Stephen D. Silberstein, MDStephen D. Silberstein, MD
Anti-calcitonin gene-related peptide (CGRP) therapies have significantly altered the way clinicians address migraine, providing unprecedented relief from a chronic pain that has long frustrated both patients and prescribers alike. In a recent Peer Exchange panel discussion led by Stephen D. Silberstein, MD, professor of neurology, director of the Jefferson Headache Center at Thomas Jefferson University, and editor in chief of NeurologyLiveTM, key thought leaders in the migraine space spoke about the impact that these new therapies have had on migraine treatment, all while maintaining strong safety profiles.

The Anti-CGRP Class

The anti-CGRP medication class currently comprises 3 FDA-approved medications—erenumab (Aimovig; Amgen/ Novartis), galcanezumab (Emgality; Eli Lilly), and fremanezumab (Ajovy; Teva)—and 1 treatment pending approval, eptinezumab (Alder Biopharmaceuticals). As Stewart J. Tepper, MD, professor of neurology at the Dartmouth Geisel School of Medicine, explained, erenumab, the first approved member of the class, is slightly different from the other 3 because it is a purely human monoclonal antibody that targets the canonical CGRP-α receptor.

“The other 3 target the CGRP ligand itself,” Tepper said. “They do not target the receptor. The other 3 are humanized or fully humanized, meaning that they are 5% to 10% murine. We don’t know whether that has immunologic consequence, but most of our neurologic monoclonal antibodies that are used in practice are humanized.”

The approval of erenumab was followed by that of fremanezumab and then galcanezumab, both in September 2018. Eptinezumab, an investigational agent, was submitted to the FDA in early 2019, with a decision expected in 2020. Like the first, the fourth member of the class is slightly different; eptinezumab is designed as a quarterly intravenous infusion, whereas the other 3 are available as monthly, in-home subcutaneous injections.

Safety and Patient Selection

Thus far, the tolerability of the therapies has been very favorable, as Andrew Blumenfeld, MD, director of the Headache Center of Southern California, noted. “Now we have treatments that don’t have as many adverse effects as the oral medications. We don’t have as much of an issue with adherence because these are self-injected monthly or quarterly injections, as in the case of Ajovy,” he said.

“It has changed the whole dynamic. I would preferentially choose a monoclonal antibody as the starting point,” Blumenfeld added, although drug failure with at least 2 therapies is currently required prior to starting anti-CGRP treatments. The American Headache Society has made recommendations to payers that would allow patients to meet certain prerequisites to qualify for first use of these treatments.

“In an ideal world—where costs have no bearing on our deci- sion—I would feel that [anti-CGRP medications] were the ones that had the best safety, the best tolerability, and the greatest effi- cacy,” Blumenfeld said.

Refractory Migraine

One of the most significant impacts of these new drugs has been on the way that clinicians think about refractory migraine. According to Stephanie J. Nahas, MD, MSEd, associate professor of neurology and director of the Headache Medicine Fellowship Program at Thomas Jefferson University, the age-old concept has been that more treatment failures equal more refractory disease.

“What’s fascinating is that we’re seeing in these clinical trials that the more treatment failures one has, the better they might do,” Nahas, who is also assistant director of Thomas Jefferson’s Neurology Residency Program, explained. “This again speaks to the mechanisms of migraine and the mechanisms of treating it. If you fail to respond to these nonspecific preventive treatments that don’t directly target CGRP, maybe that’s the reason.”

She added that the field is inching closer to root contributors to migraine, noting that if clinicians can treat a patient on the ground level with a CGRP-targeted agent, the odds of success for those who have experienced failure before are improved. Blumenfeld agreed and said that based on the existence of subgroups with poor response, other chemicals must be involved in migraine.

Silberstein added that although the overarching disease is referred to as migraine, it in fact encompasses underlying disorders that manifest in different phenotypes, similar to epilepsies.

“The new terminology is no longer grand mal or petit mal, but in the old days, we gave a drug for one of them, and the other worked,” Silberstein said. “Maybe we’re dealing with the same thing in migraines. We need to change our thinking; every other prior trial would exclude people whose drugs failed them twice. Now we’ve come to the conclusion that all that does is protect the ability to get a greater effect size comparing active drugs [with] placebo.”

Deborah I. Friedman, MD, MPH, a professor of neurology, neurotherapeutics, and ophthalmology at The University of Texas Southwestern Medical Center, added that the level of response she has observed in her clinical practice from the CGRPs has impressed her, describing some of her patients’ responses as “miraculous.”

“Patients who are in those trials, who were overusing medications—symptomatic medications, not butalbital and not opioids but mostly either triptans or nonsteroidals—also benefited just as well as everybody else did and were able to reduce their use of symptomatic medication,” Friedman said.

Tepper concurred, explaining that in recently presented data for fremanezumab and erenumab, the majority of patients with acute medication overuse converted to nonoveruse with these medications, in addition to observing the conversion of a number of patients from chronic to episodic migraine.

"In an ideal world- where costs have no bearing on our decision- I would feel that (anti-CGRP medications) were the ones that had the best safety, the best tolerability, and the greatest efficact," Andrew Blumenfield, MD, said in a statement. 

“It’s really shifting the way that I practice in terms of a patient coming in who’s overusing combination analgesics and triptans,” Tepper said. “I can put them on these medicines, and have a discussion about it, but be relatively confident that there’s a greater likelihood than not that 3 months down the pike, that patient is going to have a very dramatic [change in] use of what had been a previous overuse, with the potential for gastroenteropathy and nephropathy and all the problems that the overuse causes.”

Cumulative Benefits

Silberstein then shifted the conversation to the ongoing benefit of the CGRP-targeted agents, asking the panel about their ideal time frame for phasing out antibody treatment in a patient. Although many patients in clinical trials achieved 50% or higher response rates, some were still considered nonresponders. However, Silberstein noted that a patient could possibly achieve a response a few months later.

“We analyzed that nonresponders at 1 month have a 40% chance they’ll have response within 3 months. It looks like, just as with the small molecules, we should wait 6 months,” Silberstein explained. “Originally, we thought they’d get better in a week. That’s not the answer. They can get better in a week, but it might take months.” Friedman added that patients in her practice have halted these monoclonal antibodies after 1 month of use, after their physician told them that the response time should be within a week. “I think it’s really important to realize that was sort of an erroneous thought and they don’t work that fast on everybody,” she said.

Silberstein also noted that investigators have not yet analyzed those stratified by a 10%, 20%, 30%, and 40% response to explore any possible long-term benefit. He and Nahas noted that some of their patients do not show any response until their third and sometimes even fifth injections.

“The sequential benefit that you see with these medications is, the longer they get treated, the bigger the response,” Blumenfeld said. “We’re seeing the same thing in the long-term studies of the monoclonal antibodies. Once you start responding, your response rate and your reduction in migraine days increase.”

Tepper added that data from a 12-week trial of erenumab, in which 40% of patients with any dose had a ≥50% reduction in monthly migraine days, showed that more than 40% of patients had a ≥75% reduction with 12 months of use on the 140-mg dose.

He explained that physicians can now tell their patients that with a reduction of 10 days per month, they will achieve a 4-month migraine-free total period by the end of 1 year’s use—an effect that he claimed no physician would consider minimal. “That’s why I really don’t like to use placebo-controlled analyses to explain to patients what’s going on. It’s dropped from baseline; it’s cumulative benefit,” Tepper said.

“When you present that to patients, it’s very encouraging to the patient to think, ‘If I stay on this drug for all this time, I will start to see this progressive improvement,’” Blumenfeld noted. “I think that’s a concept that patients often miss. They think, ‘Well, I’ve seen 6 days, and that’s all I’m going to get.’ In fact, they will get a lot more over time.”