Migraine: New Treatments CGRP antagonists and Gepants

The underlying pathophysiology is largely unknown, but calcitonin gene-related peptide (CGRP) most likely plays an important role. The first time CGRP was hypothesized to be involved in migraine was in 1985. This hypothesis was later supported by the finding of CGRP release during acute migraine attacks and the subsequent demonstration of normalization of CGRP levels in migraine patients after efficacious sumatriptan treatment. In animal studies, triptans also inhibit the release of CGRP. Evidence for the causative role of CGRP in migraine came from a study showing that intravenous provocation with CGRP induces migraine-like attacks in migraine patients.

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. The receptor for this neuro-peptide is a complex heterodimer containing a class B G-protein coupled receptor called CLR (calcitonin receptor-like receptor).

CGRP receptors are found at all of the known central and peripheral sites involved in migraine pathogenesis, including the hypothalamus and parabrachial nucleus, and CGRP levels are elevated during migraine attacks and lower between attacks. Studies in animals first showed that stimulation of the trigeminal ganglion was associated with increased blood flow and release of CGRP, which could be inhibited by sumatriptan or dihydroergotamine. Studies in humans showed that sumatriptan, in addition to relieving migraine, lowered CGRP levels in the internal jugular vein. CGRP has also been shown to induce migraine-like symptoms after intravenous infusion.

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 and neuralgias such as trigeminal neuralgia, chronic paroxysmal hemicranias, and even rhinosinusitis. Levels are elevated during a migraine attack and between migraine attacks in patients with chronic migraines. Also, CGRP from exogenous infusions was shown to trigger migraine attacks. 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.

The first CGRP antagonists to be studied were small molecules, with names ending in the suffix “-gepant.” These so-called gepants block CGRP receptors, and 6 were found to be effective in acute treatment of episodic migraine. However, their development was discontinued due to reports of hepatotoxicity. The Second generation gepants include rimegepant, ubrogepant, atogepant and vazegepant. Rimegepant and ubrogepant have shown positive results as acute treatments leading to FDA approval. Rimegepant and atogepant have positive results as preventive treatments, with the latter being developed only for this indication.

Next to be developed were monoclonal antibodies targeting CGRP. These agents are metabolized by the reticuloendothelial system and, as a result, bypass hepatic metabolism; to date, no adverse effects on the liver have been reported. Further, the current injectable antibodies are not thought to be contraindicated in patients with coronary artery, cerebrovascular, peripheral vascular, or kidney disease.

Episodic migraine is defined as having fewer than 15 headache days per month fulfilling diagnostic criteria for migraine.

Chronic migraine is defined as headaches on 15 or more days per month for 3 months or more in a patient with a preexisting diagnosis of migraine. Of the total headache days, at least 8 days per month should meet migraine criteria.

Clinical trials of the monoclonal antibodies have found them to be superior to placebo and similar in efficacy to current prophylactic treatments for episodic and chronic migraine. Roughly half of patients receiving these drugs achieved at least a 50% reduction in the number of headache days per month, compared with roughly one-fourth of patients receiving placebo. The new drugs have also been shown to be tolerable and safe, with no significant effects on blood pressure or peripheral vasoconstriction.

Erenumab (Aimovig)

Unlike galcanezumab and fremanezumab, erenumab targets the canonical CGRP receptor rather than the CGRP ligand itself.

There are 2 available doses, 70 mg and 140 mg, which patients give themselves once a month at home using a preloaded subcutaneous autoinjector.

In episodic migraine. Three trials looked at 50% responder rates and mean decrease in monthly migraine days with use of erenumab in patients with episodic migraine. Results were reliably better with erenumab than with placebo, including in groups with so-called refractory migraine for whom 2 to 4 oral preventive therapies had failed.

In chronic migraine, the results were similar. Adverse effects noted included injection site pain (reported by 4% of patients receiving active treatment), constipation (4% of those on 140 mg), and muscle spasm (4% of those on 140 mg).

Erenumab received FDA approval for prevention of migraine on May 17, 2018.

Fremanezumab (Ajovy)

Fremanezumab targets the CGRP ligand rather than the receptor. It can be taken as a monthly subcutaneous injection of 225 mg or as a quarterly injection of 675 mg.

 In episodic migraine. A phase 3 trial in episodic migraine showed a decrease in mean monthly headache days and increases in the 50% responder rate and 75% responder rate with either dose compared with placebo (P < .0001).

In chronic migraine. The same trial also compared fremanezumab and placebo in patients with chronic migraine. The number of days with headache of moderate to severe intensity was reduced by 4.2 days in the placebo group and by 6 days in both a group receiving 225 mg monthly and a group receiving 675 mg quarterly. In a separate study, investigators found that patients noted an improvement as early as 1 week from initiation of therapy in both dose regimens.

Fremanezumab received FDA approval for prevention of migraine on September 14, 2018.

Galcanezumab (Emgality)

Galcanezumab also targets the CGRP ligand. It is given subcutaneously once a month with an autoinjector or prefilled syringe in a recommended monthly dose of 120 mg after an initial loading dose of 240 mg.

In episodic migraine. Two 6-month trials compared galcanezumab monthly injections of galcanezumab 120 mg, galcanezumab 240 mg, and placebo. Both studies demonstrated a reduction of migraine days and an increase in 50% responder rate superior to placebo. Interestingly, about 17% of patients had a 100% reduction in mean migraine days. This was seen most commonly in the last 3 months of the trials and was statistically significant compared with placebo (P < .001).

In chronic migraine. In a phase 3 trial, galcanezumab showed a significant decrease in mean monthly migraine days compared with placebo. Also, differences in the 50% and 75% responder rates were statistically significant in each treatment group compared with placebo (P < .001). Similar to the episodic migraine trial, 11.5% of galcanezumab recipients in the chronic migraine trial also noted 100% reduction in mean migraine days, again noted most commonly in the last 3 months of the clinical trial (P < .001).

This drug received FDA approval for prevention of migraine on September 27, 2018.

Eptinezumab  (Vyepti): 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.

CGRP is an ubiquitous peptide that is not only involved in migraine, but also in several physiological processes and in homeostatic responses during pathophysiological conditions. As such, it is vital to consider the possible side effects caused by the non-selective blockade of α- and β-CGRP with the CGRP (receptor)-antibodies. Even though the knowledge of the presence and function of CGRP in the CNS is sparse, the function in both the peripheral and enteric nervous system is well established and CGRP is expressed widely throughout both systems. Thus, a wide variety of possible adverse events could be anticipated when blocking CGRP. However, reported adverse events after blocking of CGRP have in general been mild to moderate and the incidences have been low.

In the cardiovascular system, CGRP is present in nerve fibers that innervate blood vessels and the heart, and participates in the regulation of blood pressure. Furthermore, it has also been described to have a role in the maintenance of (cardio)vascular homeostasis during ischemic events and in tissue remodeling in pulmonary hypertension. This protective role raises a concern, since migraine patients present an increased cardiovascular risk. Hence, it is important to consider preexisting cardiovascular risk factors in patients (i.e. family history, tobacco exposure, obesity) to prevent a possible cardiovascular event.

Although CGRP participates in inflammatory processes, it has also been associated with facilitation of wound healing. This is thought to be mediated through its ability to promote keratinocytes proliferation, enhance revascularization, reduce expression of tumor necrosis factor-α (TNF-α) and attenuate macrophage infiltration. A consequence of blocking CGRP could thus be alterations in wound healing and increased inflammatory responses in skin injuries at the site of injection for the antibodies. However, this is a theoretical risk which has so far not been observed in clinical trials.

The antibodies against CGRP are not selective for α-CGRP but also block β-CGRP. The gastrointestinal tract is highly innervated by β-CGRPergic fibers from the enteric nervous system. In fact, animal studies with antibodies against CGRP showed extensive mucosal damage, suggesting a role of CGRP in maintaining the mucosal integrity of the gastrointestinal tract. Blocking this could thus contribute to inflammatory bowel disease. Gastrointestinal motility is also considered to be modulated by CGRP, and administration of this peptide induces a dose-dependent biphasic response, which could lead to episodes of diarrhoea or constipation. Furthermore, studies with CGRP KO mice have suggested CGRP agonists as a possible treatment for ulcer healing; therefore, monitoring of gastrointestinal complications (i.e. ulcers, constipation) is recommended, even though 12 week studies have not reported these.

Most importantly, none of the mABs have shown liver toxicity. This is in line with the theoretical probability of mABs causing liver toxicity, which is very low, since metabolism of mABs do not result in production of toxic metabolites. In addition, despite the potentially harmful inhibition of vasodilation due to CGRP inhibition, no cardiovascular concerns have been disclosed with any of these drugs. In trials, eptinezumab, galcanezumab and fremanezumab, monoclonal antibodies which all target CGRP, showed variable percentages of adverse events, which in line with the gepants, were mild to moderate (e.g. upper respiratory or urinary tract infection, fatigue, back pain, arthralgia, nausea and vomiting). Erenumab, which binds to the CGRP receptor, was also safe and well tolerated in a phase 2 trial. No central side effects have been reported.

The long-term risks of blocking CGRP are still unknown. Even though the absence of liver toxicity or other abnormalities in routine blood testing is in support of no or low long-term risks, studies testing the cardiovascular safety of the long-term blockade are warranted in order to answer the numerous questions on the possibility of higher risk in cardio- and cerebrovascular compromised patients. For example, it is unknown whether blocking CGRP could potentially transform transient mild cerebral ischemia into a full-blown brain infarct and whether these risks are higher in women. To investigate these aspects, future studies should include patients with preexisting cardiovascular conditions.

The exact site of action of blocking CGRP is still partly unknown and CGRP could exert its effects on receptors distinct from the CGRP receptor. Recently it was put forward that CGRP may act on the amylin receptor in Trigeminal Ganglion as well as in human coronary arteries. If this is the case, this could pose an additional – unknown – potential risk of wiping out CGRP. We can also only guess whether patients not benefitting from receptor blockade would benefit from blockage of the peptide itself. Future studies should investigate how to differentiate responders from non-responders.

A disadvantage when using antibodies is the risk of development of antibodies against the drug. Indeed, antidrug antibodies were detected with all four antibodies, but these did not seem to affect efficacy. However, long-term studies are needed to investigate whether, at long term, neutralizing antidrug antibodies will pose a problem for efficacy and safety of blocking CGRP with monoclonal antibodies.

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 be conducted to establish the same.

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.

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.

Erenumab: The only contraindication for the use of Erenumab is hypersensitivity to drug or excipients. 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.

Currently, there are no guidelines in place for monitoring CGRP receptors-acting drugs. However, the general monitoring of responsiveness to monoclonal antibodies (Erenumab, Eptinezumab, Galcanezumab, and Fremanezumab) against the CGRP receptor is by periodic assessment of changes in mean Monthly Migraine Days (MMD) or monthly Migraine Physical Function Impact Diary (MPFID) activity scores. Changes in these values usually occur 3 to 4 months after starting the drug.

The Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society in 2012 reviewed the evidence and ranked the migraine preventive therapies available in the United States at that time according to the evidence of their efficacy.

Level A medications, ie, those rated as having “established efficacy,”:

• The antiepileptic drugs divalproex sodium, sodium valproate, and topiramate
• The beta-blockers metoprolol, propranolol, and timolol
• The tripan frovatriptan (for short-term prophylaxis).

Level B medications, ie, those that are “probably effective,” :

• The antidepressants amitriptyline and venlafaxine
• The beta-blockers atenolol and nadolol
• The triptans naratriptan and zolmitriptan.

Level C medications, ie, “possibly effective,” :

• The angiotensin-converting enzyme inhibitor lisinopril
• The angiotensin II receptor blocker candesartan
• The alpha-agonists clonidine and guanfacine
• The antiepileptic drug carbamazepine
• The beta-blockers nebivolol and pindolol
• The antihistamine cryptoheptadine

Patients in whom CGRP antagonists can be considered

• Those with 4 to 7 migraine days per month who have been unable to tolerate a 6-week trial of at least 2 oral preventive medications with level A or B evidence (see above). In addition, patients should also have at least moderate disability on the Migraine Disability Assessment Scale or the Headache Impact Test 6, both of which are used to assess functional impairment secondary to migraine.
• Those with 8 to 14 headaches per month who cannot tolerate a 6-week trial of at least 2 oral preventive drugs with level A or B evidence (no need to demonstrate functional impairment).
• Those with 15 or more headaches per month (ie, chronic migraine) if at least 2 preventive medications with level A or B evidence have failed or if botulinum toxin A has produced an inadequate response after at least 2 administrations or has caused adverse effects precluding further use.

Patients with medication-overuse headaches may also benefit from anti-CGRP monoclonal antibodies. Both Erenumab and Fremanezumab have shown efficacy in treating the subgroup of chronic migraine patients with medication-overuse headaches. Erenumab 70 mg led to a reduction of 5.2 migraine days per month, and 140 mg had a reduction of 5.4 days, compared with a reduction of 3.5 days with placebo in patients with medication-overuse headache (P < .001).

Erenumab is also being considered for evaluation in pediatric patients with chronic migraine.