Anti-CGRP Monoclonal Antibodies: a Breakthrough in the Treatment of Migraine

Home , Eptinezumab, Erenumab, Olcegepant, Telcagepant

Journal of Neurology & Stroke

Review Article Open Access Anti-CGRP monoclonal antibodies: a breakthrough in the treatment of migraine

Abstract Volume 9 Issue 5 - 2019 To date, the prophylactic treatment of migraine has included only nonspecific drugs of Julia Azimova,1,2 Yaroslav Ashikhmin,1 Mikhail various pharmacological groups: the beta-blockers propranolol and metoprolol, the Kukushkin,2 Aleksandr Amelin,3 Eugene anticonvulsants topiramate and valproic acid, the antidepressants amitriptyline and 4,5,6 1 venlafaxine, candesartan, and Ona botulinum toxin A. As these drugs were developed Klimov, Kirill Skorobogatykh 1 for treatment of other diseases, their use was associated with adverse effects: decreased University Headache Clinic LLC, Russian Federation 2Institute of General Pathology and Pathophysiology, Russian blood pressure, mental retardation, weight increase, nausea, and some others. CGRP is a Federation neuropeptide that was regarded as the main biomarker of migraine as its level in this disease 3The First St. Petersburg State medical University of Acad. I.P. rise. The emergence of humanized monoclonal antibodies has opened up the possibility Pavlov Ministry of Health of Russia, Russian Federation of blocking the action of CGRP and developing a new class of drugs that includes 4Faculty of Biology, Lomonosov Moscow State University, fremanezumab, erenumab, galcanezumab, and eptinezumab. Anti-CGRP monoclonal Russian Federation antibodies can be prescribed to patients with chronic and episodic migraine. The use of 5University Diagnostic Laboratory LLC, Russian Federation anti-CGRP monoclonal antibodies in clinical studies was associated with a small number of 6Center of Experimental Embryology and Reproductive adverse effects, with severe adverse reactions being extremely rare. Biotechnologies, Russian Federation

Keywords: migraine, calcitonin gene related peptide, CGRP, antibody Correspondence: Julia Azimova, University Headache Clinic LLC, 121467, Moscow, Molodogvardeyskaya Str. 2, Bldg. 1, Russian Federation, Russia, Email

Received: August 29, 2019 | Published: September 12, 2019

Abbreviations: CGPR, calcitonin gene-related peptide; CNS, on chromosome 11. After synthesis, CGRP is transported by vesicles central nervous system; RAMP1, receptor activity-modifying protein to the axon terminal.4 The release of calcitonin gene-related peptide is 1; КАТР, АТР-sensitive potassium channel; GI, gastrointestinal stimulated by capsaicin. Presynaptic neurons are located on trigeminal neurons, and regulate CGRP release. Activation of 5-HT1B, 5-HT1D, Introduction and 5-HT1F serotonin receptors (the target for triptans and ditans, specific agents used to relieve migraine attacks) inhibits the release Patients with migraine, a primary headache disorder affecting of CGRP.5 15% of the population; will soon have access to drugs of a new pharmacological class, monoclonal antibodies to calcitonin gene- After release into the synaptic cleft, calcitonin gene-related peptide related peptide (CGRP). To date, the prophylactic treatment of migraine is degraded by metalloproteases 6. Amidation of the carboxyl terminus has included only nonspecific drugs of various pharmacological of the peptide protects it from decomposition, thus prolonging the groups: the beta-blockers propranolol and metoprolol, the half-life. This property allows CGRP to reach the receptor and exert anticonvulsants topiramate and valproic acid, the antidepressants its effects some distance from its release site in a process called amitriptyline and venlafaxine, candesartan, and Ona botulinum toxin volume transmission.7 A. As these drugs were developed for treatment of other diseases, their The CGRP receptor is a complex consisting of several proteins each use was associated with adverse effects: decreased blood pressure, of which is necessary for ligand specificity and function of the receptor mental retardation, weight increase, nausea, and some others. Adverse itself. The central part of the receptor, G-protein, is the CGRP receptor effects significantly worsen compliance with prophylactic treatment proper (CALCRL) belonging to the family of secretin receptors. To of migraine that should last 6–12months. Therefore, migraine is still be able to bind CGRP, the receptor has to form a heterodimer with one of the most maladaptive conditions, which, according to WHO receptor activity-modifying protein 1 (RAMP1).8 The CGRP binding data, is among the top ten diseases with regard to number of years of site is located between the CALCRL and RAMP1 receptors. Therefore, disability.1 An active search for biomarkers of migraine that would CGRP can affect its receptor only when CALCRL and RAMP1 enable specific therapy of this disease has been going on for a few receptors are co-expressed.3 Activation of the receptor results in an decades. increase in intracellular cAMP levels, which triggers phosphorylation The CGRP system of various targets, such as potassium channels (КАТР), extracellular signal-regulated kinases, and transcription factors, including CREB. The neuropeptide calcitonin gene-related peptide (CGRP) was In smooth muscle cells of cerebral blood vessels, CGRP-induced discovered in 19822 and promoted the study of the trigeminovascular cAMP increase leads to vascular wall relaxation and dilatation of system and its role in the development of migraine. CGRP is the vessel.9 There is also a second CGRP receptor, amylin receptor synthesized in peripheral sensory neurons and some regions of the (AMY1). It consists of RAMP1 and the calcitonin receptor, and is also central nervous system (CNS). There are two forms of CGRP, α and found in the trigeminal ganglion. The role of this type of receptors in β.3 α-CGRP consists of 37 amino acids, and is synthesized in neurons the mechanisms of migraine and in its treatment is unknown.4 through tissue-specific mRNA splicing. β-CGRP is found in the gastrointestinal tract. Transcription begins at the CALCA gene located An important specific feature of CGRP neurotransmission is desensitization of the receptor by agonists. When CGRP binds to the

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CALCRL receptor, the latter is quickly phosphorylated and internalized migraine, decreasing the frequency of both days of headache and days into endosomes from where it can soon return to the membrane. of migraine. In the STRIVE trial, 995 patients with episodic migraine Chronic exposure to CGRP triggers the process of internalization with were administered erenumab 70mg, erenumab 140mg, or placebo once capture of the receptor by lysosomes and subsequent destruction.10 monthly for 6months. A 50% or greater reduction in migraine days at treatment months 4–6 was observed in 43.3% of patients treated CGRP and migraine with erenumab 70mg, in 50% of subjects in the erenumab 140mg arm, and in 26.6% of placebo-treated patients (р<0.001 for comparisons The key role of trigeminal sensory fibres in the development of 11 primary headaches was already known at the time when CGRP was between each of the dose levels and placebo). The LIBERTY trial discovered. Since CGRP is mainly found in trigeminal neurons, it evaluated the efficacy of erenumab in patients with episodic migraine was thought to play a role in the pathogenesis of migraine. Besides, after failure of one or two drugs for the prevention of migraine. In this calcitonin gene-related peptide acts as a potent vasodilator, perfectly patient population, a 50% or greater reduction in migraine days was observed in 30.3% of patients treated with erenumab 140 mg and in fitting into the vascular theory of migraine that was commonly adopted 11 at the time.9 In 1990, Goadsby et al.11 demonstrated that CGRP is the 13.7% of placebo-treated subjects (p=0.002). only neuropeptide whose levels are increased in migraine. Calcitonin Eptinezumab was investigated in two studies, PROMISE 1 gene-related peptide was regarded as a potential diagnostic biomarker (episodic migraine) and PROMISE 2 (chronic migraine). In the of migraine; however, its instability and short half-life precluded PROMISE 1 protocol, patients received eptinezumab 30mg, development of an informative test.12 Intravenous administration of eptinezumab 100mg, eptinezumab 300mg, or placebo. A 50% or CGRP in patients with migraine triggers a migraine attack,13 which greater reduction in migraine days at treatment week 12 was observed allowed modeling of the disease. Finally, CGRP receptor antagonists, in 50.2% of patients administered eptinezumab 30mg (р=0.006), gepants, were synthesized and allowed effective relief of migraine 49.8% of subjects in the eptinezumab 100mg group (р=0.009), and attacks.1 56.3% of patients receiving eptinezumab 300mg.20 Anti-CGRP monoclonal antibodies HALO was the pivotal efficacy and safety study of fremanezumab in episodic and chronic migraine. Subjects with episodic migraine Antibody drugs are the mainstream in the development of novel were administered fremanezumab 675mg quarterly or fremanezumab 15 medicines, which is due to: 225mg monthly or placebo. A 50% or greater reduction in migraine a. Very high specificity. days was observed in 44.4% of patients treated with quarterly fremanezumab, in 47.7% of patients given monthly fremanezumab, b. Optimal pharmacokinetic characteristics that allow drug and in 27.9% of placebo-treated patients (р<0.001 for comparisons administration once in 2–5weeks. between each of the dose levels and placebo).21 In the same study, c. Significantly better (compared with small molecules) spectrum patients with chronic migraine were given fremanezumab 675mg of adverse effects, including hepatotoxicity, nephro-, cardio-, and quarterly and 225 mg at weeks 4 and 8, fremanezumab 675 mg neurotoxicity (except where due to direct effects on the target). quarterly and placebo at weeks 4 and 8, or placebo. A 50% or greater reduction in migraine days was observed in 38% of patients treated d. Greater opportunities for protection of intellectual property, as with quarterly fremanezumab, in 41% of subjects given monthly antibodies are difficult to “copy”. fremanezumab, and in 18% of placebo-treated patients (р<0.001 for comparisons between each of the dose levels and placebo).22 Efficacy of anti-CGRP monoclonal antibodies The efficacy of galcanezumab 120mg and 240mg versus placebo The first anti-CGRP monoclonal antibodies were synthesized after in patients with episodic or chronic migraine was assessed in the the discovery of the peptide in 1982, but these were used for diagnostic EVOLVE-1 and REGAIN studies. In episodic migraine, a 50% or purposes in liquid chromatography and immunohistochemistry to 2 greater reduction in migraine days at 6months was observed in 62.3% study CGRP in tissues. The emergence of humanized monoclonal of patients treated with galcanezumab 120mg, in 62.3% of subjects antibodies has opened up the possibility of blocking the action given galcanezumab 240mg, and in 42.5% of placebo-treated patients of CGRP and developing a new class of drugs that includes 4 (р<0.001 for comparisons between each of the dose levels and fremanezumab, galcanezumab, and eptinezumab. The development placebo).23 of anti-CGRP receptor monoclonal antibodies also provided a new approach to blocking the receptor. Erenumab is a human monoclonal New efficacy endpoints, proportions of patients with 75% and antibody to the extracellular domains of CALCRL and RAMP1.16 100% reductions in migraine days, were used for the first time in anti- Fremanezumab, galcanezumab, and erenumab are available for CGRP studies. subcutaneous injection, and eptinezumab for intravenous infusion. The maximum serum concentration (Cmax) of the subcutaneous Practical aspects of the use of anti-CGRP monoclonal dosage forms is 4–13days, while the Cmax of the intravenous antibodies eptinezumab is achieved on the day of administration. The short Anti-CGRP monoclonal antibodies can be prescribed to patients time to maximum concentration results in quick onset of action of with chronic and episodic migraine. These drugs are mostly indicated the drugs. The elimination half-life is in the range of 25–32days, so for patients with pre-chronic migraine (8–14days of migraine a 17–19 the drugs can be given once a month. Monoclonal antibodies are month), as well as for patients with chronic migraine or episodic eliminated by the reticuloendothelial system. migraine with an average frequency of attacks (4–7days of migraine a 24 All drugs based on monoclonal antibodies to CGRP or to its month). These agents should be considered for patients who cannot receptor have shown their efficacy in both episodic and chronic be administered standard therapy due to comorbidities, adverse effects

Citation: Azimova J, Ashikhmin Y, Kukushkin M, et al. Anti-CGRP monoclonal antibodies: a breakthrough in the treatment of migraine. J Neurol Stroke. 2019;9(5):262‒267. DOI: 10.15406/jnsk.2019.09.00387 Copyright: Anti-CGRP monoclonal antibodies: a breakthrough in the treatment of migraine ©2019 Azimova et al. 264

and low compliance.25 Monoclonal antibodies can prove effective ones (which are usually more expensive to manufacture). Chimeric/ after failure of one or two standard preventive migraine drugs.26 humanized monoclonal antibodies are between the two extremes in this regard.27 The switch from standard therapy to treatment with monoclonal antibodies has some specific aspects. It is recommended to discontinue The IgG subclass that the antibody belongs to is important as well: standard therapy before initiating antibodies in patients with episodic IgG1 is significantly more likely to activate the complement system migraine. In chronic migraine or episodic migraine in a patient (which is undesirable in the treatment of migraine) than IgG4 and with a history of chronic migraine, anti-CGRP antibodies should be IgG2.28 On the other hand, IgG2 has the lowest potential antibody- administered without discontinuing standard therapy. After that, once dependent cell-mediated cytotoxicity, so this antibody class is most an effect has been achieved, standard therapy may be discontinued suitable for the manufacture of drugs for the treatment of migraine. on an individual basis. The recommended duration of monoclonal Based on the properties of the antibodies in question, one can assume antibody therapy is 6–12months. In the presence of concurrent that the humanized antibody fremanezumab and the human antibody medication-overuse headache, monoclonal antibodies may be started erenumab, both of the IgG2 subclass, can have the best safety profile either before or after detoxification. The main contraindications to the and the lowest immunogenicity.29 This was confirmed by results of use of monoclonal antibodies are pregnancy and lactation; alcohol Phase II studies in which the frequency of immunogenicity reactions dependence and other types of dependences; relevant cardiac and was found to be 1% for fremanezumab,29 6% for erenumab,27 12% for cerebrovascular disorders; severe psychiatric disorders.25 eptinezumab29 and up to 30% for galcanezumab. The study’s authors Safety issues associated with the use of anti- underline that the development of autoantibodies to galcanezumab did not result in any changes in blood concentrations of the drug or CGRP CGRP monoclonal antibodies in the Phase II studies.30 Safety of the antibody platform of anti-CGRP drugs Drugs with lower risk of immunogenicity may be potentially Hazards associated with the use of monoclonal antibodies may preferable for patients with chronic migraine who may require longer be due to specific effects on the target (see below) or abnormal use of anti-CGRP monoclonal antibodies. response of the immune system. The latter may vary in severity It is essential to note that anti-CGRP monoclonal antibodies exhibit from mild reactions of chills and fever to a potentially fatal cytokine no impact on the central nervous system, as their high molecular storm. Other disadvantages of antibody drugs include their potential weight makes them unable to cross the blood-brain barrier.4 immunogenicity (formation of anti-drug antibodies potentially leading to decreasing efficacy in long-term use) and high cost of General safety considerations associated with the use manufacturing. Both immunogenicity and the risk of abnormal of anti-CGRP monoclonal antibodies immune response depend on the type of the antibody. Apparently, the risk is highest with mouse antibodies and lowest with human The spectrum of adverse effects of anti-CGRP monoclonal antibodies is presented in Table 1.31 Table 1 The most frequent adverse effects and adverse reactions reported during Phase II and III clinical trials (CTs) of anti-CGRP MAs

Drug Fremanezumab Erenumab Galcanezumab Eptinezumab

Injection site reactions (3–6%) Common adverse Injection site reactions (up Constipation Injection site reactions Equal to or less than reactions (incidence to 45%) (18%) placebo 1–10%) Muscle cramps Weakness

Hypersensitivity reactions, such as rashes, angioneurotic oedema, and anaphylaxis, were also observed with all anti-CGRP MAs; their occurrence did not exceed that with other antibodies. Other adverse reactions identified during phase III CTs included nasopharyngitis and upper respiratory tract infections, urinary tract infection, dizziness, nausea, and arthralgia. The frequency of these adverse effects was comparable to the placebo arm. As eptinezumab was administered intravenously, no complications associated with subcutaneous administration were detected. Reactions at the injection site were evaluated in the studies in different ways: either all reactions were evaluated as one adverse event, or pain at the injection site, redness, infiltration, etc. were reported separately. Regardless of the method of evaluation, there was no difference with placebo.

The use of anti-CGRP monoclonal antibodies in clinical studies protection of the mucous membrane from deleterious factors.32 In was generally associated with a small number of adverse effects, with animal experiments, exposure to anti-CGRP monoclonal antibodies severe adverse reactions being extremely rare. Below we will discuss resulted in pronounced damage to the gastrointestinal mucous safety issues associated with the specific inhibition of the CGRP lining.33 Analysis of available clinical study results does not reveal system resulting from binding of therapeutic antibodies to the ligand any increase in the incidence of gastrointestinal adverse effects during or CGRP receptor. treatment with anti-CGRP monoclonal antibodies, as compared with placebo. In particular, in the Phase III study of erenumab, ARICE, Gastrointestinal safety of anti-CGRP monoclonal constipation was observed in 1.4% of erenumab-treated patients and antibodies in 2.1% subjects of the placebo group.34 According to Medscape The gastrointestinal (GI) tract has massive CGRPergic innervation. data, constipation can occur in 3% of patients treated with erenumab Its functions include regulation of gastrointestinal motility and medscape.com.

Cardiovascular safety of anti-CGRP monoclonal noted that the clinical studies of anti-CGRP monoclonal antibodies antibodies mainly recruited female patients at very low risk of cardiovascular events. To study the effects of these drugs in patients at high risk, CGRP plays a considerable role in the regulation of cardiovascular erenumab was investigated in a separate double-blind, placebo- function, both in the central and peripheral nervous system and directly controlled, randomized study that enrolled 90 subjects with stable 32 at the level of the heart and vessels. CGRP receptors are expressed angina, including patients after acute myocardial infarction.46 A stress in peripheral arteries and the heart; besides, they are innervated by test revealed that erenumab 140mg i.v. had no effect on physical CGRPergic nerve fibres. exercise tolerance or development of myocardial ischaemia. It was To date, experimental studies have yielded the following aspects concluded that CGRP receptor blockade is safe for the cardiovascular of the effects of CGRP and its agonists on the cardiovascular system: system. The authors underlined that erenumab blocks only the canonical CGRP receptor without exerting any effect on the binding 1. CGRP is a potent vasodilator, and exerts positive inotropic and of CGRP to the amylin 1 receptor for which the former shows high chronotropic effects;35 affinity. These data are consistent with results that were obtained in a 2. CGRP gene knockout mice used in various hypertension models study of telcagepant in patients with stable angina pectoris. The use of telcagepant did not result in myocardial ischaemia, as revealed by demonstrated significantly elevated blood pressure levels and 47 more profound involvement of the target organs of hypertension a stress test, either. Therefore, the available data imply a rather good compared with control animals;36 medium-term cardiovascular safety profile of anti-CGRP monoclonal antibodies in a typical population of migraine patients. 3. Use of CGRP in a rat acute cerebral artery occlusion model was associated with less severe cerebral oedema;35 Further steps in the study of the cardiovascular 4. Use of a slow-release system to deliver CGRP into the safety of anti-CGRP monoclonal antibodies cerebrospinal fluid in a monkey subarachnoid haemorrhage Notwithstanding the promising results of a single study of model was associated with relieved vascular spasm.38 Similarly, erenumab in patients with stable ischaemic heart disease, the question administration of CGRP in patients with subarachnoid of the safety of anti-CGRP monoclonal antibodies in patients at high haemorrhage was associated with decreased severity of vascular risk of cardiovascular complications, particularly in the long term, spasm;39 is still open to debate. Currently these agents are contraindicated in 5. In biological models of myocardial infarction, CGRP decreased patients with serious cardiovascular diseases. It is advisable to include the volume of ischaemic myocardium and prevented the 24-hour blood pressure monitoring in the protocols of new large- development of life-threatening arrhythmias;40 scale studies of CGPR inhibitors. In small-scale studies that enroll patients with heart disease, cardiac MRI with myocardial perfusion 6. Recently developed CGRP analogues demonstrated an assessment and analysis of biomarkers (such as ultra-high sensitivity antihypertensive effect, prevented pathological myocardial troponin and NT-pro-BNP) are the best tools to clearly demonstrate the remodeling, and stimulated angiogenesis in biological models of absence of cardiac toxicity. The role of endothelial dysfunction in the hypertension and heart failure;41 pathogenesis of migraine and the influence of anti-CGRP monoclonal antibodies are not clearly understood yet, which warrants endothelial 7. Use of CGRP in patients with congestive heart failure resulted in function studies in migraine patients treated with these drugs. improved pumping capacity of the heart.42 These experiments, as well as a number of others that are Acknowledgments not mentioned in this paper, allow a conclusion that CGRP has This research received no specific grant from any funding agency cardioprotective and vasoprotective properties. Accordingly, the in the public, commercial, or not–for–profit sectors. initially cautious use of anti-CGRP monoclonal antibodies was due to the risk of vasoconstriction, which in turn can elevate blood pressure Conflicts of interest and induce cerebral and myocardial ischaemia. The author declares no conflict of interest. As a result, a programme was started to study the effects of CGRP antagonists on the cardiovascular system. In the overwhelming Funding majority of experiments in biological models, use of CGRP antagonists did not affect haemodynamic parameters and had no None. effect on the severity of ischaemia in arterial occlusion.43 A study in a pithed rat model found that the CGRP antagonist olcegepant References enhanced sympathetic adrenergic effects, which resulted in elevated 1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. blood pressure.44 Administration of CGRP antagonists in healthy Global, regional, and national incidence, prevalence, and years lived with volunteers did not increase blood pressure or have any other negative disability for 328 diseases and injuries for 195 countries, 1990–2016: a consequences either.45 systematic analysis for the global burden of disease study 2016. Lancet. 2017;390(10100):1211–1259. The most important clinical trial data were obtained for anti- 2. Amara SG, Jonas V, Rosenfeld MG, et al. Alternative RNA processing CGRP monoclonal antibodies in Phase II and III studies that included in calcitonin gene expression generates mRNAs encoding different office blood pressure monitoring and ECG recording. None of the polypeptide products. Nature. 1982;298(5871):240–244. studies, including a long-term follow-up (for more than 1.5years), has yet been able to demonstrate any negative effect of anti-CGRP 3. Russell FA, King R, Smillie SJ, et al. Calcitonin gene– related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099–1142. monoclonal antibodies on the cardiovascular system. It should be

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