Drugs Against Calcitonin Gene-Related Peptide and its Receptor Used in the Treatment of Migraine: What are the New Progresses?

Mohtashem Samsam

Associate Professor, Burnett School of Biomedical Sciences (BSBS), College of Medicine, University of Central Florida, Orlando, Florida, USAUnited States

DOI: https://doi.org/10.17140/noj-2-117 · Published 2015-10-07 · Licence: https://creativecommons.org/licenses/by/4.0 · © 2015 The Author(s)

Also available as PDF (figures and tables appear in the PDF).

Keywords: Migraine; Calcitonin gene-related peptide; Migraine; Calcitonin gene-related peptide

Introduction

Migraine is believed to be a brain disorder, a deficiency of sensory modulation, and probably a system failure of normal sensory processing of the brainstem that regulates the vas- 1,2 cular tone and the pain in migraine.1,2 Although the aura phase of migraine is believed to be due to cortical spreading depression, a similar mechanism of neuronal excitation is believed to be the headache phase of migraine seems to involve the trigeminovascular system consisting of mainly trigeminal nerve and meningeal vessels.

brainstem, hypothalamus, and the brain, and that activation is often unaffected even after relief 3-5 of the headache by antimigraine drugs.

A major part of the dura mater specially the supratentorial part of dura is innervated by the trigeminal nerve, mainly the ophthalmic branch. The Trigeminal Ganglionic (TG) neurons contain several neurotransmitters and neuromodulators among them glutamic acid and various neuropeptides including the calcitonin gene-related peptide.6,7 Several neuropeptides coexist together in TG sensory neurons and may be released at the first central trigeminal synapses in the brainstem upon stimulation,8 but clinically, significant CGRP increase has been seen in 9,10 migraine patients. CGRP administration in human provoked a migraine-like attack in migraine patients11 and CGRP-antagonists alleviated the headache to a comparable level to other potent anti-migraine drugs such as sumatriptan.12 Currently, some of the first choice antimigraine drugs include the triptan family drugs that are the serotonin receptor agonists (5-HT1B/D), and the Non-steroid anti-inflammatory drugs (NSAIDs) according to the “European Federation of Neurological Societies (EFNS)”. 14-16 Please see for a comprehensive review of the triptan family 5,17 drugs and their receptors, and see5,17 for a brief review of several other drugs that are being used for the treatment of migraine including their actions, effects and side effects.

However, research in the treatment of migraine is one of the active fields of the neurological research and several studies in recent years focused on new and alternative treatment strategies including antagonizing CGRP receptors and/or blocking the CGRP activity by mAbs against CGRP and/or its receptor.

Calcitonin gene-related peptide consists of 37 amino acid detected by alternative processing of Ribonucleic acid (RNA) transcripts from the calcitonin gene which result in the production of distinct messenger RNA (mRNAs) that encodes the hormone calcitonin.18

There are two forms of CGRP in humans: the α-CGRP and the β-CGRP that are derived from different genes that differ in 3 amino acids but show similar functions.19 The α-CGRP is expressed in sensory neurons including the trigeminal ganglion and is the relevant one in migraine pathophysiology while the β-CGRP is expressed in the enteric nervous system and in hypophysis and its role in migraine is not known.

There is a wide anatomical distribution of CGRP in the body including the central and peripheral nervous system and is involved in many functions including nociception, glucose uptake, and stimulation of glycolysis in the skeletal muscles.23 CGRP is a potent vasodilator in human and rat and may mediate hyperemia in some pathological conditions.24

The headache phase of migraine is believed to be caused by vasodilation of cranial vessels activating the trigeminal and 25-28 other sensory nerves, although migraine has been reported without the initial dilatation of the middle cerebral artery and even during cerebral hypoperfusion.

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CGRP Receptor and its Localization in the Nervous System

CGRP receptor has an unusual structure and consists of a hetero-oligomeric complex with a transmembrane Gs proteincoupled receptor, the “Calcitonin receptor-like receptor (CLR)” 6,7 and an accessory protein known as the “Receptor activity-modifying protein 1 (RAMP1)” which is necessary to transport CLR to the plasma membrane. Both the CLR and RAMP1 subunits have extracellular domains that interact with one another and 33-36 together form a complex for the peptide-binding site. The extracellular domain of RAMP1 is very important for the binding of CGRP-receptor antagonist molecules to the CGRP receptors37 and function of RAMP1 is crucial for the activity of CGRP receptor in the trigeminal ganglion.38 Another related structure of the CGRP receptor is the Receptor Component Protein (RCP) which is crucial for signaling pathway and determines the G- 13 29,35 protein to which the receptor should be coupled with.

The CLR acts as a receptor for either CGRP or adrenomedullin, depending on which members of RAMPs are expressed. RAMP1 is a CGRP receptor at the cell surface and acts as a mature glycoprotein as well. RAMP2-transported receptors are adrenomedullin receptors and are core-glycosylated mol- 33,39 ecules.

Although originally two CGRP receptors (1 and 2) were recognized40 the nomenclature changed later and the “CGRP(1)” 17,41 receptor is now known as the “CGRP” receptor.

Various signaling molecules and second messengers are involved following the CGRP receptor activation. These + 42 include the CGRP activation of ATP-sensitive K+ channels42 or +2 + 43 large-conductance Ca -activated K channels with a subsequent increase of intracellular cAMP44 leading to vasodilation and headache. Nitric oxide activation of CGRP release in trigeminal ganglion neuronal cell culture however involves extracellular calcium and T-type calcium channels.45

CGRP receptor (both CLR/RAMP1 components) mRNA and protein are expressed in several regions of the CNS including the spinal cord and spinal trigeminal nucleus, area pos- 20-22 trema, pineal gland, parts of hypothalamus, periaqueductal gray matter, pontine raphe nuclei and the gracile nucleus although the RAMP1 mRNA was also detected in several regions of the brainstem and that CGRP receptor was found in areas that were not supported by BBB.46

CGRP receptor is also expressed in the cerebellum.47 Localization of the CGRP receptor in the tigeminovascular system seems to be on the central trigeminal nerve endings, dural 48,49 blood vessels and mast cells, and trigeminal ganglion as well 50 22,46,51 as dorsal horn secondary neurons. Please see for a comprehensive review of the CGRP receptor sites. CNS glial cells 29 52 49 such as astrocytes and microglial cell and Schwann cells also 29-32 express CGRP receptors as well.

CGRP Receptor Antagonists in the Treatment of Migraine

One of the important properties of CGRP-antagonist drugs such as BIBN4096BS is that it prevents the CGRP-mediated vasodilation or activation of trigeminovascular afferents53 without the vasoconstrictor activities which is an advantage in patients with coronary heart disease or in patients with second 53,54 rebound attack, see for review.

The discovery of CGRP-antagonist drugs the “gepant” family, in the last decade was a breakthrough in migraine treatment research due to their lack of vasoconstrictive activity compared to some “triptan” family drugs. One of the first drugs, the BIBN4096BS, also known as olcegepant, prevents the CGRPmediated vasodilation or activation of trigeminovascular afferents,12 and presumably inhibits the central CGRP receptors.

Olcegepant is a potent anti-migraine drug that has been 55-59 examined on human arteries. The BIBN4096BS was shown to block the responses evoked by stimulants such as α-CGRP and capsaicin, or transcranial electrical stimulation of perivascular trigeminal nerve60 which reduces the increased dural blood flow without changing basal vascular parameters, whereas sumatriptan reduced only the vasodilation induced by electrical 17,60 stimulation. One important advantage of olcegepant over the triptan family drugs is that it doesn’t constrict the coronary arter- 55,63,64 ies.

Olcegepant has been shown to inhibit CGRP receptor in the trigeminal nucleus suggesting a similar central nervous system mechanism as well in treatment of migraine.65 Another drug in this class, the MK-0974 (telcagepant) is another effective CGRP receptor antagonist when administered orally for the acute treatment of migraine.66

Both olcegepant (iv) in phase I, phase II and telcagepant (oral) in phase III have been used in migraine clinical tri- 66-69 als. The efficacy of the CGRP antagonists in the central modulation of pain in the hypothalamus has also been reported by 5,70 Goadsby and colleagues.5,70 A major side effect of these drugs is hepatic toxicity and elevated transaminase levels71 although the presumably high doses of olcegepant and telcagepant alleviating the migraine symptoms are not so high after all.72A newer CGRP antagonist “BI44370TA” was reported to have a lower frequency of adverse effects in its phase II clinical trials.73 It seems that the CGRP antagonists can act on CGRP receptors however it is uncertain whether they act on peripheral or central sites or both in migraine.

74-77 Please see for a comprehensive review on the CGRP and its functions, receptors, and the implication of CGRP-receptor antagonists as a novel approach in the treatment of migraine attacks. A recent report comparing the dose-response curve for the efficacy and adverse effect of several serotonin receptor (5-HT1B/D) agonist drugs such as triptans or Lasmiditan (5-HT1F

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antagonist) and the CGRP-receptor antagonists such as telcagepant, BI 44370 TA, MK-3207, and BMS-927711 indicates that the dose-response curve for efficacy of triptans is flat while their adverse effects increase by increasing the doses. While Lasmiditan and the CGRP-receptor antagonist drugs had also a flat doseresponse curve, the efficacy-tolerability profile of the triptans is more favorable than others.78

Nevertheless, these newer drugs may have advantage in those patients that are triptan non-responders or with coronary 53,54,78 heart disease or in patients with second rebound attack. So far five different CGRP-receptor antagonist drugs with proof of efficacy have been used for the treatment of migraine but were 79-82 discontinued due to hepatic toxicity and other side effects.

Therefore, search for newer drugs against CGRP did not stop but this time, efforts were on developing antibodies 83,84 against CGRP and it receptors.

Monoclonal Antibodies against CGRP and its Receptor in the Treatment of Migraine Headaches

61,62 Antibodies against viruses have long considered as 85,86 effective preventive methods in viral infections. Antibodies against biological antigens (in this case, CGRP) can bind proteins and neutralize their effect (block the activity) whether being free in the circulation or membrane-bound and possibly intracellular proteins.

Monoclonal antibodies (mAbs) against CGRP and its 65 87 receptors are newer drugs that have emerged in recent years87 Table 1. Several investigators have been studying three mAbs for the prevention of episodic migraine and one mAb for the prevention of chronic migraine in the last couple of years.87 The main idea was to remove the excess peripheral CGRP released from the perivascular nerve endings and for the anti-CGRP re- 82,83 ceptor antibodies to prevent the CGRP signalling cascade.

Currently, three anti-CGRP mAbs have been developed that are in clinical trials. These include the LY2951742 (by Eli Lilly and Company), ALD-403 (by Alde Biopharmaceuticals) and TEV-48125 (LBR-101) developed by Teva Pharmaceuticals. The other class of mAb is against CGRP receptor complex, the AMG 334, developed by Amgen.

The ALD 403: Is a humanized Anti-CGRP mAb that has been used for episodic and chronic migraine, please see company’s 88 89-90 website. It has completed phase 1 study and is in phase 2.91 It has a half-life of approximately 31 days and has finalized positive proof-of-concept in phase 2a with a single i.v. dose of 1000 mg that can be repeated every 3-month.92 The safety of the drug was assessed at 12 weeks after the infusion; the primary efficacy endpoint was observation of changes in the frequency of migraine days from the baseline to weeks 5-8 among adult patients age 18-55 years who had 9-10 days of headache per

Drug: action Dose; Half -life

The ALD 403: mAb against CGRP

LY2951742: mAb against CGRP weeks (subcutaneous dose); Half-life: (1.2 day difference in migraine headache) in the 3 94

TEV-48125: mAb against CGRP

AMG 334: CGRP-receptor mAb Subcutaneous injection

Table 1. Monoclonal antibodies (mAbs) used in clinical trials against CGRP or its receptor in the treatment of episodic and/or chronic migraine.

month where 8-9 of them qualified for migraine days. Patients treated with ALD403 had a mean decrease of 5.6 migraine days between baseline and weeks 5-8 compared to the placebo group who had a decrease of 4.6 migraine days in the 3rd month 82,92 (1 day difference). The difference in the first month was 5.6 versus 3.9 days between the ALD403 group and the placebo 82,92 (1.7 days difference). These results showed the efficacy of ALD403 and there was no safety concern with the i.v. injection of 1000 mg of this mAb against CGRP.92 Some side effects included infections of the upper respiratory, or urinary tracts, back pain, fatigue, nausea and vomiting that were seen in 57% of the 81 patients treated with ALD403 but were also seen in 52% of the 82 individuals who received the placebo treatment.

LY2951742: Is another humanized anti-CGRP mAb (Lilly’s 93 94 clinical development pipeline)93 with a half-life of 28 days94 that has completed phase 1 clinical trials for the treatment of epi- 95,96 sodic and chronic migraine and was tested in phase 2 clinical trials. This phase 2 proof-of concept included randomized, double blind, placebo controlled investigations in 35 centres in the United States.94

The safety of the drug was assessed at 12 weeks treatment period after subcutaneous administration of 150 mg of this mAb twice per month (once every 2 weeks) for 12 weeks.94 The primary endpoint was observation of changes in the number of migraine headache days per 28-day period that were evaluated at 9-12 weeks (although follow up assessment continued over 24 weeks as well) among adult patients age 18-65 years having 4-14 days of migraine headache per month. Patients treated with LY2951742 had a mean decrease of 4.2 (62.5% decrease) migraine headache days between baseline and week 12 compared to the placebo group who had a decrease of 3 migraine days (42.3%).94 This study indicated that LY2951742 may be beneficial in prevention of migraine.94

Adverse effects such as pain and erythema or both at

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Decrease in migraine days per month from

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