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Home , Prevention of migraines

ARxCH Annual Review of Changes in Healthcare

Calcitonin Gene-Related Peptide Receptors and the Prevention of

Brian Schuler, PharmD Candidate 20181 1University of Findlay College of Pharmacy

Abstract

Migraines are the third most prevalent disease in the world affecting approximately 15% of the population, or over one billion people. Each year, employers lose greater than $13 billion due to 113 million missed work days due to . A great cost-burden and high incidence rate show a continued need for options. In choosing a treatment for a migraine attack, quick onset of action is one of the most important qualities. Common choices include the class, NSAIDs, and a combination of , caffeine, and acetaminophen. In addition, there has been increased research into calcitonin gene-related peptides (CGRP). Due to side effect profiles, the monoclonal antibodies have been more successful than the antagonists studied. Monoclonal antibodies alone, though, have not completely eradicated migraine days per month and more research is needed.

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Volume 2, Issue 1

ARxCH Annual Review of Changes in Healthcare

lthough drug developers have and selective serotonin agonists. What does attempted to find a cure in numerous remain relatively clear in migraine A drug classes, migraines continue to pathophysiology is that genetics play a role. afflict humans worldwide. Behind dental Children with at least one parent with a cavities and tension headaches it is the most history of migraines have a 50% chance of prevalent disease in the world affecting developing this disease. This continues into approximately 15% of the world population. extended family as 80 to 90% of patients 1 This is broken down to more than 39 with migraines report having family million men, women and children in the members who also have a history of United States and over 1 billion worldwide.1 migraines.1 This alone has a greater prevalence than The word migraine originates from asthma, diabetes and epilepsy combined.2 the Greek word, hemicrania, meaning half of Although not commonly associated with a the skull.2 This coincides with one of the high mortality rate, studies have shown that common characteristics of a migraine being patients with migraines have a 50% greater a unilateral headache. According to the risk for cardiovascular disease and death.3 It International Classification of Headache is estimated that United States employers Disorders (ICHD) criteria, diagnosis of lose more than $13 billion due to 113 migraine can be confirmed if the patient has million workdays lost each year due to the following five qualities: 1. Headache migraines.1 These issues show that there is a attacks lasting anywhere from 4-72 hours, 2. continued need for research in migraine Headache meets two of the following four medication development. symptoms: pulsating headache, unilateral in Although its prevalence is great, the location, causing moderate to severe pain, pathophysiology of migraines is still exacerbated by or causing avoidance of unclear. Over the past several centuries, two routine , 3. Headache causes hypotheses have dominated the photophobia and phonobia or causes nausea pathophysiology debate. The vascular and/or vomiting, 4. History of at least five hypothesis, which is now beginning to fall attacks meeting the above criteria, and 5. out of favor, theorized that migraines were Symptoms are not more accurately due to an increased vasodilation of accounted for by another ICHD-3 cerebrovascular arteries. Further studies diagnosis.5 using a vasodilator, nitroglycerin, and a In the clinical presentation of a vasoconstrictor, , showed that migraine, patients may endure numerous vasodilation of these arteries did not trigger phases including prodromes, auras and migraines.4 This led to a hypothesis postdromes. These migraines can often be involving neuronal transmission and triggered by an external or internal stimulus. research into calcitonin gene-related peptide Some examples are bright lights, loud 2

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ARxCH Annual Review of Changes in Healthcare

noises, lack of sleep, certain foods or smells prevention becomes the priority. According and changes in hormones. A prodrome is the to the 2012 American Academy of first sign a patient could experience before a and American Headache Society migraine occurs and gives warning to the guidelines multiple classes of medications patient to begin treatment. This prodrome are considered to have established efficacy can appear in many forms from fatigue and in prevention of migraines. These classes excessive yawning, to euphoria and include beta-blockers (, excitement, or photophobia or , and ), antiepileptic drugs phonophobia.6 Fortunately a majority of (divalproex sodium, sodium , and patients experience prodromes, which ) and for short-term allows them to begin treatment before the prophylaxis for menstrual related migraines. headache attack phase begins. While a These guidelines also stated that prodrome can last anywhere from one hour ( and to 48 hours, an is much shorter and venlafaxine), beta-blockers ( and usually less than an hour. An aura begins the ) and ( and next phase of a migraine and precedes the for short term prophylaxis for headache attack phase. Auras are not nearly menstrual related migraines) are probably as common as prodromes as only 15 to 20% effective at preventing migraines.7 With of patients experience this phase.6 Visual uncertainty regarding the pathophysiology disturbances such as blurry vision, colored of migraines, it is not surprising that there spots and zigzags of light make up one of are a number of classes potentially involved the most common auras experienced before in the treatment of migraines that all involve migraine. Other symptoms may include different mechanisms. Beta-blockers are feeling pins and needles in extremities or believed to inhibit arterial dilation seen in difficulty speaking. The next phase is the migraines. The antidepressants amitriptyline actual migraine in which the patient and venlafaxine are believed to be effective experiences a debilitating pulsing unilateral in migraine prophylaxis due to their down- headache. Varying from patient to patient, regulation of serotonin receptors. the frequency and duration of these Antiepileptics are believed to provide migraines are unpredictable. Following the prophylaxis of migraines through the attack phase, the patient enters the suppression of neuronal hyperexcitability by postdrome phase of exhaustion, confusion increasing gamma-aminobutyric acid and hangover-like symptoms.6 (GABA), an inhibitory neurotransmitter.8

Migraine Prophylaxis Migraine Treatment Because of a migraine’s quick onset For the treatment of an acute and ability to incapacitate a patient for days, migraine headache, therapies mimic regular 3

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ARxCH Annual Review of Changes in Healthcare

pain recommendations. According to the a past medical history of the previous stated 2011 American Association of Family cardiovascular and cerebrovascular Physicians, NSAIDs are considered a first diseases.10 The combination analgesic of line therapy for acute migraine attack. acetaminophen (250mg), aspirin (250mg) Serotonin receptor agonists, commonly and caffeine (65mg) is an inexpensive referred to as triptans, are also a first line choice that is available without a therapy for these attacks. Unlike NSAIDs, prescription.9 which have many indications, triptans were Even with numerous drug classes developed for the treatment of migraine.9 explored for prophylaxis and treatment, and was the first serotonin receptor many FDA approved medications for agonist to be released to market. In 1993, migraine therapy, it remains one of the most Imitrex (sumatriptan) was FDA approved debilitating chronic diseases in the United for the treatment of migraines with or States. Therefore research has continued into without aura. Sumatriptan agonizes the 5- finding a solution for the prevention of HT1B/1D receptors in the intracranial blood migraines. With the transition from vascular vessels.10 This results in cranial vessel theory to neuropeptide theory, researchers vasoconstriction and believed inhibition of have honed in on calcitonin gene-related pro-inflammatory neuropeptides. There are peptides (CGRP). CGRP is a neuropeptide now seven different FDA approved triptans made up of 37 amino acids that is found in with numerous formulations and salts.11 Due sensory neurons as well as the to the strong efficacy of triptans and cardiovascular and cerebrovascular NSAIDs as monotherapy, a combination of systems.14 One of the leading cases for and sumatriptan (Trexima) has CGRP’s involvement in migraine also been studied.9 Studies in 2007 and 2013 pathophysiology is the evidence of increased found that this combination provided more CGRP levels in a patient currently favorable clinical benefits than monotherapy experiencing a migraine attack. When of sumatriptan, naproxen or with a patients are given triptans to resolve the tolerable side effect profile.12, 13 One of the migraine attack, CGRP levels have been concerns with the triptan class is the shown to decrease. Even further evidence of increased risk of cardiovascular and association comes from patients that cerebrovascular events. Myocardial received intravenous calcitonin gene-related infarction, coronary artery vasospasm, peptide and quickly began experiencing an subarachnoid hemorrhages, ventricular acute migraine attack.14 tachycardia and ventricular fibrillation are In targeting calcitonin gene-related rare but have been seen in patients several peptide, researchers could focus on the hours after taking a 5-HT1. Therefore the use peptide itself or its receptor. The first of triptans is contraindicated in patients with medications developed were small molecule 4

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antagonists of the CGRP receptor.14 completed phase III trials and are now and are two of the applying for biologic licensing applications small molecule antagonists that continue to with the FDA.16 , move towards market, while was , and , developed pursued and then discontinued. Although by Teva Pharmaceuticals, Eli-Lilly and pain relief rate and pain free rate show Alder Biopharmaceuticals, respectively, significant support for telcagepant and target the molecule calcitonin gene-related olcegepant compared to placebo, there are peptide.16 For Alder’s eptinezumab, phase concerns of chronic use resulting in III results were positive and showed a 50% hepatotoxicity; one of the causes of or greater reduction in migraine days in 61% telcagepant’s discontinuation.14 Calcitonin of patients compared to 39% in the placebo gene-related peptide has been shown to be a group (p<0.0001), a 75% or greater potent vasodilator.15 It would make sense reduction in migraine days in 33% of that antagonizing this peptide would result patients compared to 15 % in the placebo in vasoconstriction and relieve migraine group (p<0.0001), and three-month migraine headaches similar to the triptan class. One free period in 15% of patients compared to theory that has been supported through these 5% in the placebo group (p<0.0001).17 In trials is that although the calcitonin gene- Teva’s fremanezumab, patients were divided related peptide antagonists do cause in a 1:1:1 ratio to receive monthly dosing of vasoconstriction and more importantly a fremanezumab, a quarterly dose followed by decrease in neurogenic inflammation, they placebo, and placebo dosing.18 The study do not have an effect on the coronary found at least a 50% reduction in migraine arteries and do not increase blood pressure days for 41% of the monthly dosing group, like the triptan class.15 This selective 38% of the quarterly dose group and 18% of antagonism introduces a new therapy option the placebo group (p<0.001).18 For Eli- for patients with migraines, especially those Lilly’s galcanezumab, studies showed a with cardiovascular and cerebrovascular reduction of 4.7 migraine days per month for diseases that preclude them from taking 120 mg, 4.6 days for 240 mg and 2.8 days triptans. With concerns of hepatoxicity and for placebo (p<0.001).19 A fourth other side effects, research continued in the being studied is search of a safe and effective antagonist of , co-developed by Amgen and CGRP. . Erenumab differs from the Monoclonal antibodies have previous three monoclonal antibodies in that continued to be developed in more disease it targets the calcitonin gene-related peptide states as targeted and effective therapies. receptor instead of the peptide itself.16 There are currently several different Recently published phase III trials showed a monoclonal antibodies that have recently reduction of 3.2 migraine days per month for 5

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ARxCH Annual Review of Changes in Healthcare

the 70mg monthly group and 3.7 days for statistically significant when compared to the 140mg monthly group compared to 1.8 placebo.17-20 days for the placebo group (p<0.001).20 Continued advances in migraine Amgen and Novartis also found at least a therapy signify a positive future outlook for 50% reduction in migraine days per month patients hindered by this disease every day. in 43.3% of the 70 mg monthly dose and Monoclonal antibodies appear to have a 50.0% of the 140 mg monthly dose more favorable side effect profile over the compared with 26.6% of patients in the small molecule antagonists, while still placebo group (p<0.001).20 While this maintaining a strong reduction in migraine reduction of migraine days per month is a days per month. However a complete positive in developing an efficacious drug, solution has not been found as patients still one of the most significant findings in each experience multiple migraine days per of these trials was the low rate of adverse month while being prophylactically treated. effects. Only fremanezumab showed a slight Further research is needed into the calcitonin increase in hepatoxicity compared to gene-related peptide, as this appears to be a placebo, a side effect that derailed several of significant contributor to a migraine. the small molecule inhibitors from FDA Through this target as well as other approval. Other side effects of eptinezumab, pathways, a combination may be found to galcanezumab and erenumab were effectively prevent a disease that impacts considered either mild and minimal or not over one billion people.

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References 1. About Migraine. Migraine Research 13. Landy S, Hoagland R, Hoagland D, et al. Foundation. 2018. Available from: Sumatriptan-naproxen sodium http://migraineresearchfoundation.org/about combination versus its components -migraine/migraine-facts/ administered concomitantly for the acute 2. Facts and Figures. The Migraine Trust. treatment of migraine: a pragmatic, Available from: crossover, open-label outcomes study. https://www.migrainetrust.org/about- Therapeutic Advances in Neurologic migraine/migraine-what-is-it/facts-figures/ Disorders. 2013 Sep; 6(5): 279–86. 3. Kurth T, Winter AC, Eliassen AH, et al. 14. Yao G, Yu T, Han X, et al. Therapeutic Migraine and risk of cardiovascular disease effects and safety of olcegepant and in women: prospective cohort study. British telcagepant for migraine: A meta-analysis. Medical Journal. 2016 Apr 25; 353:1-6. Neural Regeneration Research. 2013 Apr 5; 4. Charles A, Brennan KC. An update on the 8(10): 938–47. blood vessel in migraine. Current Opinion 15. Durham PL. Calcitonin Gene-Related in Neurology. 2010 June; 23(3): 266–74. Peptide (CGRP) and Migraine. Headache. 5. Cephalalgia: The International Classification 2006 June; 46(Suppl 1): S3–S8. of Headache Disorders, 3rd edition. 16. Tso AR, Goadsby PJ. Anti-CGRP International Headache Society. 2018; Monoclonal Antibodies: the Next Era of 38(1): 1-211. Migraine Prevention? Current Treatment 6. Rothrock JF. Acute Migraine: Treating Options in Neurology. 2017 Jun 27. 19(8): Early. American Headache Society. 2009; 27. 635-6. 17. Cadle A. Alder Announces Eptinezumab 7. Silberstein SD, Holland S, Freitag F, et al. Significantly Reduces Migraine Risk Meets Evidence-based guideline update: Primary and All Key Secondary Endpoints Pharmacologic treatment for episodic in Pivotal PROMISE 2 Phase 3 Trial for migraine prevention in adults. Chronic Migraine Prevention. Alder Neurology. 2012 Apr; 78(17): 1337-45. Biopharmaceuticals. 2018 Jan 8. Available 8. Miles O. Migraine Treatment. Health Union. from: http://investor.alderbio.com/news- 2010 Nov. Available from: releases/news-release-details/alder- https://migraine.com/migraine-treatment/ announces-eptinezumab-significantly- 9. Gilmore B, Michael M. Treatment of Acute reduces-migraine-risk Migraine Headache. American Family 18. Silberstein SD, Dodick DW, Bigal ME, et Physician. 2011 Feb 1; 83(3): 271-80. al. Fremanezumab for the Preventive 10. Lexi-Comp Online [database on the Treatment of Chronic Migraine. NEJM. Internet]. Hudson (OH): Lexi-Comp, Inc. 2017 Nov 30; 377: 2113-22. 2018 [cited 2018 March 11]. Available 19. Dial J, Johnson P. Lilly Announces Positive from: http://online.lexi.com/ Results for Three Phase 3 Studies of 11. FDA Approved Drug Products. United Galcanezumab for the Prevention of States Food and Drug Administration. Episodic and Chronic Migraine. Lilly. 2017 Available from: May 12; Available from: https://www.accessdata.fda.gov/scripts/cder/ https://investor.lilly.com/releasedetail.cfm?r daf/index.cfm eleaseid=1026201 12. Brandes JL, Kudrow D, Stark SR, et al. 20. Goadsby PJ, Reuter U, Hallstrom Y, et al. A Sumatriptan-naproxen for acute treatment of Controlled Trial of Erenumab for Episodic migraine: a randomized trial. JAMA. 2007; Migraine. NEJM. 2017 Nov 30; 377:2123- 297(13): 1443–54. 32.

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