Calcitonin Gene-Related Peptide and Gepants

Calcitonin Gene-Related Peptide and Gepants: History

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Subjects: Neurosciences

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Calcitonin gene-related peptide (CGRP) antagonists are a class of medications that act as antagonists of the CGRP receptor or ligand. They can be divided into monoclonal antibodies and non-peptide small molecules, also known as gepants. CGRP antagonists were the first oral agents specifically designed to prevent migraines. The second generation of gepants includes rimegepant (BHV-3000, BMS-927711), ubrogepant (MK-1602), and atogepant (AGN-241689, MK-8031). Zavegepant (BHV-3500, BMS-742413) belongs to the third generation of gepants characterized by different administration routes.

rimegepant
ubrogepant
atogepant
zevagepant

1. Introduction

Migraine is a disabling disorder that affects approximately 15% of the global population [1]. In the United States (US), migraine is encountered among 70 million people and is the second most prevalent neurological disorder. The incidence of migraine headaches was 1722 cases per 100,000 people in 2017. The “Burden of Neurological Disorders Across the US From 1990–2017” estimated that migraine is the third most burdensome neurological disorder in terms of disability-adjusted life-years [2]. Migraine also most commonly occurs at productive age, in which the frequency of migraine headache days correlate with increased disability, leading to a decreased quality of life involving negative psychological impacts on performances within social and familial contexts [3]. Moreover, the estimated mean cost for migraine-related care per outpatient visit is $139.88, per emergency room visit is $775.09, and per inpatient hospitalization is $7317.07 [4]. Therefore, this disease affects an important percentage of the US population and represents a significant burden to the health care system.

The pathophysiology of migraine remains poorly understood. However, some specific vasoactive substances and neurotransmitters probably play a role in the mechanism of neurovascular and cortical spreading depression [5]. Calcitonin gene-related peptide (CGRP), neurokinin A, nitric oxide, and substance P are released with perivascular nerve activity [6]. They likely interact with the blood vessel wall, causing dilation, protein extravasation, and sterile inflammation [7]. The stimulation of the trigeminocervical complex by these chemical substances is relayed to the thalamus and cortex, both of which register the pain [8]. Interestingly, it was observed that the patients with migraine have reduced functioning of endogenous pain-control pathways that gate the pain [9]. Thus, the headache pain process requires not only the activation of nociceptors of pain-producing intracranial structures but also an impairment in its neuromodulation.

2. CGRP and GEPANTS

In 1982, the CGRP structure was discovered by Amara et al [14]. They noted that this compound was mainly synthesized in the hypothalamus, suggesting a hormonal effect for CGRP. A few years later, it was observed that CGRP-specific mRNA could be encountered throughout the central nervous system and in the peripheral nervous system, including the visceral motor functions mediated by the vagus nerve [15]. Rabbit models showed that intradermal injection of CGRP induced microvascular dilatation, resulting in increased blood flow [16]. Interestingly, CGRP is the most potent peripheral and cerebral vasodilator molecule ever discovered [17].

The potential role of the neurovascular system in migraine was hypothesized. In 1988, the first preclinical studies in cat models showed a potential association between CGRP and migraine [18]. It was observed that the irritation of the trigeminovascular system released CGRP in the extra-cerebral circulation. Two years later, Goadsby et al demonstrated dynamic changes in the concentrations of CGRP during migraine attacks in the external jugular but not in the cubital fossa blood [19]. Lassen et al infused CGRP in individuals with migraine to elucidate the mechanism of CGRP and migraine. They observed that intravenous administration of CGRP caused migraine in migraineurs [20].

CGRP receptors are transmembrane G protein-coupled receptors produced by the association between calcitonin receptor-like receptors (CALCRL) and a receptor activity-modifying protein (RAMP1) [21]. CGRP-expressing neurons are either C-fiber or Aδ-fiber [22]. Interestingly, more than thirty percent of trigeminal ganglion neurons exhibit CGRP receptors [23]. CGRP antagonists are a class of medications that act as antagonists of the CGRP receptor or ligand. They can be divided into monoclonal antibodies and non-peptide small molecules, also known as gepants (Table 1).

Table 1. Comparative analyses of pharmacokinetics, dosage, and formulations of rimegepant, ubrogepant, and atogepant.

Drugs	Rimegepant	Ubrogepant	Atogepant
Other names	BHV-3000, BMS-927711	MK-1602	AGN-241689, MK-8031
Trade name	Nurtec^®, Nurtec ODT®, Vydura®	Ubrelvy^®	Qulipta^®
Marketed	Biohaven Pharmaceuticals, Pfizer	Allergan Pharmaceuticals	Allergan Pharmaceuticals
FDA approval	February 2020 (acute); May 2021 (prevention)	December 2019	September 2021
Molecule
Indication	Acute treatment of migraine with or without aura in adults. Preventive treatment of episodic migraine in adults	Acute treatment of migraine with or without aura in adults	Preventive treatment of episodic migraine in adults
Dose	75 mg PO as needed. Not to exceed 75 mg/ 24 h. Safety of >18 doses/30 days has not been established	50 or 100 mg PO as needed. If needed, may take second dose at least 2 hrs after initial dose. Not to exceed 200 mg/24 h. Safety of treating >8 migraines/30 days has not been established	10, 30, or 60 mg PO
Dose adjustments	Renal impairment (CrCl < 15 mL/min); hepatic impairment (Child–Pugh > C); drug interactions	Renal impairment (CrCl < 30 mL/min); hepatic impairment (Child–Pugh ≥ C); drug interactions	Renal impairment (CrCl < 30 mL/min); hepatic impairment (Child–Pugh ≥ C); drug interactions
Route of administration	Oral	Oral	Oral
Contraindications	History of hypersensitivity	Concomitant use with strong CYP3A4 inhibitors	None
Adverse effects	Nausea (2%), hypersensitivity (including delayed)	Nausea (2–4%), somnolence (2–3%), dry mouth (2%)	Nausea (5–9%), constipation (6%), somnolence (4–6%), elevated AST/ALT (1%)
Pregnancy and lactation	Data not available	Data not available	Data not available
Pediatric	Data not available	Data not available	Data not available
Considerations	Orally disintegrating tablet. It can be swallowed without additional liquid	High-fat meal delayed plasma concentration	High-fat meal effect was not significant.

The first generation of gepants raised concerns about liver toxicity and poor oral availability [24]. These drugs were BI 44370 TA (BI 44370), MK-3207, olcegepant (BIBN-4096BS), and telcagepant (MK-0974). Thus, the studies in the early 2010s were terminated, and the results were probably overlooked [25]. After almost a decade, the pharmaceutical industry retrieved and reanalyzed the results with rimegepant. They observed that rimegepant was effective, compared to the placebo and sumatriptan 100 mg for managing acute migraine. Furthermore, rimegepant did not show significant abnormalities in liver enzymes, even with participants receiving a single dose (four capsules of 150 mg each) of rimegepant 600 mg orally within 45 days of randomization once they experienced a migraine headache of moderate to severe intensity [26].

The favorable results of rimegepant’s first clinical trials were followed by ongoing studies with other gepants. In this way, the second generation of gepants emerged, and it includes rimegepant (BHV-3000, BMS-927711), ubrogepant (MK-1602), and atogepant (AGN-241689, MK-8031). These drugs revealed a low number of side effects, with excellent bioavailability due to molecular modifications. In December 2019, the FDA approved ubrogepant (Ubrelvy^®) for the acute treatment of migraine with or without aura in adults. This drug was the first oral gepant approved by the FDA [27]. It is worth mentioning that the second generation has an affinity for different receptors besides the CGRP receptors [28]. The first-generation affinity for the human CGRP receptors is also higher than the second generation of gepants [29].

Rimegepant has a unique drug formulation, characterized as an oral dissolving tablet that disperses in the mouth, facilitating medication delivery and adhesion [30]. In addition, this formulation improves patients’ compliance to the medication due to decreased triggers such as nausea and vomiting commonly associated with migraine [31].

The third generation of gepants is characterized by different routes of administration. In this context, zavegepant (BHV-3500, BMS-742413) is under study for different types of routes, including subcutaneous and intranasal, due to the pharmacological properties of this molecule [32].

We calculated the chemical and pharmacological properties of the second and third-generation gepants using the SwissADME tool (Figure 1). These properties can help identify compounds suitable for oral use [33]. All the parameters analyzed were within the normal range, except for the molecular weights that were slightly higher than those desired for oral molecules, which can reduce oral bioavailability. Refer to the Supplementary Materials for a complete description of physicochemical descriptors and pharmacokinetic characteristics of rimegepant, ubrogepant, atogepant, and zavegepant (Supplementary Materials S2). It is important to mention that some pharmacological features of this new group of medications still require further investigation.

Figure 1. Physicochemical properties of rimegepant (A), ubrogepant (B), atogepant (C), and zavegepant (D).

This entry is adapted from the peer-reviewed paper 10.3390/brainsci12121612

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