Calcitonin gene-related peptide is a 37-amino acid neuropeptide and a potent vasodilator produced by neurons in both the central and peripheral nervous systems.[1] The receptor for this neuro-peptide is a complex heterodimer containing a class B G-protein coupled receptor called CLR (calcitonin receptor-like receptor).

In the central nervous system, researchers observed that a raised level of blood and salivary levels of CGRP occur in patients with headache disorders such as migraines and cluster headaches, as well as in neuralgias such as trigeminal neuralgia, chronic paroxysmal hemicranias, and even in rhinosinusitis. Levels are elevated during a migraine attack and between migraine attacks in patients with chronic migraines. Also, CGRP from exogenous infusions were shown to trigger migraine attacks.[2] Later studies showed that CGRP released in the trigeminal neurons was associated with the release of vasoactive neuropeptides and vasodilation of the cerebral vasculature, thus playing a role in the pathogenesis of migraine.

Migraine is a neurovascular disorder characterized by unilateral, throbbing/pounding headache accompanied by photophobia, phonophobia, nausea, vomiting and, disability and usually has a duration of around 4 to 72 hours.[3]

Currently, FDA approved drugs acting on the CGRP, or its receptor, are those used in the treatment or prophylaxis of migraine. This group includes monoclonal antibodies (erenumab, eptinezumab, galcanezumab, fremanezumab) against the CGRP receptor and CGRP receptor antagonists (rimegepant and ubrogepant). atogepant and vazegepant are other receptor antagonists that are undergoing clinical trials and are yet to receive FDA approval.

The monoclonal antibodies (erenumab, eptinezumab, galcanezumab, fremanezumab) are used for migraine prophylaxis in episodic and chronic migraine. Rimegepant and ubrogepant are used for acute treatment of migraine with or without aura. galcanezumab and fremanezumab are under development for the preventive treatment of cluster headache.   

CGRP was also shown to have cardio-protective action in pathological conditions, as demonstrated in rodent models of different cardiovascular diseases. Studies in humans have also demonstrated that CGRP decreases afterload and increases inotropy, which is cardioprotective in heart failure. However, there are no drugs developed to date that takes advantage of this effect on the cardiovascular system.[4]

Similarly, newer studies find that CGRP is also involved in several other physiological/pathological phenomenon such as peripheral nerve regeneration, Alzheimer disease, vascular tone of mesenteric arteries, and pregnancy. However, no drugs have been developed which take advantage of these effects of CGRP. 

To understand the mechanism of action, a bit of information on the anatomy of the CGRP receptors may prove useful.           

The CGRP receptor is a heteromeric receptor complex composed of three subunits:

• CLR (calcitonin receptor-like receptor) which is a type B, G protein-coupled receptor.[5] CLR has a 55% overall identity with the calcitonin receptor for the thyroid hormone.[6] The CLR receptor (class B GPCR) contains a structured N-terminal extracellular domain (ECD) or ectodomain, a seven helix transmembrane (7-TM) domain, and an intracellular carboxyl terminus. The ECD functions as a receptor for the CGRP molecule.[7]
• RAMP1 (Receptor Activity Modifying Protein 1): This is a member of the single transmembrane RAMP family and is necessary for the proper functioning of CLR. RAMP presents CLR to the plasma membrane as a mature glycoprotein.[6] Amino termini of RAMPs determine the glycosylation of CLR, which in turn, correlates with the receptor phenotype.[8] The main CGRP receptor forms when CLR is delivered and modified via RAMP1. Different combinations of CLR/CTR and RAMPs (1, 2, and 3) create different glycosylation products, thus producing different receptors such as the ones for amylin and adrenomedullin.[5] CGRP may also signal via receptors other than the CLR/RAMP1 complex, such as the CLR/RAMP3 combination, which is an adrenomedullin receptor. RAMP1 may also serve as an antagonist binding site, but its role as a ligand for binding of CGRP or its antagonists remains unclear.[8]
• RCP (Receptor Component Protein) is important in the intracellular G protein signaling.[5]

Erenumab:  is a human immunoglobulin G2 (IgG2) monoclonal antibody produced from Chinese hamster ovary cells. Erenumab acts by potently and competitively inhibiting the binding of CGRP to its receptor.[2]

Eptinezumab is a humanized immunoglobulin G1 produced in Pichia pastoris yeast cells by recombinant DNA technology. Eptinezumab potently and selectively binds to the α and β-forms of human CGRP ligand and prevents the activation of the CGRP receptor. It has a rapid onset of action and prolonged clinical activity. This action may be due to the rapid binding and inactivation of CGRP and slow dissociation and from the peptide.[9]

Galcanezumab is a humanized IgG4 monoclonal antibody produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Galcanezumab binds to human CGRP with high affinity and prevents CGRP-induced receptor activation.

Galcanezumab also inhibits capsaicin-induced vasodilation, which is a CGRP induced, concentration-dependent, long-lasting relaxation of human coronary arteries.[10]

Fremanezumab is a fully-humanized IgG2 produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Fremanezumab selectively targets and binds to both the α and β isoforms of CGRP and prevents CGRP-induced receptor activation.[11]

These monoclonal antibodies act rapidly and prevent the binding of CGRP. This receptor blockade is long term, which leads to a reliable method of migraine prophylaxis using only a few doses of the drug per month. As with other monoclonal antibodies, these drugs are degraded into small peptides and amino acids by enzymatic proteolysis before excretion.

CGRP receptor antagonists ("gepants") are the first class of migraine-specific medication that does not have vasoconstrictive action, shows similar efficacy, has fewer adverse effects, and has a possibly longer period of activity than triptans.[7] Gepants demonstrate an extremely high affinity for CGRP receptors of human and non-human primates, preventing in this way the interaction between CGRP and its receptor.[12] The structured N-terminal extracellular (ECD) domain of CLR serves as a binding site for gepants, thus providing its fast-acting antagonistic action. The currently FDA approved gepants are rimegepant and ubrogepant.

The first four drugs listed are monoclonal antibodies used in the prophylaxis of chronic and episodic migraine.

Erenumab: is a self-administrable subcutaneous injection. The recommended dosage is 70 mg subcutaneously once or twice a month in the abdomen, thigh, or upper arm. Alternatively, 140 mg dose may be administered once a month.[13]

Eptinezumab: The recommended dosage is 100 mg of eptinezumab, administered as an intravenous infusion after dilution in 100 mL of 0.9% sodium chloride. Infusion is done over approximately 30 minutes every three months. Some patients could potentially benefit from a dosage of 300 mg.[9]

Galcanezumab: is administered as a subcutaneous injection. A loading dosage of 240 mg (administered as two consecutive injections of 120 mg each), followed by monthly doses of 120 mg, is recommended. Subcutaneous injection is administered in the abdomen, thigh, back of the upper arm, or buttocks.[10]

Fremanezumab: is administered as a subcutaneous injection. The recommended dose is 225 mg monthly or 675 mg every three months administered as three consecutive injections of 225 mg each. Subcutaneous injection is administered in the abdomen, thigh, back of the upper arm, or buttocks. This drug provides effective prophylaxis against episodic and chronic migraines by reducing the mean number of migraine attacks per month and improvement in the mean monthly Migraine Physical Function Impact Diary (MPFID).[11]

Rimegepant: is given for the acute treatment of migraine with or without aura. Rimegepant is administered as an orally disintegrating tablet containing 75mg of rimegepant free base orally/sublingually. Dosage should not exceed 75 mg in a 24-hr period.[14] The safety of treating more than 15 migraines in 30 days has not been established. The current commercially available tablet disintegrates in saliva so that patients can swallow it without additional liquid.[15]

Ubrogepant: is given orally at a dosage of 50 mg or 100 mg. 2 hours after the initial dose, a second dose may be taken if necessary. The dose should not exceed 200mg in 24 hours. Treating any more than eight episodes of migraine in 30 days is not recommended, as its safety has not yet been established. Like rimegepant, ubrogepant is for the acute treatment of migraine with or without aura.[16]

Erenumab: The adverse effects reported during the clinical studies of erenumab were injection site reactions such as injection site pain, erythema, and pruritus. There were also reports of constipation, cramps, and muscle spasms.

Renal or hepatic impairment is not expected to affect the pharmacokinetics of erenumab. However, sufficient studies have to not been conducted to establish the same.[13]

Eptinezumab: The adverse effects reported during the clinical studies include nasopharyngitis angioedema, urticaria, facial flushing, and rash. Hypersensitivity reactions may also occur days after administration and may be prolonged. If a serious hypersensitivity reaction occurs, discontinue the administration of eptinezumab and initiate appropriate therapy.[9]

Galcanezumab, fremanezumab: The adverse effects reported during the clinical studies of these drugs were injection site reactions such as injection site pain, erythema, and pruritus. Hypersensitivity reactions may also occur days after administration and may be prolonged. If a serious hypersensitivity reaction occurs, discontinue the administration of these drugs and initiate appropriate therapy.[10][11]

Rimegepant: The adverse effects reported during the clinical studies of rimegepant include nausea and rarely hypersensitivity reactions (less than 1%). Severe hypersensitivity reactions may also occur with symptoms such as dyspnea and rash. In such cases, the drug should be discontinued, and appropriate therapy is given. Hypersensitivity reactions may occur even days after administration.[15]

Ubrogepant: The adverse effects reported during the clinical studies of ubrogepant were sedation, somnolence, and dryness of the mouth. There was an increased incidence of these adverse effects when the dosage increased from 50 mg to 100 mg.

Dose adjustment is not recommended for patients with mild or moderate hepatic impairment. For patients with severe hepatic impairment, the recommendation is for dose adjustment.

Dose adjustment is recommended for patients with severe renal impairment.[16]

However, the data provided for all these drugs may not correspond accurately to the clinical incidence of these adverse effects. Further studies and proper clinical evaluation are necessary to predict the incidence of adverse effects properly.

There is no adequate data on the developmental risk associated with the use of these drugs in pregnant women, as well as their presence in human milk, the effects on milk production, or its effects on the breastfed infant. Safety and effectiveness in pediatric patients have also not been established.

Clinical studies of the drugs mentioned above did not include sufficient numbers of patients aged 65 and over to determine whether this cohort responds differently from younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, and extra caution is necessary for those patients with decreased cardiac, hepatic, or renal function.

Erenumab: The only contraindication for the use of erenumab is hypersensitivity to drug or excipient. The current commercially available form of erenumab makes use of substances such as latex. Allergic history to such substances should also be obtained before administration.[13]

Eptinezumab, galcanezumab, fremanezumab: These drugs are contraindicated in patients with serious hypersensitivity to these or any of their excipients.[9][10][11]

Studies have also shown the development of anti-drug antibodies (ADAs) against erenumab, eptinezumab, galcanezumab, and fremanezumab, with the highest prevalence of the same being in the case of eptinezumab. This reaction may also reduce the efficacy of these drugs in the long term.

Rimegepant: The contraindications for use of rimegepant include,

• History of hypersensitivity to rimegepant especially delayed serious hypersensitivity reactions.
• In patients with severe hepatic impairment (Child-Pugh C), the plasma concentrations of rimegepant were significantly higher; thus, the use of rimegepant in such cases should be avoided.
• Avoid the use of rimegepant in patients with end-stage renal disease (CLcr < 15 mL/min).
• Avoid concomitant administration with potent CYP3A4 inhibitors.
• Avoid concomitant administration as well as a second dose of rimegepant within 48 hours, if the patient is on moderate CYP3A4 inhibitors.
• Avoid concomitant administration with P-gp or BCRP Inhibitors.[15]

Ubrogepant: The contraindications for the use of ubrogepant include,

• Co-administration of ubrogepant with a potent CYP3A4 inhibitor is contraindicated.
• If the patient is on moderate CYP3A4 inhibitors such as ciprofloxacin, cyclosporine, grapefruit juice, an initial dose of 50mg may be taken. But avoid the use of the second 50 mg dose within 24 hours.
• A loss of ubrogepant exposure, and thus efficacy, is expected in patients taking strong CYP3A4 inducers such as rifampin, barbiturates, and phenytoin. So, avoid concomitant use.
• If ubrogepant and moderate or weak CYP3A4 inducers are given concomitantly, dose adjustment is recommended.
• 9Ubrogepant acts as a substrate of and P-gp and BCRP efflux transporters but clinical drug interaction studies with inhibitors of only P-gp and/or BCRP (such as carvedilol, quinidine) were not conducted. Dose adjustment is recommended when administering these concomitantly. 
• Avoid the use of ubrogepant in end-stage renal disease (CLcr <15 mL/min).[16]