain-free at two hours compared with 12% of patients assigned to placebo.

However, there are some safety concerns surrounding this class of drugs related to potential hepatotoxicity. Research into one gepant, telcagepant, was terminated after a data safety monitoring board identified two patients with significant elevations in serum aminotransferase levels.

Price, value

The manufacturers of the two additional CGRP antibodies are expected to file for approval with the FDA in the next year or so, and the expectation is that they will likely be approved, according to Dr. Loder.

“In clinical trials the benefits and harms of the antibodies appear very similar,” Dr. Loder said. “The only thing that would change that is if any postmarketing safety problems are identified with erenumab and fremanezumab. That would clearly have implications for the other antibodies, since all of these treatments work through the same pathway.”

Generally speaking, all of the injectable CGRP antibodies are fairly similar for migraine prevention, according to Philip A. Bain, MD, FACP, division chief of internal medicine at SSM Health Dean Medical Group in Madison, Wisc.

“The difference is going to come down to cost and ease of use,” Dr. Bain said.

In a draft evidence report issued earlier this year, the Institute for Clinical and Economic Review (ICER) used a placeholder price of $8,500 per year to evaluate the value of this class of drugs. However, Amgen/Novartis later announced a list price of $6,900 per year for erenumab. Using this updated price, in early July, the ICER released a final evidence report on three of the CGRP antibodies, including erenumab. The panel voted that “erenumab represents an intermediate [long-term] value in adults with chronic migraine,” according to an ICER press release. Votes were split between an intermediate value and a low long-term value when used in patients with episodic migraine. However, the final evidence report also included results on efficacy from a network meta-analysis that showed no significant difference in reduction of monthly migraine days when comparing CGRP antibodies to other available therapies.

“The treatment is very expensive and the price, I think, is out of line with the value that the drug brings,” Dr. Loder said. “That of course is in the eye of the beholder.”

This raises the question of what insurance companies might require of patients before approving payment for these drugs, said Gary I. Rogg, MD, FACP, who is co-founder of WMC Headache Specialists in Valhalla, N.Y.

“I expect that, just like what often occurs with Botox [for migraine], part of the approval process is that patients will have to have been on certain other prophylactic medications first,” Dr. Rogg said. “It will be required that they have used beta-blockers, Topamax, or other prophylactic medicines.”

What clinicians should know

The other big question, Dr. Rogg said, is how sustainable the use of these medications will be over a period of years. “Is this something that is maintained or something that may lose its efficacy in three to four years?” Dr. Rogg said.

Migraine is a lifelong condition, and many people who use preventive treatments are on them for decades, Dr. Loder added. “The existing evidence about safety and tolerability pales in comparison to what will happen in clinical practice,” she said. “It is important that physicians are careful to communicate that long-term safety of these treatments is unknown.”

In clinical trials, CGRP antibodies appeared to be well tolerated, with the most common adverse events including injection-site reactions, constipation, muscle spasms, or cramps. But tolerability is not safety, Dr. Loder said. Caution should be taken, especially in patients who are young women of childbearing age, as the long-term safety and effects on pregnancy are still unknown.

It is also important that physicians set expectations for efficacy, Dr. Loder noted. “Most headaches will not be eliminated or eradicated,” she said. “Some patients are lucky and have almost complete relief, but there are also cases where some patients do not benefit at all. We don't have any good way yet to identify ahead of time who will get good results and who will not benefit at all.”

Because of this uncertainty, it remains to be seen whether the approval of these and other drugs will greatly change clinical practice, Dr. Loder said.

Dr. Minen said she plans to use erenumab and fremanezumab in her more refractory patients who have unsuccessfully tried a number of other migraine prevention medications.

“These drugs were studied in fairly healthy patients, and there needs to be postmarketing studies to best assess which patients are the best responders and to assess long-term safety,” she said. “We are excited that these new medications have come to market, but everyone must be comfortable with the medications that we already have as well.”