Author: Mamoru Shibata

Anti-CGRP therapy in Japan: progress and expectations

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.

References

  1. 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
  2. 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.

 

 

My reflections on CGRP-targeted monoclonal antibody therapy

Migraine is not only a common disease but also one of the most disabling brain disorders, explains Mamoru Shibata, MD, PhD Department of Neurology, Keio University School of Medicine, Tokyo, Japan.

According to the Global Burden of Disease Study 2015, migraine is the second largest contributor of disability-adjusted life-years (DALYs) in neurological diseases1. Migraine affects chiefly young people; the magnitude of loss of productivity it causes is considerable worldwide. CGRP-targeted therapy is based a great deal of scientific and clinical efforts to elucidate the disease mechanism of migraine.
Unlike pre-existing migraine prophylactic therapy, CGRP-targeted therapy is rational and science-based. In the real world, galcanezumab, eptinezumab, fremanezumab and erenumab have already been shown to be efficacious for migraine in Phase II clinical trials. Furthermore, evidence is emerging that CGRP-target therapy is also effective for chronic migraine, which is generally intractable with current prophylactic interventions.
When given as add-on to current preventive medications in episodic and chronic migraine patients, fremanezumab significantly decreased the mean monthly number of migraine days relative to placebo. Improvement by ≥ 50% for this parameter was seen almost twice as frequently with fremanezumab as with placebo2.
Yet another encouragingly report was encountered at IHC2017. Erenumab decreased migraine headache days per month in chronic migraine patients who had been resistant to plural prophylactic agents. The data showed that the placebo effect was minimal in such patients, which makes it likely that the real power of erenumab was being demonstrated. I look forward to seeing similar results with the other monoclonal antibodies.
Additionally, the efficacy of these antibodies seems to emerge early. There were significant decreases in the mean number of headache hours after one week of therapy for fremanezumab 675/225mg and 900 mg relative to placebo3. As for moderate to severe headache days, the lower dose (675/225 mg) non-significantly reduced the number of days with moderate severity headaches in Week 1 and Week 3, whereas the 900 mg showed separation as early as after 1 Week. Such quick efficacy is likely to enhance therapeutic adherence.
In terms of tolerability, the monoclonal antibodies seem to be favorable. As the passage of immunoglobulin through blood–brain barrier is quite limited, CNS side-effects are expected to be encountered much less frequently compared to those seen with small molecules4. Given that anti-epileptic agents, such as valproate and topiramate, are known to cause sleepiness and dizziness that lead to reduced performance, this is a very beneficial point.
Taken together, CGRP-targeted monoclonal antibody therapy has a promising potential that may change the currently unsatisfactory scene of migraine prevention therapy. How should we prudently utilise this novel modality of migraine therapy in daily medical practice?
It is not realistic to apply this costly therapy blindly to many of the migraine cases that meet the indication for preventive therapy. To narrow down candidate patients, we need to obtain biomarkers capable of detecting responders as soon as possible. To pursue this goal, close collaboration between industry and academia should be required. Traditionally, migraine research has been under-funded though governmental bodies. This situation should be corrected promptly. We should make every endeavor to raise awareness of migraine in society as a whole.
References

  1. Group GBDNDC. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol 2017; Sept 17 [epub ahead of print]
  2. Cohen JM, Dodick DW, Yang R, et al. Fremanezumab as add-on treatment for patients treated with other migraine preventive medicines. Headache 2017; Sept 1 [epub ahead of print]
  3. Bigal ME, Dodick DW, Krymchantowski AV, et al. TEV-48125 for the preventive treatment of chronic migraine: Efficacy at early time points. Neurology 2016;87:41-48.
  4. St-Amour I, Pare I, Alata W, et al. Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier. J Cereb Blood Flow Metab 2013;33:1983-1992.

Targeting the CGRP receptor or ligand: does it make a difference?

As a novel migraine therapeutic approach, monoclonal antibodies against CGRP or its receptor are currently in clinical trials for migraine prophylaxis. The key question then is: Does it make a difference whether we choose the CGRP receptor or CGRP itself as a therapeutic target?

This is hard to answer. Intuitively, blocking the receptor is likely to be easier and more efficient than neutralizing a great deal of circulating ligands. Contrary to this idea, however, there is evidence with several antibodies and a chimera protein targeting tumor necrosis factor α (TNFα) showing efficacy in controlling the disease activity of rheumatoid arthritis.1 As for migraine, as far as we see from currently available clinical data from the Phase II studies of anti-CGRP and anti-CGRP receptor antibodies, they do not seem to differ in efficacy with respect to prophylaxis of episodic migraine.2-5

The canonical CGRP receptor is a heterodimer that consists of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). Interestingly, it has been recently reported that there are additional functional CGRP receptors. The amylin receptor 1 (AMY1) is comprised of the calcitonin receptor (CTR) and RAMP1. Although amylin is known principally as a pancreatic hormone related to glucose metabolism, this peptide hormone is also involved in nociception6 and expressed in trigeminal ganglion (TG) and dorsal root ganglion neurons.7 In post-mortem human tissue, the colocalization of CTR with RAMP1 was observed in discrete neurons in the TG.8 Immunoreactivities for CTR and RAMP1 were found also in the nerve fibers in the spinal trigeminal complex and vessels.8 These regions are closely related to migraine pathophysiology. Functionally, both CGRP and amylin were found to be agonists in rat TG neuron-enriched cultures.8 In transfected cells that expressed human or rat CTR and RAMP1, CGRP proved to be a more potent agonist than amylin.8 These data indicate that CGRP is surely a functional agonist for the AMY1 expressed in the trigeminal system. Moreover, a truncated splice variant of the AMY1 with a 47 amino acid deletion at the N-terminal is known to be potently activated by CGRP.9  Pharmacological assays revealed that AMG 334 (Erenumab), a fully human monoclonal antibody against the CGRP receptor now being investigated for migraine prophylaxis, had no antagonist activity at the human AMY1 up to 10 µM, far beyond the therapeutic tissue level.10 Hence, AMG 334 is likely to be incapable of blocking the AMY1.

Currently, it remains elusive to what extent the AMY1 is relevant to migraine pathophysiology. Long-term clinical efficacy data of the above-mentioned monoclonal antibodies may provide an important clue to this issue.

Mamoru Shibata (Keio University School of Medicine, Tokyo, Japan)

Contact: Mamoru Shibata, MD, PhD
Assistant Professor, Department of Neurology, Keio University School of Medicine
35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Phone: +81-3-5363-3788; Fax: +81-3-3353-1272
Email: [email protected]

References

  1. Monaco C, Nanchahal J, Taylor P, Feldmann M. Anti-TNF therapy: past, present and future. Int Immunol 2015;27:55-62.
  2. Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016;15:382-90.
  3. Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015;14:1081-90.
  4. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014;13:1100-7.
  5. Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014;13:885-92.
  6. Huang X, Yang J, Chang JK, Dun NJ. Amylin suppresses acetic acid-induced visceral pain and spinal c-fos expression in the mouse. Neuroscience 2010;165:1429-38.
  7. Mulder H, Leckstrom A, Uddman R, Ekblad E, Westermark P, Sundler F. Islet amyloid polypeptide (amylin) is expressed in sensory neurons. J Neurosci 1995;15:7625-32.
  8. Walker CS, Eftekhari S, Bower RL, Wilderman A, Insel PA, Edvinsson L, et al. A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann Clin Transl Neurol 2015;2:595-608.
  9. Qi T, Dong M, Watkins HA, Wootten D, Miller LJ, Hay DL. Receptor activity-modifying protein-dependent impairment of calcitonin receptor splice variant Delta(1-47)hCT((a)) function. Br J Pharmacol 2013;168:644-57.
  10. Shi L, Lehto SG, Zhu DX, Sun H, Zhang J, Smith BP, et al. Pharmacologic Characterization of AMG 334, a Potent and Selective Human Monoclonal Antibody against the Calcitonin Gene-Related Peptide Receptor. J Pharmacol Exp Ther 2016;356:223-31.