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NARRATIVE REVIEW
Year : 2023 | Volume
: 11
| Issue : 1 | Page : 11-18
Advances in CGRP monoclonal antibodies as migraine therapy: A narrative review
Suruchi Aditya1, Aditya Rattan2
1 Department of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Chandigarh, India
2 Cardiology Clinic, Heart Line, Panchkula, Haryana, India
Correspondence Address:
Suruchi Aditya
Department of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Chandigarh
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/sjmms.sjmms_95_22
Migraine is a potentially disabling disorder, yet it remains underdiagnosed and undertreated. The release of the neuropeptide calcitonin gene-related peptide (CGRP) in the trigemino-cerebrovascular system plays a vital role in the evolution of migraine. It enhances peripheral sensitization by mediating neurogenic inflammation and also influences central sensitization. The majority of the drug classes available for migraine prophylaxis are nonspecific and associated with numerous side effects and drug interactions. Anti-CGRP monoclonal antibodies (mAb) are an innovative therapeutic class that fulfills the need for more efficacious and tolerable preventive therapy. While erenumab is a mAb to the CGRP receptor, eptinezumab, fremanezumab, and galcanezumab bind to the CGRP molecule. They decrease the number of headache days and improve disability. Upper respiratory tract infection, nausea, constipation, pain at the site of injection, and fatigue are the associated side effects. CGRP mAbs are an excellent advancement in translational research and are a promising addition in migraine therapy. This article discusses the recent advances in the development of the CGRP mAbs.
Keywords: Anti-CGRP antibody, CGRP, calcitonin gene-related peptide receptors, eptinezumab, erenumab, fremanezumab, galcanezumab, headache, migraine, monoclonal antibodies
Migraine, an important cause of disability, is a significant public health concern affecting >1 billion people worldwide.[1] The prevalence of migraine has been reported to largely vary across countries and epidemiological studies from 2.6% to 21.7%.[2] Being aged 25–55 and female gender are reported to be predisposing factors of migraine.[3] The burden of migraine is also found to be increasing among students and veterans.[4],[5] More than half of migraineurs are functionally impaired to a severe degree and the resultant lost productivity at work, home, and social context contributes to substantial socioeconomic burden.[6]
The moderate to severe unilateral throbbing headache, worsened by movement is a characteristic attribute. Other features are nausea, appetite loss, vomiting, photophobia, sensitivity to noise and hypersensitivity to certain smells. Bilateral headache and pain involving the face or the whole body have also been observed.[7] Alcohol, certain foods, seasonal changes, light, noises, smells, stress, menstruation, and delayed meals trigger and/or aggravate migraine attacks.[8] A few migraineurs experience aura, defined as characteristic visual disturbances that precede, accompany, or follow the pain. Sensory aura comprises tingling and numbness that may spread over the limbs and face.[7]
Migraine is categorized as episodic or chronic. According to the International Headache Society, a patient with ≤14 headache days in a month is labeled to have episodic migraine (EM), while ≥15 headache days per month for >3 months with ≥8 headaches that fulfill the criteria for migraine classify for a label of chronic migraine (CM).[9] Progression to CM may be accelerated by concomitant low socioeconomic status, obesity, medication overuse (MO), unsuccessful treatment, comorbid pain, female gender, and stress.[10]
The pathophysiology of migraine is regarded as a genetically predisposed hypersensitivity of the central nervous system (CNS) to triggers, both inside and outside the brain. Functional changes observed in the brain of CM patients are hyperexcitability of the cortex, sensitization of the trigemino–thalamic area, and flawed descending pain modulation.[11] Recent evidence disproves the vascular hypothesis, which claims that headache is caused by dilation of blood vessels (dural and extracranial). Vasodilatation is now considered as a consequence rather than the cause.[12] Migraine is a neurovascular disorder, with a central role of the trigeminovascular system (TVS) in the causation of pain.
Calcitonin-like gene receptor peptide (CGRP), the body's strongest vasodilator, is abundant in the neurons of trigeminal ganglia (TG) and the trigeminal nerve.[13] It is stored in vesicles at nerve terminals and released from perivascular sensory afferent nerves, dural mast cells, Schwann cells, and satellite glia in the TVS.[14] After its release, it is carried to the jugular vein through the sagittal sinus.[15] Research by Goadsby and Edvinsson led to notable findings confirming that CGRP is a critical molecule in migraine, shifting the focus away from substance P or neurokinin A.[16] During migraine attacks, the levels of CGRP increase in the cranial circulation and saliva.[16] Blood levels of CGRP during the interictal period are significantly higher, suggesting that it may be used as a biomarker for disease activity.[17] In migraine patients, intravenous infusion of recombinant human CGRP 2 μg/min over 20 min can start a headache that is very similar to a spontaneous attack.[18] Raised CGRP serum concentrations can be brought to baseline levels with the use of triptan.[16] The most convincing reasoning for the assertion is that anti-CGRP therapeutics (ligand and receptor antagonists) are effective in both the acute and preventive treatment of migraine.[19]
US Food and Drug Administration (FDA) has approved four CGRP mAbs –erenumab, fremanezumab, galcanezumab (in 2018), and eptinezumab (in 2020)–offering a novel therapeutic option for chronic migraineurs. Aptly called disease-modifying migraine drugs, they represent the first disease-specific preventive migraine therapies.[19]
This narrative review presents an update on the role of CGRP in migraine and CGRP antibodies along with their clinical studies in the prevention of migraine. For the collection of relevant studies, Medline (through PubMed), EMBASE, Cochrane databases, Medscape, Scopus, and clinicaltrials.gov were searched using the search terms “migraine”, “CGRP”, “monoclonal antibodies (mAbs) to CGRP”, “erenumab”, “eptinezumab”, “fremanezumab”, “galcanezumab” and “pathophysiology of migraine”. Journal articles published in English from 2010 to 2021 that discussed the role of CGRP in the pathogenesis of migraine, CGRP antibodies, and their clinical trials, were screened.
Current Pharmacotherapy of Migraine and Its DrawbacksPharmacological treatment aims to reduce headache severity and frequency and manage comorbidities. The choice of pharmacological agent is based on the migraine headache frequency (EM or CM), degree of impairment, history of drugs used in the past, tolerability, comorbid diseases, and patient bias.[20]
At present, nonsteroidal anti-inflammatory drugs, triptans, antiemetics, and combinations of analgesics are recommended for the treatment of acute attack. All medications used in acute cases may lead to the complication of MO headache or rebound headache, which has a frequency of ≥15 days in a month while using the anti-migraine drug for ≥10 days per month for 3 months.[21] Clinicians discourage the use of barbiturates and ergotamine-related drugs due to the risk of side effects and/or dependence.[15] Opioids prevent reversal of central sensitization, are pro-nociceptive, and affect triptan effectiveness.[22] Moreover, the use of polytherapy to treat comorbidities such as cardiovascular and psychiatric diseases may hinder the actions of anti-migraine drugs.[23]
Drug classes available for prophylaxis are calcium channel blockers (flunarizine, verapamil), antidepressants (tricyclic antidepressant: amitriptyline), antiepileptic drugs (topiramate, sodium valproate, divalproex sodium), antihypertensives (beta blockers-metoprolol, propranolol, timolol), and onabotulinum toxin A. Topiramate has side effects that limit its long-term use.[24],[25] Onabotulinum toxin A is administered to 31–39 sites every 12 weeks.[25] These classes of medications were originally developed for other conditions and have multiple therapeutic targets.[9] The majority of these drugs have drawbacks of modest efficacy, poor tolerability, and inconsistent response.[15] Approximately 40% of persons who have EM would benefit from prophylactic therapy; however,<15% of the patients continue its regular use.[24] Poor adherence due to adverse events and tolerance are grave issues that point to an unmet need for specific prophylactic agents.[26] Acknowledging previous ineffective attempts of treatment, patients with “refractory” migraine form a complex subset for whom finding a suitable medication is a challenge. The European Headache Federation labels the failure to respond to three drug classes as resistant migraine, and the failure of all drug classes with established evidence in migraine as refractory migraine.[27]
Role of Cgrp in the Pathophysiology of MigraineCalcitonin, α and β CGRP, amylin, adrenomedullin, and adrenomedullin 2 make up the CGRP family. β CGRP differs from α CGRP by 1 to 3 amino acids in different species and is expressed exclusively in the enteric sensory neurons.[28] CGRP receptors are heteromers, comprising the calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1(RAMP1) and the receptor component protein. CGRP binds in a pocket made by heteromers CLR and RAMP1.[29]
In the CNS, CGRP is expressed in the neurons of the cerebral cortex, hippocampus, substantia nigra, cerebellum, brainstem, thalamic and hypothalamic nuclei. CGRP and its receptor largely have a common distribution, but their expression is also discrete in many areas.[14],[30] It is intriguing to note that while CGRP-expressing neurons are small to medium in diameter (C fibers), its receptors (colocalized CLR and RAMP1) are found on larger neurons, myelinated Aδ fibers, and satellite glial cells.[30] In conformity with the differential location of CGRP and its receptors, it was observed that CGRP antibody fremanezumab selectively inhibited the myelinated Aδ fibers but not the C fibers.[31] Whether this difference in site of action contributes to any differential effect between antibody to the peptide and antibody to the receptor remains to be clarified.
The TVS, abundant in CGRP, consists of sensory pseudounipolar neurons of the TG with first-order afferent neurons innervating the pial and dural meningeal vessels, and efferent projections synapsing with second-order neurons in the trigeminal nucleus caudalis.[32] During activation of the TVS, CGRP leads to neurogenic inflammation in the meningeal vasculature and mast cell degranulation resulting in peripheral sensitization, which is an enhanced afferent activity of nociceptive neurons to a stimulus.[33] It is responsible for intracranial hypersensitivity (patient experiences pain aggravation on physical exertion due to fluctuations in intracranial pressure) and the throbbing headache.
Russo et al. have proposed that CGRP enhances neural sensitization through CGRP-triggered feedback loops.[34] Firstly, endogenously generated nitric oxide (NO) can form nitroxyl (HNO) with hydrogen sulfide, to cause CGRP release from trigeminal dural fibers.[35] Secondly, CGRP increases purinergic P2X3 gene expression in nociceptive TG neurons, furthering CGRP release.[36] Finally, CGRP can induce its own synthesis in TG neurons by paracrine and autocrine mechanisms.[13] In addition, studies point to a role of the neuron–glia interplay: the release of CGRP activates the satellite glia cells, which release proinflammatory cytokines and results in a positive feedback loop.[32],[37]
The information from the second-order neurons is relayed to the third-order neurons in the posterior thalamus and hypothalamus. Thalamocortical projections convey the craniovascular nociceptive signals to neurons in the cortical regions such as visual, motor, auditory, and somatosensory.[32] Long-term changes suggest that CGRP may activate transcription factors and pronociceptive proteins, ultimately enhancing nociception.[29] It was shown to induce long term potentiation in the anterior cingulate cortex, where it enhanced synaptic transmission through glutamate N-methyl D-aspartate receptors.[38] It has been proposed that peripherally situated CGRP leads to distant amplification of central neuronal circuits, leading to a decreased capability to control the pain.[15] Central sensitization of nociceptive signals leads to autonomic, cognitive, and affective symptoms.[39] It may lead to cutaneous allodynia when even a non-noxious stimuli is perceived as painful; in migraineurs, pain can be evoked by light touch during brushing hair or taking bath.[39] More corroborative evidence will unravel the role of antidromic release of CGRP in mediating central sensitization. The complex interplay between meningeal vasculature, meningeal milieu, and trigeminal afferents sustains the sensitization but the role of CGRP in modulating the ascending transmission of nociceptive signaling in migraine remains to be elucidated.
CGRP AntagonistsThe actions of CGRP can be blocked using many approaches such as non-peptide CGRP inhibitors called “gepants” and mAbs. The site of action of both gepants and mAbs is outside the blood-brain barrier.[15]
Gepants
Olcegepant and telcagepant, were associated with liver toxicity on repeated use.[26] Safety data for ubrogepant, atogepant, and rimegepant do not disclose notable risk for hepatotoxicity. Ubrogepant (oral) and rimegepant (orally disintegrating tablets) were approved by the FDA for the treatment of acute migraine in 2019 and 2020, respectively.
CGRP monoclonal antibodies
mAbs directed at CGRP molecule (eptinezumab, fremanezumab, and galcanezumab), and mAbs for CGRP receptor (erenumab) are in clinical use.[19],[40],[41]
Clinical Studies with Monoclonal AntibodiesErenumab
Erenumab, a CGRP receptor blocker, is a humanized IgG2 mAb that has been found to have an early-onset efficacy. In one trial, patients who received erenumab (140 mg) reported a ≥50% decrease in the migraine days/week in the first week of use.[42] In a study from Italy, treatment with erenumab for 1 month reduced the monthly migraine days (MMDs) in patients with CM by 12.2 days, in addition to resulting in reduced use of medication, intensity of pain, and disability.[43] Two phase III randomized controlled trials (RCTs) have evaluated the efficacy of subcutaneously administered erenumab (70 mg and 140 mg monthly) in the prevention of EM and found ≥50% reduction in MMDs in a significant proportion of patients [Table 1].[44],[45] A Phase IIIb trial (LIBERTY) that included EM patients with a history of 2–4 preventive drug failures verified the superiority of erenumab 140 mg.[55] In a real-world audit in patients with medically refractory CM, 62% of the patients obtained a 50% reduction in MMD at 6 months with the use of erenumab140 mg.[27] In a retrospective analysis, patients unresponsive to or with contraindications to six preventive medications (five orally administered drugs [beta-blockers, flunarizine, topiramate, amitriptyline, valproate] and onabotulinum toxin A) showed a reduction of 4.7 MMD over three treatment cycles.[56] In the subset of patients with MO, the use of erenumab lead to a reduction of 6.6 MMDs compared with reduction of 3.5 MMDs with placebo in a 3-month study.[57] In the interim safety analysis of a 5-year open-label study, erenumab was found to be a safe drug.[58]
Eptinezumab
Eptinezumab, a humanized IgG1 mAb that targets both the α and β isoforms of CGRP, is the only CGRP mAb that is administered intravenously quarterly.[59]
Two Phase III RCTs have assessed the efficacy of eptinezumab as a prophylactic treatment for both EM and CM and significant reductions in the number of MMDs and ≥50% reduction in MMDs were noted [Table 1].[46],[47] In the trial that included EM patients, eptinezumab 100 mg and 300 mg reduced the probability of experiencing migraine on the first day after infusion by >50%.[46] In a 1 year, open-label safety study, the use of eptinezumab 300 mg in patients with CM reduced migraine-associated disability and improved functionality.[60]
Fremanezumab
Fremanezumab is a humanized IgG2 mAb that can bind to both the α and β isoforms of CGRP. Trials have evaluated its use in the prevention of EM at 225 mg (subcutaneous) monthly and 675 mg quarterly (single high dose; placebo at weeks 4 and 8)[48] and in the prevention of CM at 675 mg quarterly (placebo at weeks 4 and 8) and 225 mg monthly (with a one-time high dose of 675 mg at start) and found significant reductions in the number of MMDs and ≥ 50% reduction in MMDs [Table 1].[49] In the FOCUS trial, fremanezumab was effective in migraineurs unresponsive to up to four classes of preventive agents. A notable improvement in depressive symptoms for patients with comorbid depression was observed.[50] In a long-term study with fremanezumab, in the EM group, more than one-third of patients had a ≥75% reduction in MMD, while one-fifth attained 100% reduction.[51]
Galcanezumab
Galcanezumab is a humanized IgG4 mAb that binds to both the α and β forms of CGRP.[40] Trials have demonstrated the effectiveness of subcutaneous monthly doses of 120 mg (with a single loading dose of 240 mg) and 240 mg as a prophylactic therapy for both EM and CM [Table 1].[52],[53],[54],[61] In a year-long study, galcanezumab was found to improve functional impairment and reduce disability.[62],[63] In patients with EM or CM with a documented failure of two to four preventive medications, galcanezumab group reported 4.1 fewer MMDs from baseline compared with one fewer than baseline with placebo.[64]
Ongoing phase 3 and phase 4 studies are evaluating the efficacy and safety of the mAbs in children, concomitant depression, vestibular migraine, and cluster headache.[65]
Advantages and disadvantages of monoclonal antibodies
Excellent patient response and safety profile make anti-CGRP mAbs a great leap forward in migraine therapy. They are the first mechanism-based migraine-specific drugs and have shown fast response and better compliance than other currently used medications. An effective prophylactic anti-migraine drug lowers the headache frequency by ≥50% in 3 months.[21] About 48%–62% patients have shown a >50% reduction in MMD with the use of these mAbs.[40] In one study, patients with a history of a positive response to a triptan at any time had a higher probability to respond to erenumab compared with triptan non-responders.[66] Data from trials in resistant and refractory CM show that mAbs may be more useful in patients with inadequate response, poor tolerability, or contraindications than other prophylactic agents.[27],[50],[56],[64] Another advantage is that the therapeutic effect lasts long after stopping the drug.[67] In addition, CGRP antibodies show a low potential for drug–drug interactions, as there is an absence of hepatic metabolism or renal clearance. They are degraded by proteolysis to smaller peptides and amino acids that does not involve the liver.[68],[69] A meta-analysis reported that compared with topiramate, anti-CGRP mAbs showed a stronger placebo and weaker nocebo phenomena in the RCTs in the prophylaxis of EM. The difference between the anti-CGRP mAbs and onabotulinum toxin A in the treatment of CM was not significant.[70]
Parenteral administration carries the disadvantage of requiring the help of medical staff. This can increase the placebo response as well as the risk of initiating an infection. Besides local site reactions, there is also an issue of systemic immunological effects. Although these mAbs do not have a target within the immune system, antidrug antibodies may decrease effectiveness or start immunoallergic reactions.[17] Favorably, such an effect has not been seen in trials. Use in wound healing is cautioned, as CGRP promotes keratinocytes, helps in increasing revascularization, and decreases macrophage invasion.[41] As CGRP is a multifunctional neuropeptide involved in the maintenance of physiological processes, side effects related to cardiovascular and CNS are being monitored in the post-marketing surveillance. The FDA recently added a label change stating the possibility of development of hypertension or worsening of pre-existing hypertension in patients starting erenumab.[25] Constipation has been commonly reported in recent trials as well as in the real-world experience.[27],[67] Long-term risks, especially in comorbid conditions, will be revealed through use in the future.[41] The risks have also not yet been assessed in population subsets such as in children and pregnant and lactating women. Antibodies should not be used in coronary heart disease, ischemic stroke, subarachnoid hemorrhage, or peripheral arterial occlusive disease. They are contraindicated in patients with inflammatory bowel disease, pulmonary hypertension, chronic obstructive pulmonary disease, Raynaud's syndrome, and wound-healing disorders as well as in patients who have received transplantation.[24]
CGRP mAbs are costly, but they provide more migraine-free days and increase health-related quality of life when compared with no treatment.[68] mAbs reduce migraine-related direct and indirect costs, with each migraine-free day having been estimated to save approximate between $130 and $340.[71],[72]
Current Scenario of CGRP Monoclonal Antibodies in Migraine TherapyAmerican Headache Society guidelines state that mAbs treatment with established dosing may be used in adults demonstrating intolerance or unresponsiveness to at least two well-established prophylactic agents after 6 weeks of treatment initiation.[68] Evaluation of the treatment should be done after 3 months for drugs given monthly and after 6 months for those administered quarterly. In addition, patient feedback on functional ability and quality of life should be taken into consideration.[68] Data regarding interchanging CGRP mAbs in unresponsive patients is inconclusive.[73]
Besides the use of drugs, managing CM involves patient education, lifestyle changes, avoiding MO, and treating associated comorbidities.[11] In patients where most of the available drugs are contraindicated, such as overweight/obese patients with comorbid depression, CGRP mAbs maybe used as the first-line treatment together with onabotulinum toxin A. For others, failure with onabotulinum toxin A maybe a precondition before using CGRP mAbs. Treatment with erenumab for 9 months in onabotulinum toxin A-resistant CM patients has been found to reduce pain and medication use and improve the quality of life.[74] Use of oral rimegepant for the acute treatment of migraine was found to be safe and tolerable in patients concomitantly receiving erenumab, fremanezumab, or galcanezumab as a prophylactic treatment of migraine.[75] Real-world experience will disclose more information on their safety and efficacy, as these mAbs will be combined with drugs of different classes.
ConclusionMigraine is a highly prevalent disabling disease occurring in the most productive years of life. CGRP plays a central role in the neurobiology of migraine headaches. Anti-CGRP mAbs represent the first prophylactic therapy designed specifically for migraine. CGRP mAbs show advantages of fast onset, good patient response, acceptable safety profile, less off-target effects, and long duration of action that allows once a month administration. Considering the limitations of the currently available agents, these injectable biologics offer exciting prospects in migraine prevention.
Peer review
This article was peer-reviewed by four independent and anonymous reviewers.
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Nil.
Conflicts of interest
There are no conflicts of interest.
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