Pharmacology

Pharmacodynamics. The actions of CRGP antagonist MAbs are facilitated particularly by the location of CRGP in dorsal root and trigeminal ganglions, which makes its role in causing migraine plausible. CRGP is the main mediator of trigeminal pain signal and is involved in the cascade of molecular events leading to a painful crisis in migraine. Intravenous administration of CGRP to patients prone to migraine can induce migraine-like headache. CGRP, and not substance P, is elevated in the cranial circulation during acute migraine. This explains the failure of substance P/neurokinin-1 receptor antagonists and the success of blocking CGRP mechanisms for relieving the pain of acute migraine. CGRP promotes mast cell degranulation, which results in the release of several inflammatory and proinflammatory substances. By binding to its glial receptors, CGRP promotes the release of cytokines in the trigeminal ganglia and nerve, which, in turn, produces sensitization of sensory neurons. CGRP significantly increases the expression and activity of cyclooxygenase 2, as well as the expression of the inducible form of nitric oxide synthase and IL-1β, and these effects are reversed by a specific CGRP receptor antagonist (05). CGRP is also involved in other migraine-related phenomena, eg, photophobia and gastrointestinal symptoms, such as nausea.

Involvement of CGRP in the pathophysiological processes underlying migraine led to the development of CGRP antagonists: gepants and 4 monoclonal antibodies (MAbs) targeting CGRP receptor (erenumab) or targeting CGRP ligand (eptinezumab, fremanezumab, and galcanezumab). Anti-CGRP MAbs in development for migraine either remove the excessive CGRP released at the perivascular trigeminal sensory nerve fibers or block the receptor from signaling. Thus, MAbs against both the CGRP ligand and receptor would inhibit CGRP-induced activation of sensitized trigeminal pathways to decrease headache frequency over time (03). Studies to date have confirmed the peripheral site of action of MAbs, but central effect cannot be excluded. Compared with small molecules, MAbs are highly specific for their target. Anti-CGRP pathway MAbs specifically target the CGRP receptor or ligand and are not associated with the off-target toxicity that can occur when targeting the immune system. Due to their large size, MAbs do not penetrate the blood-brain barrier. This is not a limiting factor because the primary site of action of anti-CGRP, the trigeminovascular system, is outside the blood-brain barrier (09). It has been concluded that the efficacy of anti-CGRP MAbs goes beyond the mere control of pain and prevents the activation of mechanisms involved in the complete manifestations of the migraine attack (29).

Erenumab. This is the only MAb that targets the CGRP receptor instead of the ligand, with high specificity and affinity of binding. The binding site of CGRP is with the calcitonin receptor-like receptor and receptor activity-modifying protein 1.

Pharmacokinetics. Most of the MAbs have nonlinear pharmacokinetics. Anti-CGRP MAbs have long terminal half-lives that allow for less frequent dosing, such as once monthly or greater, but, unlike small molecules, they must be injected. Subcutaneous bioavailability for most MAb therapeutics is 50% to 100%. They are not metabolized in the liver, and, therefore, hepatotoxicity is not expected. Most of these are administered subcutaneously, except eptinezumab, which has an intravenous formulation.

Erenumab. The pharmacokinetics of erenumab, as well as its inhibitory effect on capsaicin-induced dermal blood flow (CIDBF), a tool for assessing the target engagement of compounds that inhibit CGRP for migraine therapy, were studied in a 2-compartment target-mediated drug disposition model (30). Important findings include the following:

Galcanezumab. The pharmacokinetics of galcanezumab have been studied in healthy volunteers (17). Following a single subcutaneous dose, there was an extended period of absorption, with a median time to peak concentration (Tmax) between day 7 and day 14. Cmax and the area under the concentration-time curve were proportional to a full range of dosage from 1 to 600 mg. The mean serum half-life (t1/2) of galcanezumab was similar at all dose levels 1 month later.

Eptinezumab. This is the first and the only drug for intravenous prophylaxis of migraine so far. The pharmacokinetics of eptinezumab is characterized by rapid attainment of maximum plasma concentration and a terminal half‐life of 27 days (01). Dose‐ and exposure‐response analyses found a plateau of effect between 100 and 300 mg. A saturable inhibitory Emax model found the exposure over 12 weeks produced by single‐dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy.

Clinical trials

The status of anti-CGRP MAbs in development for migraine is shown in Table 1.

Table 1. Clinical Trials of Anti-CGRP Monoclonal Antibodies for Migraine Prevention

The randomized, placebo-controlled trial results of CGRP-antagonist MAbs eptinezumab, galcanezumab, fremanezumab, and erenumab have been published (06; 07; 02; 26; 24). They showed an increase in migraine-free days versus baseline. These MAbs appear to be well-tolerated, with no significant adverse events across the studies and no emerging safety issues from earlier studies (31; 10). Two phase 2 trials (one for episodic migraine and one for chronic migraine) and 2 phase III trials for episodic migraine have shown the efficacy and safety of erenumab in the prevention of migraine (14).

Fremanezumab, a humanized MAb targeting CGRP, is being investigated as a preventive treatment for migraine. A 12-week, phase III, randomized clinical trial found that fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo (23). Erenumab (AMG334, Amgen and Novartis), a subcutaneous anti-CGRP MAb, significantly reduced migraine frequency, effects of migraines on daily activities, and the use of acute migraine-specific medication in the randomized phase III STRIVE trial (11). In a phase II, randomized, double-blind, placebo-controlled, multicenter study of erenumab for adults aged 18 to 65 years with chronic migraine, erenumab (70 mg and 140 mg) reduced the number of monthly migraine days with a safety profile like placebo, providing evidence that erenumab could be a potential therapy for migraine prevention (28). Further research is needed to understand the long-term efficacy and safety of erenumab, and the applicability of this study to real-world settings.

Review of literature and discussion of clinical data from phase II and III trials of the 4 MAbs targeting the CGRP pathway—eptinezumab, erenumab, fremanezumab, and galcanezumab—collectively show a positive effect in the preventive treatment of episodic and chronic migraine (15). A systematic review of randomized controlled clinical trials found significant reduction of monthly migraine days with CGRP-MAbs versus placebo and few adverse reactions, but trials of larger sample sizes are recommended to verify the current findings (12). Another review of clinical trials shows that the efficacy of all 4 MAbs is modest over placebo in the prevention of episodic and chronic migraine (21).

Multiple phase III trials are underway to further determine the efficacy and safety of this new drug class. It may be particularly important to assess the effects of long-term CGRP blockade.

A metaanalysis was conducted to identify placebo and nocebo phenomena in the placebo-controlled randomized trials with the monoclonal antibodies targeting the calcitonin gene-related peptide (anti-CGRP MAbs) pathway. Results showed that the stronger placebo and weaker nocebo phenomena in trials with anti-CGRP MAbs versus those with topiramate in the prophylaxis of episodic migraine may decisively determine the success of treatment with anti-CGRP MAbs (16). No differences were detected between the anti-CGRP MAbs and onabotulinum toxin A in the treatment of chronic migraine.

A clinical trial of long-term safety of acute treatment of migraine with rimegepant (a small molecule CGRP receptor antagonist) in 2 patients resulted in improvement of response to rimegepant in aborting 9 out of 9 attacks of migraine (19). The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study.

Indications

Prevention of episodic and chronic migraine.

Off-label uses.

Cluster headache. In review of clinical trials, galcanezumab has shown benefit in decreasing the weekly frequency of cluster headache attacks across week 1 through week 3 (18). Negative results of some trials of galcanezumab for chronic cluster headache may be due to its refractory nature.

A clinical study is in progress to better understand the function of the autonomic nervous system in patients with migraine (NCT04628429). The aim is to understand whether the autonomic functions change depending on the migraine status (ie, whether they are between or during attacks) and whether the CGRP monoclonal antibody class of drugs affects the autonomic functions.

Contraindications

None have been defined.

Goals and duration of treatment

The primary endpoint in clinical trials is the reduction of frequency of migraine. Most of the trials are 12 weeks in duration. Long-term studies have not yet been reported. Patients who respond to erenumab are very susceptible to migraine induction by CGRP provocation, and this may be useful as a test to determine responsiveness to erenumab (04).

Use of erenumab may be a cost-effective approach for preventing monthly migraine days in patients with chronic migraine as compared with onabotulinum toxin A and offers good value for money for those with episodic migraine if lost productivity costs are considered (27). However, the Institute for Clinical and Economic Review does not consider erenumab to be a cost-effective medicine due to its high annual cost of $6900, except for in chronic migraine patients who have failed other preventive treatments and have no other options (22).

Dosing

Recommended doses of each of the MAbs will be available when they are approved. Doses used in clinical trials are as follows:

Special considerations

Pediatric. Use of anti-CGRP MAbs in children with migraine has not been studied.

Geriatric. No risk has been identified in elderly patients receiving anti-CGRP MAbs.

Pregnancy. Considerations related to pregnancy have not yet been investigated for anti-CGRP MAbs. Outcomes in women who become pregnant while taking erenumab are being tracked.

Anesthesia. No special risk for general anesthesia has been identified during clinical trials of anti-CGRP MAbs.

Interactions

No drug interactions have been reported.

Adverse effects

A review of safety data from published clinical trials has concluded that there was no difference in total adverse events or main adverse events (including upper respiratory tract infection, nasopharyngitis, nausea, injection site pain, and back pain) between the MAbs and placebo injections except, apparently, for dizziness (21). However, injection site reactions were reported significantly more frequently with galcanezumab (13.9%) than with placebo (5.8%) in a phase IIb study of galcanezumab (20).

Management

Although the safety record of erenumab has been very good during the past 3 years of clinical trials, there is a theoretical concern about long-term effects such as ischemic stroke or myocardial infarction. This will be resolved after several years of use on thousands of patients in clinical practice setting.