Erenumab for Episodic Migraine Prophylaxis: Current Evidence

It is estimated that more than 37 million people in the United States have migraines.¹ For episodic migraine occurring 1 to 3 times per month, abortive medications are usually adequate for treatment, but for those with a monthly frequency of 4 to 14 episodes, prophylactic medications and analgesics are required.²

However, many patient’s migraines are not responsive to currently available preventive treatments such as calcium channel blockers, tricyclic antidepressants, and β-blockers.

In addition, most of these therapies are nonspecific and can be accompanied by side effects and drug-drug interactions with prescriptions for migraine comorbidities.³ 

There is a clear need for specific mechanism-based agents for migraine prophylaxis. To that end, attention has increasingly turned to agents that block the activity of calcitonin-gene-related peptide (CGRP), which has been identified as a key factor in migraine pathophysiology. “In this context, erenumab (AMG334, co-developed by Amgen and Novartis) holds a prominent place, being the only mAb [monoclonal antibody] against the CGRP receptor rather than against the ligand,” wrote the authors of a recent review on the drug’s pharmacology, efficacy, and safety.⁴

“I think it’s a breakthrough drug for the treatment of chronic and episodic migraine — this is the second migraine-specific drug after 27 years from the time triptans were introduced in 1991,” Nauman Tariq, MD, assistant professor of neurology and director of the Headache Center at Johns Hopkins School of Medicine in Baltimore, told Clinical Pain Advisor.

CGRP and mAbs

There are 2 major forms of CGRP in humans. The form involved in migraine is α-CGRP, which is expressed in the trigeminal system, sensory neurons of the dorsal root ganglia, and the vagal ganglia. The enteric nervous system is the primary site of expression for the other form, β-CGRP.

Whereas it was previously believed that the effect of CGRP on migraine was solely mediated through its binding on smooth muscle receptors leading to vasodilation, it has since been discovered that the peptide also “modulates neuronal excitability, particularly facilitating pain responses in the trigeminal system and trigeminal nucleus caudalis, being thus implicated in mechanisms of both peripheral and central sensitizations underlying migraine pain,” as described in the review.^5-7

In addition to the advantages of mAbs in general, including target specificity, a long half-life appropriate for monthly administration, and low hepatoxicity, an mAb that targets the receptor vs the ligand is thought to have higher specificity and thus should be accompanied by “a reduction of the side effects, particularly long-term ones, linked to a complete blockade of CGRP action,” according to review authors. Further research is needed to confirm this hypothesis.

A number of studies support involvement of CGRP in migraine pathophysiology, including one showing increased plasma levels of CGRP after activation of the trigeminal ganglion.⁸ Other research has observed elevated serum levels of CGRP between episodic and chronic migraine attacks.^9,10

Erenumab trial results

The results of phase 2 and 3 trials that have investigated the efficacy of erenumab in episodic migraine are summarized below.

• In a phase 2 randomized, double-blind, placebo-controlled trial involving 59 centers in North America and Europe (n=483), study participants assigned to receive a dose of 70 mg erenumab had a greater reduction in monthly migraine days compared with patients in the placebo group at week 12 (−3.4±0.4 days vs −2.3±0.3 days, respective3ly; 95% CI, −2.1 to −0.2; P =.021).¹¹
• In a phase 3 randomized, double-blind, placebo-controlled trial of 577 patients with 4 to 14 monthly migraine days, erenumab was found to reduce the mean number of monthly migraine days compared with placebo from baseline to weeks 9 through 12 (2.9 days vs 1.8 days, respectively; P <0.001).¹² The erenumab group also had fewer days of migraine medication use (1.2 days vs 0.6 day reduction; P <0.003).
• In a phase 3 randomized, double-blind, placebo-controlled trial lasting 24 weeks, 955 patients from multiple sites with high-frequency migraine were assigned to receive placebo or erenumab 70 mg or 140 mg.¹³ Erenumab treatment was associated with a reduction in monthly migraine days (erenumab 70 mg, −3.2 days; erenumab 140 mg, −3.7 days), compared with −1.8 days for placebo, in the last 3 months of treatment (P <0.001). Both treatment groups experienced a reduction in physical impairment and in impact of migraine on daily activities compared with the placebo group (P <0.001).

Two phase 2 trials have also demonstrated the efficacy of erenumab in the prevention of chronic migraine.^14,15 A phase 3b multicenter, double-blind, randomized trial of erenumab for episodic migraine is currently recruiting patients.¹⁶

There were no significant differences in reports of adverse events between the treatment and placebo groups, indicating a favorable safety profile for erenumab. “I am most impressed with the safety profile because so far, I believe it’s the safest among all the current antimigraine drugs available,” said Dr Tariq. It remains to be seen “what postmarketing surveillance will reveal with regard to safety, but based on the clinical trials data, the safety profile is very impressive,” he added.

Next steps

Based on trial data collected thus far, Amgen submitted a Biologics License Application for erenumab to the United States Food and Drug Administration in May 2017, which was accepted for review by the agency in July 2017.

The cost/benefit ratio of erenumab should be examined in longer-term studies, noted review co-author Maria Adele Giamberardino, MD, associate professor of internal medicine and head of the Fibromyalgia and Headache Center at the G. D’Annunzio University in Chieti, Italy. “It will also be important to evaluate if the positive effects are confirmed in more complex migraine patients than the ones selected for the studies conducted so far — for example, those with other pain comorbidities, such as fibromyalgia or pelvic pain, who are very frequently encountered in clinical practice,” she told Clinical Pain Advisor.

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References

1. Miles O. Migraine Statistics. Migraine.com. https://migraine.com/migraine-statistics/. November 2010. Accessed January 25, 2018.
2. Giamberardino MA, Martelletti P. Emerging drugs for migraine treatment. Expert Opin Emerg Drugs. 2015;20(1):137-147.
3. Lionetto L, Borro M, Curto M, et al. Choosing the safest acute therapy during chronic migraine prophylactic treatment: pharmacokinetic and pharmacodynamic considerations. Expert Opin Drug Metab Toxicol. 2016;12(4):399-406.
4. Giamberardino MA, Affaitati G, Costantini R, Cipollone F, Martelletti P. Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab. J Pain Res. 2017;10:2751-2760.
5. Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache. 2006;46(Suppl1):S3-S8.
6. Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169(2):683-696.
7. Moore EL, Salvatore CA. Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine. Br J Pharmacol. 2012;166(1):66-78. 
8. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol. 1988;23(2):193-196.
9. Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J. Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain. 2000;86(1):133-138.
10. Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81(14):1191-1196.
11. Sun H, Dodick DW, Silberstein S, 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(4):382-390.
12. ClinicalTrials.gov. Study to evaluate the efficacy and safety of AMG 334 compared to placebo in migraine prevention (ARISE). https://clinicaltrials.gov/ct2/show/NCT02483585. Updated June 6, 2017. Accessed January 25, 2018.
13. Goadsby PJ, Reuter U, Bonner J, et al. Phase 3, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab (amg 334) in migraine prevention: primary results of the strive trial. J Neurol Neurosurg Psychiatry. 2017;88:e1.
14. Giamberardino MA, Costantini R. Challenging chronic migraine: targeting the CGRP receptor. Lancet Neurol. 2017;16(6):410-411.
15. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434.
16. ClinicalTrials.gov. A study evaluating the effectiveness of AMG 334 injection in preventing migraines in adults having failed other therapies (LIBERTY). https://clinicaltrials.gov/ct2/show/NCT03096834. Updated November 9, 2017. Accessed January 25, 2018.