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Migraine Treatment Set for Reboot

Inside the anticipated CGRP game-changers; Plus, neuromodulation devices for chronic headache continue to evolve.

With Natalia Murinova, MD

With a series of calcitonin gene-related peptide (CGRP) antibody medications that promise to prevent migraines under regulatory review, anticipation is growing across the healthcare and patient community. In the video below, director of the University of Washington’s Neurology Headache Clinic in Seattle, Natalia Murinova, MD, and migraine patient Svetlana Gaivoronski, discuss how the novel therapy class works to attack migraine triggers and may change the way chronic headaches are treated as early as the second half of this year. 

(Video courtesy UW Washington, April 2018)

Anti-CGRP therapies Coming in 2018

Four monoclonal antibodies (mAbs) targeting the CGRP pathway are currently under evaluation for the prevention of episodic and chronic migraine:

  • eptinezumab (ALD403, Alder Pharmaceuticals, targets the CGRP itself)
  • erenumab (AMG334, Amgen/Novartis, targets the CGRP receptor) *Update: Approved by FDA May 2018
  • fremanezumab (TEV-48125, Teva Pharmaceuticals, targets the CGRP itself)
  • galcanezumab (LY2951742, Eli Lilly, targets the CGRP itself)

All four antibodies, administered via infusion or injection, have been proven effective, tolerable, and safe as migraine prophylactic treatments, according to Dr. Murinova. In addition, oral anti-CGRP targeted therapies are also under development: Biohaven Pharma’s rimegepant/BHV-3000 for acute migraine and BHV-3500 for migraine prevention, and Allergan’s ubrogepant for acute migraine and atogepant for migraine prevention. Prior concerns with liver toxicity and oral administration are being analyzed.

The hype surrounding this new migraine management class has to do with the fact that anti-CGRP peptide and anti-CGRP receptor antibodies “are the first effective treatments specifically designed for migraine prevention and acute treatment,” noted Dr. Murinova. Until now, standard-of-care preventive migraine therapies have been those formulated to treat other conditions, such as high blood pressure. CGRP is 37-amino-acid neuropeptide involved in migraine pathophysiology, and researchers have been working on how to block its signals in relation to migraine for the past 15 years.

In a follow-up to the UW Medicine video, Dr. Murinova, who also serves as a diplomate of the American Academy of Neurology, discussed with Practical Pain Management some of the additional promises—and potential downsides—of these monoclonal antibodies.

Individual and Overall Impact

In clinical trials to date, some patients have experienced immediate relief after the antibody infusion, while others have waited a month to experience migraine relief. About 30% of subjects experienced total migraine freedom after drug administration, noted Dr. Murinova, while others had a recurrence of migraine three months after treatment. Individual patient outcomes, therefore, are likely to differ, especially given other potential factors, such as comorbidities (see below).

What’s most exciting, however, is the treatment’s potential effect on overall patient wellness. In addition to preventing the migraine and its commonly associated side effects—such as light, sound, odor sensitivity and nausea—the therapeutic class has proven to field off the pre- and post-drome migraine effects, said Dr. Murinova.

Patients living with chronic migraine often feel “off” a few days before and a few days after a migraine attack. “This may include depression, lethargy and food cravings during the pro-drome phase, and weakness, tiredness, dizziness, lightheadedness, difficulty concentrating, and decreased energy in the post-drome phase,” she said.

Triggers & Alarms

This does not mean that the treatment is a cure-all, however. Long-term benefits and underlying mechanisms of anti-CGRP therapy have yet to be determined. Therefore, Dr. Murinova advises that clinicians who consider prescribing the new medication also advise patients to continue with any alternative therapies they may be using to field off migraines. For example, Svetlana, who appears in the video, continues to keep stress levels under control, limit her acute medications, and maintain an exercise program.

To further explain, the CGRP antibody may help decrease migraine activation—what Dr. Murinova calls the “alarm,” but it does not decrease what caused alarm in the first place. Therefore, if patients want to avoid living on monthly injections, they need to work on decreasing the alarm activation.

In Dr. Murinova’s practice, a holistic multimodal approach to care is utilized to address medication overuse headache, as well as weight gain (obesity can cause an increase in CGRP), physical deconditioning, stress, and any other factors that can worsen brain balance, and thus, set off the alarm.

Underlying Conditions & Cost

Patient selection for clinical trials is often very selective, leaving many unknowns when a new medication is used for the first time in a larger population. A majority of patients with chronic migraine are also likely to have comorbidities, and a “big proportion of migraine patients have very significant side effects with most medications,” said Dr. Murinova. Anti-CGRP therapy may, therefore, require a process of trial-and-error once it enters the market.

Specifically, “CGRP may affect other functions in the body, such as hypertension control, so there are vascular concerns that still need to be studied,” she added. “So far, we have not discovered any significant side effects – but many side effects are discovered only with more extensive population use. In the short term, a patient who has had a previous stroke, for example, may not want to try this therapy.”

Another issue that will require more attention is the impact of CGRP antibody therapy in the female population. According to Dr. Murinova, none of the trials to date were conducted in pregnant women. Females receiving CGRP antibody treatment will likely be advised to hold off on becoming pregnant for six to 12 months after treatment ends as potential adverse effects are unknown. If an unexpected pregnancy occurs during treatment, potential adverse effects on the woman or the fetus are also unknown.

As with any new interventional treatment, healthcare costs can present hurdles. No price has been set, but many biological therapies cost $10,000 to $20,000 per year and some are much more, and with insurance coverage undetermined, access to CGRP antibody therapy may be limited.

Overall, however, said Dr. Murinova, “It is exciting to see new treatments, and especially to have better understanding of what is provoking the migraine in the first place.”

Device Options Continue to Grow as Well

In addition to CGRP medications, there are a number of medical devices continuing to make headway in the treatment and prevention of chronic migraine. Among neuromodulation devices, single pulse transcranial magnetic stimulation (sTMS) devices, such as that developed by eNeura (Spring TMS, Baltimore, MD), offer portable, self-administered options. FDA recently expanded the device’s indication from treatment of aura symptoms to include migraine prevention. 

A study led by Starling et al, examined the effect of sTMS devices in general through an analysis of headache diary submissions from approximately 220 eligible patients with migraine; data incorporated a 1-month baseline followed by 3 months of treatment. The protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment with the device, according to the paper. Patients were asked do describe their daily headache status, medication use. Device use and data were compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity.

According to the abstract, researchers found a −2.75 ± 0.40 mean reduction in headache days from baseline (9.06 days) compared to the performance goal (−0.63 days) (p < 0.0001). Secondary results were also significant, and with migraine frequency reduced, authors concluded that "sTMS may be an effective, well-tolerated treatment option for migraine prevention.”

Read also about Cefaly Technologies’ transcutaneous electrical nerve stimulation device for acute migraine treatment and migraine prevention. 

More coverage of developing therapeutics for migraines and headaches:

Last updated on: May 21, 2018
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Employing Monoclonal Antibody Therapy Lessens Episodic and Chronic Migraine Pain
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