This is one of the most exciting times in headache medicine, with many new migraine-specific biologics available for both acute and preventive treatment.
Migraine is a central nervous system disease that is both prevalent and disabling. In individuals age 15-49, it is the second leading cause of years lived with disability.1 The prevalence is 12% in the general population.2 An estimated 1-2% of the population has chronic migraine, which is headache occurring more than 15 days/month for at least 3 months.2 About 10% of the population has episodic migraine, in which headache occurs fewer than 15 days/month.2
Antibody therapy has many advantages, including a long half-life and specificity, which reduces potential side effects. The current preventive monoclonal antibodies target calcitonin gene-related peptide (CGRP), which is a peptide implicated in many functions including bone metabolism, vasodilation and migraine.3
CGRP and its receptors are found throughout the nervous system (both peripheral and central). Studies in patients with migraine showed CGRP level elevation in the jugular blood during a migraine, which normalized after treatment with sumatriptan.3 It is thought that the monoclonal antibodies exert their effect by blocking the binding of CGRP to the A-delta pain fibers, thus reducing nociceptive (pain-detecting) signals.1
There are currently three monoclonal antibodies on the market for the treatment of migraine, all of which target CGRP and are administered by subcutaneous injection.
Erenumab-aooe (Aimovig), which binds to the CGRP receptor, was first on the market. In the STRIVE study, monthly injection of 70 mg or 140 mg significantly reduced migraine frequency and the use of acute migraine-specific medications in patients with episodic migraine.4 In another study, it was shown to significantly improve health-related quality of life, headache impact and disability in patients with chronic migraine.5
Fremanezumab-vfrm (Ajovy) is a humanized monoclonal antibody that binds to the CGRP ligand, preventing its binding to the receptor.6 Compared to a placebo, it significantly decreased the number of headache days per month in patients with chronic migraine using both quarterly dosing of 675 mg and monthly dosing of 225 mg.6 Mean number of headache days per month was reduced by 4.3 ±0.3 days in the fremanezumab-quarterly group, 4.6 ±0.3 days in the fremanzemab-monthly group, and 2.5 ±0.3 days in the placebo group.6 The most common adverse effect was injection-site pain, which was noted in about 30% of patients receiving medication.6
Galcanezumab-gnlm (Emgality) also exerts its effect by binding to the CGRP ligand itself. In the REGAIN trial, galcanezumab, when given in monthly doses of 120 mg or 240 mg, was superior to a placebo in the mean reduction of monthly migraine headache days in patients with chronic migraine.7 It also had a higher percentage of patients with >50% or >75% reduction of mean headache days.7 Galcanezumab is also studied in the treatment of episodic cluster headache. When given at monthly doses of 300 mg, it decreased the weekly frequency of cluster headache attacks compared to a placebo.8
Another class of CGRP antagonists is the small molecules, or gepants. These medications are administered orally. While an early generation of these agents showed promise, trials ended due to hepatotoxicity.1 Ubrogepant (Ubrelvy), the first of a new generation of agents approved by the FDA, is used as an acute migraine treatment. In ACHIEVE I and ACHIEVE II trials, 100 mg of ubrogepant was superior to a placebo for 2-hour pain freedom and most bothersome symptoms, with a low side effect rate.10 The most common side effects were dry mouth, nausea, fatigue and somnolence.10 Rimegepant (acute migraine treatment) and atogepant (preventive migraine treatment) are currently in clinical trials as of this writing.
Ditans are another class of migraine biologics currently in development. Serotonin (5-HT) has multiple receptors. 5-HT1D and 5-HT1F mediate anti-migraine effects. Triptans and ergots agonize the 5-HT1D as well as the 5-HT1B receptor; the 5-HT1B receptor is implicated in vasoconstriction.1 Risk of vasoconstriction is one of the main disadvantages of triptans and ergots and limits their use in patients with cardiovascular and cerebrovascular disease. The ditans are a new class of highly specific 5-HT1F agonists, which avoid the risk of vasoconstriction.1 They exert their effect by mediating neuronal pulse transmission.1 A Phase 3 clinical trial demonstrated that lasmitidan (Reyvow) was superior to a placebo in proportion of patients with headache pain freedom and most bothersome symptom-free 2 hours post-dose at all studied doses (50 mg, 100 mg, 200 mg).9 The most common side effects were dizziness, somnolence and paresthesias.9 Lasmitidan was approved by the FDA on October 11, 2019.
The era of biologics in headache treatment continues to build momentum. The CGRP monoclonal antibodies are the first class of migraine preventive medications that target the specific pathophysiology implicated in the disease.
One of these agents is also approved for the treatment of episodic cluster headache. Their low side-effect profile, lack of drug interactions and easy dosing make them ideal for many patients.
The gepants are CGRP antagonists with the advantages of being orally administered and have a place in both acute and preventive treatment. The ditans are a third class of migraine biologics and the first migraine-specific abortives to target the 5-HT receptors since the triptans were approved in the 1990s, without the same cardiovascular risk.
As new medications are developed and approved for the treatment of headache disorders, the pharmacologic approach to patients will continue to evolve.
References
1. Ceriani CEJ, Wilhour DA, Silberstein SD. Novel medication for the treatment of migraine. Headache. 2019;59:1597-1608.
2. Parikh SK, Silbersetin SD. Preventive treatment for episodic migraine. Neurol Clin. 37 (2019) 753-770.
3. Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019;394: 1765-1774.
4. Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123-2132.
5. Lipton RB, Tepper SJ, Reuter Uwe et al. Erenumab in chronic migraine: patient-reported outcomes in a randomized double-blind study. Neurology. 2019;92:e1-e11.
6. Silberstein SD, Dodick DW, Bigal ME. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113-2122.
7. Detke HC, Goadsby PJ, Wang S et al. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91:e2211-e2221.
8. Goadsby PJ, Dodick DW, Leone M et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381:132-141.
9.Goadsby PJ, Wietecha LA, Dennehy EB. Phase 3 randomized, placebo-controlled, double-blind study of lasmitidan for acute treatment of migraine. Brain. 2019;142:1894-1904.
10. Voss T, Lipton RB, Dodick DW, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016;36:887-898.
11. Trugman J, Finnegan M, Lipton R, et al. Efficacy, safety, and tolerability of ubrogepant for the acute treatment of migraine: results from a single-attack phase III study, ACHIEVE I. Neurology. 2018;90:e2186.
