Dr Andrew C. CharlesAndrew C. Charles, MD
Following the approval of 3 novel agents in 2018 and one more therapy expected to reach the FDA in 2019, the anti-CGRP monoclonal antibodies are now poised to transform the treatment paradigm for patients with migraine and cluster headache, according to a presentation by Andrew C. Charles, MD, at the 2018 ANA Annual Meeting.

"This may be irrational exuberance at this point, but I think that these therapies have the possibility to transform our clinical approach to migraine and cluster headache," said Charles, from the University of California, Los Angeles. "This is an example of how migraine science has led to a migraine therapy unlike any we've had in the past. If anything, that is a good reason to be excited."

Across the clinical trials that led to the approvals, the CGRP-targeting antibodies were shown to work rapidly, with a reduction in migraine days compared with placebo observed within the first week following treatment. Moreover, nearly half of patients in the trials experienced a ≥50% reduction in migraine days, a third had a 75% response, and a portion even had a 100% response.

"Around 50% of patients have a 50% responder rate. What may be more exciting is that between 30% and 40% of patients have a 75% response rate. This is where we really start to get interested, because these are the kinds of numbers we really haven't seen before with other therapies," said Charles. "Moving up to 100% response rate, it is not huge numbers, but 10% and even up to 20% of patients in the trials are showing at least 1 month where they are completely headache free. This is not something we generally see with our other therapies."

Now that the anti-CGRP agents are approved as preventives, anecdotal clinical observations are also beginning to add to clinical trial findings. Charles noted having treated approximately 500 patients with erenumab (Aimovig), following its approval in May 2018. He said that responses to erenumab were consistent or often better than reported in clinical trials, with a majority of patients responding.
 
"I know it is hard to make much from anecdotal information, but this is what we have right now. Our responses are consistent but, generally speaking, better than the clinically trial results," he said. "We've been surprised by how well the patients are doing, and I can't say that about all of the treatments we've used in the past. We're seeing very encouraging results with these therapies."

Across the clinical trials, patients had approximately 2 fewer migraine days per month with the CGRP inhibitors compared with placebo. Additionally, there was a 1- to 2-day decrease in the use of acute medications days versus placebo. Reduction in disability and improvements in quality of life were also noted with the antibodies.

"All of these monoclonal antibodies have hit primary endpoints consistently in phase 2 and 3 studies, and all are showing rapid onset and a clinically meaningful response within a month," Charles said. "Almost all of the secondary endpoints, including acute medication use, measures of disability, and quality of life are all remarkably positive."

Although the average 2-day reduction was meaningful, it does not tell the complete story, Charles noted, as there were many patients in the trial who had a 75% or 100% response. At this time, a definitive predictor of response has not been identified; however, in his experience, Charles suggest that prior responsiveness to triptans could predict response to a CGRP inhibitor. Moreover, he added, those with daily headaches are often unresponsive.

"Whether there is a predictor of response is a big question right now," he said. "It seems that patients that are still responding are the ones who were triptan responsive."

While anecdotal observations have noted better efficacy in the clinic than clinical trials, Charles noted that the rates of constipation have been higher than expected. One explanation for this may be the role of CGRP, which also plays a role in the gastrointestinal system. "At least around 25% of our patients are reporting some type of constipation," he said.

Erenumab, which was joined by fremanezumab (Ajovy) and galcanezumab (Emgality) in September 2018, are all priced at $575 per dose, which equates to $6,900 per year. One more therapy, eptinezumab, is expected to reach the FDA in 2019, and does not yet have a released price. Charles noted that many of the manufacturers are offering free trials of the drugs that range from 2 months to a year. Moreover, he added, most insurance companies are approving treatment with preauthorization, with a copay between $25 and $50.