CGRP-based therapy is not expected to be approved in Japan until 2021, but clinical trial data have been reported on three agents and there is a high level of expectation amongst Japanese clinicians – as Mamoru Shibata, Associate Professor in the Department of Neurology at Keio University School of Medicine, Tokyo, Japan, explains.
Globally, monoclonal antibodies targeting CGRP or its receptor are now used as prophylactic therapy for migraine. Their efficacy and safety in patients with episodic and chronic migraine have been demonstrated in clinical trials, and real-world clinical data are emerging on one agent after another. In Japan, Phase 3 studies are ongoing but, in the meantime, only lomerizine hydrochloride, valproate, dihydroergotamine and propranolol are approved for migraine prophylaxis by the Japanese regulatory agency. Of these, dihydroergotamine is scarcely used these days. Amitriptyline and verapamil are used off-label, though they are reimbursable for migraine prophylaxis.
In addition, topiramate and angiotensin II receptor antagonists are used by headache specialists. It is notable that onabotulinumtoxin has not been introduced for the purpose of treating chronic migraine. Chinese herbal medicine, which is popular among Japanese physicians, does not necessarily show consistent efficacy. Hence, our therapeutic armamentarium for migraine in Japan obviously needs to be improved.
Recently, the results of a Phase 2, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab for the prevention of episodic migraine in Japanese patients were published.1 Four hundred and seventy-five patients were randomised to receive placebo or erenumab 28, 70, or 140 mg. Greater reductions in monthly migraine days (MMD) were observed for erenumab versus placebo, with differences of -1.25 (95% CI: -2.10 to -0.41; p=0.004), -2.31 (95% CI: -3.00 to -1.62; p<0 .001) and -1.89 (95% CI: -2.58 to -1.20; p<0.001) days for erenumab 28, 70, and 140 mg respectively. The odds of having a ≥50% response were 3.2, 5.6, and 4.7 times greater for erenumab 28 mg (95% CI: 1.30-7.88; p=0.009), 70 mg (95% CI: 2.60-12.06; p <0.001), and 140 mg (95% CI: 2.24-9.99; p<0.001) than for placebo. Erenumab 70 and 140 mg were also associated with greater improvements in quality of life. This study did not find any safety concern with erenumab.
Moreover, preliminary results of a Phase 2, double-blind placebo-controlled study to assess the efficacy and safety of galcanezumab for episodic migraine were released at the 19th Congress of the International Headache Society in September 2019 and the 47th Congress of the Japanese Headache Society in November 2019. Of note, the mean changes over the first six months in MMD were -0.59, -3.60, and -3.36 for placebo, galcanezumab 120 and 240 mg, respectively. The therapeutic gain by galcanezumab 120 mg versus placebo, 3.01, was remarkable. In both the erenumab and galcanezumab studies, placebo effects were very small.
A Phase 1 pharmacokinetics, safety and tolerability study has been published for fremanezumab 225 mg, 675 mg and 900 mg in Japanese and Caucasian healthy subjects.2 This showed similar pharmacokinetic exposure parameters and safety measures for both groups and supported once monthly and once quarterly dosing with fremanezumab.
With these reports, expectations for CGRP-related monoclonal antibody therapy for migraine prophylaxis are expanding amongst Japanese clinicians. However, we have several points of concern about this novel therapy. Once started, how long do we have to carry on administration of these antibodies? If we haphazardly administer these antibodies to pregnant patients, what kind of risks can be expected? We may find answers to these questions as more real-world data become available.
- Sakai F, Takeshima T, Tatsuoka Y et al. A randomized Phase 2 study of erenumab for the prevention of episodic migraine in Japanese adults. Headache 2019 Nov;59(10):1731-1742
- Cohen-Barak O, Weiss S, Rasamoelisolo M et al. A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects. Cephalgia 2018 Nov;38(13):1960-1971.