Small Molecule Calcitonin Gene-related Peptide Receptor Research Articles

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial

Background Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China.Methods Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests.ResultsOverall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p < 0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group.ConclusionsA single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo.Trial registration Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.Graphical

Preventive Treatment of Migraine.

This article describes strategies for the preventive treatment of migraine including the emerging role of calcitonin gene-related peptide (CGRP)-targeted therapies and introduces novel paradigms for the preventive treatment of migraine. Multiple migraine medications targeting CGRP have been introduced since 2018, including injectable monoclonal antibodies (ie, eptinezumab, erenumab, fremanezumab, and galcanezumab) and oral small-molecule CGRP receptor antagonists (ie, ubrogepant, rimegepant, atogepant, and zavegepant). With the exceptions of ubrogepant and zavegepant, which are approved only as acute treatments, all of these agents have demonstrated efficacy in the preventive treatment of migraine; the monoclonal antibodies and atogepant have evidence of effectiveness in adults with either episodic or chronic migraine. The safety and tolerability profiles of CGRP-targeted therapies in migraine are favorable. The goals of preventive migraine therapy include reducing the frequency, severity, duration, and disability associated with attacks, reducing the need for acute treatment and the risk of medication overuse, enhancing self-efficacy and health-related quality of life, and reducing headache-related distress and interictal burden. Six drugs targeting CGRP (four monoclonal antibodies and two gepants) are now available for the preventive treatment of episodic migraine in adults. The efficacy of CGRP-targeted medications in the acute and preventive treatment of migraine, together with good safety and tolerability, has led to the emergence of new approaches to preventive treatment.

Novel insight into atogepant mechanisms of action in migraine prevention.

Recently, we showed that while atogepant - a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist - does not fully prevent activation of nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C-fibers and late response probability in A™-fibers. The current study investigates atogepant effect on CSD-induced activation and sensitization of high-threshold (HT) and wide dynamic range (WDR) dura-sensitive neurons. In anesthetized male rats, single-unit recordings were used to assess effects of atogepant (5mg/kg) vs vehicle on CSD-induced activation and sensitization of HT and WDR dura-sensitive neurons. Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus (STN) revealed ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8/10 vs. 1/10 activated neurons in the control vs. treated groups, p=0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7/10 vs. 5/10 activated neurons in the control vs. treated groups, p=0.64). Unexpectedly however, in spite of atogepant inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD). Atogepant ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly unmyelinated A™ fibers. Atogepant inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibers. Molecular and physiological processes that govern neuronal activation vs. sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the STN can prevent their sensitization but not activation.

Atogepant: Mechanism of action, clinical and translational science.

Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine-specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP-mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant.

Ubrogepant: Mechanism of action, clinical and translational science.

In recent years, the treatment of migraine has experienced a breakthrough in the development of drugs that target the calcitonin gene-related peptide (CGRP) signaling pathway. Monoclonal antibodies against the receptor or ligand have been developed for the preventive treatment of migraine; whereas, orally administered small molecule CGRP receptor antagonists, called gepants, have been developed for both acute and/or preventive treatment. Both modalities have demonstrated safe and effective treatment of migraine, reducing the number of migraine days for patients as well as reducing symptoms and improving patient function and overall quality of life. Here, we provide an abridged review of ubrogepant, an oral CGRP receptor antagonist, approved for the acute treatment of migraine. We briefly summarize the role of CGRP in migraine pathophysiology, describing the mechanism of action of ubrogepant in the context of this pathway, the clinical pharmacology properties and the clinical development and outcomes, including safety, efficacy, pharmacokinetics, and pharmacodynamics, that supported ubrogepant's approval.

Calcitonin gene-related peptide receptor antagonism reduces motion sickness indicators in mouse migraine models.

Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects ∼3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. MSI measures were confounded by CGRP's effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.Trial Registration: Not Applicable.

Blocking the CGRP Receptor: Differences across Human Vascular Beds.

Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for the treatment of migraine. Here, the effect of the small-molecule CGRP receptor antagonist zavegepant (0.1 nM-1 µM) on CGRP-induced relaxation in isolated human coronary arteries (HCAs) was investigated. A Schild plot was constructed and a pA2 value was calculated to determine the potency of zavegepant. The potency and Schild plot slopes of atogepant, olcegepant, rimegepant, telcagepant, ubrogepant and zavegepant in HCAs and human middle meningeal arteries (HMMAs), obtained from our earlier studies, were compared. Zavegepant shifted the concentration-response curve to CGRP in HCAs. The corresponding Schild plot slope was not different from unity, resulting in a pA2 value of 9.92 ± 0.24. No potency difference between HCAs and HMMAs was observed. Interestingly, olcegepant, atogepant and rimegepant, with a Schild plot slope < 1 in HCAs, were all >1 log unit more potent in HMMAs than in HCAs, while telcagepant, ubrogepant and zavegepant, with a Schild plot slope not different from unity, showed similar (<1 log difference) potency across both tissues. As a Schild plot slope < 1 may point to the involvement of multiple receptors, it is important to further identify the receptors involved in the relaxation to CGRP in HCAs, which may be used to improve the cardiovascular safety of future antimigraine drugs.

Rimegepant 75mg in Subjects With Hepatic Impairment: Results of a Phase 1, Open-Label, Single-Dose, Parallel-Group Study.

Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist (gepant) with demonstrated efficacy and safety in the acute and preventive treatment of migraine. Here, we report the pharmacokinetics and safety of a single 75-mg oral dose of rimegepant in subjects with severe, moderate, or mild hepatic impairment and matched healthy subjects from an open-label, single-dose, 4-group phase 1 study. Thirty-six subjects aged 41-71 years were enrolled, including 6 each with severe, moderate, or mild hepatic impairment and 18 healthy subjects. All subjects completed the study. A <20% increase in total and unbound pharmacokinetics was observed in subjects with mild hepatic impairment and ≤65% increase with moderate hepatic impairment versus matched healthy controls. Total and unbound systemic exposure increased 2.0- and 3.9-fold in the severe hepatic impairment group. In subjects with severe hepatic impairment, geometric mean ratios (severe impairment/controls) for total concentrations were 202.2% for area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, 202.2% for area under the plasma concentration-time curve from time 0 to infinity, and 189.1% for maximum observed plasma concentration. Corresponding geometric mean ratios using unbound concentrations were 388.8% and 388.7%, respectively. Three (8.3%) subjects reported 4 treatment-emergent adverse events. Rimegepant is not recommended for use in adults with severe hepatic impairment.

Calcitonin gene relating peptide inhibitors in combination for migraine treatment: A mini-review.

The discovery of calcitonin gene-related peptide (CGRP) and its role in migraine pathophysiology has led to advances in the treatment of migraine. Since 2018, the Food and Drug Administration (FDA) has approved four monoclonal antibody (mab) therapies targeting either the CGRP ligand or receptor and 3 oral small molecule CGRP receptor antagonists. These targeted therapies have been shown to be safe and effective for either preventive or acute treatment of migraine in adults. Given their efficacy and tolerability profile, CGRP inhibitors have revolutionized the approach to migraine treatment. Theoretically, combining therapies within this therapeutic class could lead to more CGRP blockade and, subsequently, improved patient outcomes. There are providers currently combining CGRP therapies in clinical practice. However, limited data are available regarding the efficacy and safety of this practice. This mini-review provides a summary of available data and poses important considerations when combining CGRP therapies for migraine treatment.

New migraine prophylactic drugs: Current evidence and practical suggestions for non-responders to prior therapy

Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP(-R) mAbs) and small-molecule CGRP receptor antagonists (gepants) are new mechanism-based prophylactic drugs developed to address the unmet needs of pre-existing migraine prophylactic medications. However, several uncertainties remain in their real-world applications. This is a narrative review of the literature on the use of CGRP-targeting novel therapeutics in specific situations, including non-responders to prior therapy, combination therapy, switching, and treatment termination. In the case of lack of available literature, we made suggestions based on clinical reasoning. High-quality evidence supports the use of all available anti-CGRP(-R) mAbs (erenumab, galcanezumab, fremanezumab, and eptinezumab) in non-responders to prior therapy. There is insufficient evidence to support or reject the efficacy of combining CGRP(-R) mAbs or gepants with oral migraine prophylactic agents or botulinum toxin A. Switching from one CGRP(-R) mAb to another might benefit a fraction of patients. Currently, treatment termination depends on reimbursement policies, and the optimal mode of termination is discussed. New prophylactic drugs that target the CGRP pathway are promising treatment options for patients with difficult-to-treat migraine. Individualized approaches using a combination of new substances with oral prophylactic drugs or botulinum toxin A, switching between new drugs, and adjusting treatment duration could enhance excellence in practice.

Commentary: Constipation caused by anti-calcitonin gene-related peptide migraine therapeutics explained by antagonism of calcitonin gene-related peptide's motor-stimulating and prosecretory function in the intestine.

Calcitonin gene-related peptide (CGRP) pathway-targeted treatments have been shown to be efficacious in the prevention of episodic and chronic migraine. Currently approved therapies include monoclonal antibodies (mAbs) that target CGRP (eptinezumab, fremanezumab, and galcanezumab) and the CGRP receptor (erenumab), and small molecule CGRP receptor antagonists (atogepant and rimegepant). While CGRP pathway-targeted treatments are generally well-tolerated, in a review article by Holzer and Holzer-Petsche published in the January 2022 issue of Frontiers in Physiology the authors discussed the role of the CGRP pathway in gastrointestinal physiology, with a specific focus on constipation associated with the use of CGRP pathway-targeted treatments. The authors state that real-world surveys have shown constipation to be a "major adverse event" reported in "more than 50% of patients treated with erenumab, fremanezumab or galcanezumab." As described in the current commentary, the limited data from the cited references in the review article by Holzer and Holzer-Petsche do not support that statement.

Characterization of erenumab and rimegepant on calcitonin gene-related peptide induced responses in Xenopus Laevis oocytes expressing the calcitonin gene-related peptide receptor and the amylin-1 receptor

BackgroundThe clinical use of calcitonin gene-related peptide receptor (CGRP-R) antagonists and monoclonal antibodies against CGRP and CGRP-R has offered new treatment possibilities for migraine patients. CGRP activates both the CGRP-R and structurally related amylin 1 receptor (AMY1-R). The relative effect of erenumab and the small-molecule CGRP-R antagonist, rimegepant, towards the CGRP-R and AMY-R needs to be further characterized.MethodsThe effect of CGRP and two CGRP-R antagonists were examined in Xenopus laevis oocytes expressing human CGRP-R, human AMY1-R and their subunits.ResultsCGRP administered to receptor expressing oocytes induced a concentration-dependent increase in current with the order of potency CGRP-R> > AMY1-R > calcitonin receptor (CTR). There was no effect on single components of the CGRP-R; calcitonin receptor-like receptor and receptor activity-modifying protein 1. Amylin was only effective on AMY1-R and CTR. Inhibition potencies (pIC50 values) for erenumab on CGRP induced currents were 10.86 and 9.35 for CGRP-R and AMY1-R, respectively. Rimegepant inhibited CGRP induced currents with pIC50 values of 11.30 and 9.91 for CGRP-R and AMY1-R, respectively.ConclusionOur results demonstrate that erenumab and rimegepant are potent antagonists of CGRP-R and AMY1-R with 32- and 25-times preference for the CGRP-R over the AMY1-R, respectively. It is discussed if this difference in affinity between the two receptors is the likely reason why constipation is a common and serious adverse effect during CGRP-R antagonism but less so with CGRP binding antibodies.

Calcitonin gene-related peptide (CGRP) is a key molecule released in acute migraine attacks-Successful translation of basic science to clinical practice.

Migraine is a highly prevalent neurovascular disorder afflicting more than 15% of the global population. Nearly three times more females are afflicted by migraine in the 18–50 years age group, compared to males. Migraine attacks are most often sporadic, but a subgroup of individuals experience a gradual increase in frequency over time; among these, up to 1%–2% of the global population develop chronic migraine. Although migraine symptoms have been known for centuries, the underlying mechanisms remain largely unknown. Two theories have dominated the current thinking—a neurovascular theory and a central neuronal theory with the origin of the attacks in the hypothalamus. During the last decades, the understanding of migraine has markedly advanced. This is supported by the early seminal demonstration of the trigeminovascular reflex 35 years ago and the insight that calcitonin gene‐related peptide (CGRP) is a key molecule released in acute migraine attacks. The more recent findings that gepants, small molecule CGRP receptor blockers, and monoclonal antibodies generated against CGRP, or its canonical receptor are useful for the treatment of migraine, are other important issues. CGRP has been established as a key molecule in the neurobiology of migraine. Moreover, monoclonal antibodies to CGRP or the CGRP receptor represent a breakthrough in the understanding of migraine pathophysiology and have emerged as an efficacious prophylactic treatment for patients with severe migraine with excellent tolerability. This review describes the progression of research to reach the clinical usefulness of a large group of molecules that have in common the interaction with CGRP mechanisms in the trigeminal system to alleviate the burden for individuals afflicted by migraine.

P-Glycoprotein and Breast Cancer Resistance Protein Transporter Inhibition by Cyclosporine and Quinidine on the Pharmacokinetics of Oral Rimegepant in Healthy Subjects.

Rimegepant (Nurtec ODT)—an orally administered, small‐molecule calcitonin gene–related peptide receptor antagonist indicated for the acute and preventive treatment of migraine—is a substrate for both the P‐glycoprotein and breast cancer resistance protein transporters in vitro. We evaluated the effects of concomitant administration of strong inhibitors of these transporters on the pharmacokinetics of rimegepant in healthy subjects. This single‐center, open‐label, randomized study was conducted in 2 parts, both of which were 2‐period, 2‐sequence, crossover studies. Part 1 (n = 15) evaluated the effect of a single oral dose of 200‐mg cyclosporine, a strong inhibitor of the P‐glycoprotein and breast cancer resistance protein transporters, on the pharmacokinetics of rimegepant 75 mg. Part 2 (n = 12) evaluated the effect of a single oral dose of 600‐mg quinidine, a strong selective P‐glycoprotein transporter, on the pharmacokinetics of rimegepant 75 mg. Coadministration with cyclosporine showed an increase in rimegepant area under the plasma concentration–time curve from time 0 to infinity and maximum observed concentration based on geometric mean ratios (90% confidence intervals [CIs]) of 1.6 (1.49‐1.72) and 1.41 (1.27‐1.57), respectively, versus rimegepant alone. Coadministration with quinidine showed an increase in rimegepant area under the plasma concentration–time curve from time 0 to infinity and maximum observed concentration geometric mean ratios (90% CIs) of 1.55 (1.40‐1.72) and 1.67 (1.46‐1.91), respectively, versus rimegepant alone. Strong P‐glycoprotein inhibitors (cyclosporine, quinidine) increased rimegepant exposures (>50%, <2‐fold). In parts 1 and 2, rimegepant coadministration was well tolerated and safe. The similar effect of cyclosporine and quinidine coadministration on rimegepant exposure suggests that inhibition of breast cancer resistance protein inhibition may have less influence on rimegepant exposure.

Management of Migraine: An Overview

Migraine is a disabling type of headache due to a neurovascular disorder characterized by moderate to severe pain and specific associated features. Migraine has a high incidence and prevalence, affecting 20% of people at some point in their lives; women are more affected than men. There have been many pharmacologic options that have been used to treat acute migraine over the last years. Nevertheless, this article aims to point out the new drugs approved by the Food and Drug Administration (FDA), the calcitonin gene-related peptide (CGRP) inhibitor and review the traditional pharmacologic options and their combination available. There are two classes of CGRP inhibitors: small molecule CGRP receptor antagonists and anti-CGRP monoclonal antibodies. Their indications depend on the patient’s comorbidity, preference, and side effects. Due to their non-vasoconstrictive property, CGRP inhibitors can be considered a treatment option for patients with a contraindication of triptans and ergot alkaloids use. Another strategy to treat migraine attacks after they start is triptans. Therefore, this drug is considered an abortive therapy. However, triptans have many contraindications and drug interactions. Additionally, it should not be used for more than ten days per month to avoid the development of medication overuse headaches. Another classic group of drugs proven to be effective and safe for mild to moderate headache therapy is non-steroidal anti-inflammatory drugs (NSAIDs). Their easy access and lower cost are the most attractive advantages of this drug. Migraine treatment is not easy, and it might be necessary to use more than one drug. Combination drugs can be used as a first-line or second-line therapy, and they can also be helpful for refractory migraine treatment. Due to the different mechanisms of action, it can enhance the results of another drug or improve its effects. This treatment regimen can be used as the first or second line, depending on the context of the patient. Since migraine is a prevalent condition, all medical professionals must be up to date on migraine treatment methods because studies in this area are lacking.

Lipidated Calcitonin Gene-Related Peptide (CGRP) Peptide Antagonists Retain CGRP Receptor Activity and Attenuate CGRP Action In Vivo.

Signaling through calcitonin gene-related peptide (CGRP) receptors is associated with pain, migraine, and energy expenditure. Small molecule and monoclonal antibody CGRP receptor antagonists that block endogenous CGRP action are in clinical use as anti-migraine therapies. By comparison, the potential utility of peptide antagonists has received less attention due to suboptimal pharmacokinetic properties. Lipidation is an established strategy to increase peptide half-life in vivo. This study aimed to explore the feasibility of developing lipidated CGRP peptide antagonists that retain receptor antagonist activity in vitro and attenuate endogenous CGRP action in vivo. CGRP peptide analogues based on the archetypal CGRP receptor antagonist, CGRP8-37, were palmitoylated at the N-terminus, position 24, and near the C-terminus at position 35. The antagonist activities of the lipidated peptide analogues were tested in vitro using transfected Cos-7 cells expressing either the human or mouse CGRP receptor, amylin subtype 1 (AMY1) receptor, adrenomedullin (AM) receptors, or calcitonin receptor. Antagonist activities were also evaluated in SK-N-MC cells that endogenously express the human CGRP receptor. Lipidated peptides were then tested for their ability to antagonize endogenous CGRP action in vivo using a capsaicin-induced dermal vasodilation (CIDV) model in C57/BL6J mice. All lipidated peptides except for the C-terminally modified analogue retained potent antagonist activity compared to CGRP8-37 towards the CGRP receptor. The lipidated peptides also retained, and sometimes gained, antagonist activities at AMY1, AM1 and AM2 receptors. Several lipidated peptides produced robust inhibition of CIDV in mice. This study demonstrates that selected lipidated peptide antagonists based on αCGRP8-37 retain potent antagonist activity at the CGRP receptor and are capable of inhibition of endogenous CGRP action in vivo. These findings suggest that lipidation can be applied to peptide antagonists, such as αCGRP8-37 and are a potential strategy for antagonizing CGRP action.

Current status of calcitonin gene-related peptide-based therapies in migraine: a scoping review

A significant proportion of patients exhibit sub-optimal response to the standard treatment of acute migraine such as triptans and NSAIDs. Even the conventional preventive therapies (e.g. beta-blockers) indicated for patients with frequent migraine attacks have varying responses. Moreover, evidence from animal studies elucidated the role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine. Currently two classes are drug, the small molecule CGRP receptor antagonist or the ‘gepants’ (Ubrogepant, Rimegepant, Atogepant, Zavegepant) and CGRP monoclonal antibodies (Erenumab, Galcanezumab, Fremanezumab, Eptinezumab) have been found efficacious and safe in various clinical trials for the treatment and prevention of migraine. While the small molecule CGRP receptor antagonists are given orally, the monoclonal antibodies are injectable drugs. Ubrogepant and Rimegepant are the second-generation gepants approved for treatment of migraine. Zavegepant is a third generation gepant which has proven efficacy for acute treatment of migraine in a phase III trial. Atogepant has been approved for prevention of migraine. Rimegepant has also proven to be efficacious for preventing migraine attacks but has not yet been approved for this indication. Erenumab is the only monoclonal antibody which neutralizes the CGRP receptor. The latter three monoclonal antibodies target the CGRP peptide. The monoclonal antibodies have been approved for the prevention of migraine as a subcutaneously or intravenous infusion (Eptinezumab) given once a month or quarterly. Both the classes of drugs were well-tolerated in the clinical trials. Nausea was the most common adverse effect with gepants while injection-site pain was commonly reported with the antibodies.

Calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide in migraine treatment.

To review the latest advances in migraine management with a focus on medications specifically developed for the treatment of migraine. Randomized clinical trials demonstrated the efficacy of calcitonin gene-related peptide (CGRP) mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist gepants for acute abortion and prevention of migraine attacks. Pituitary adenylate cyclase-activating polypeptide (PACAP) is another signaling molecule of interest and represents a potential new drug class of mechanism-based migraine medications. Drugs targeting PACAP are currently undergoing clinical trials, and the coming years will reveal whether this class of drugs will expand our therapeutic armamentarium. Here, we summarize the role of CGRP and PACAP in migraine pathophysiology and discuss novel therapies targeting the CGRP and PACAP signaling pathways.

CGRP and migraine: from bench to bedside.

Migraine treatment has reached a new era with the development of drugs that target the trigeminal neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. The CGRP related therapies offer considerable improvements over existing drugs as they are the first to be designed to act on the trigeminal pain system, more specific and with few adverse events. Small molecule CGRP receptor antagonists, such as rimegepant and ubrogepant, are effective for the acute treatment of migraine headache. In contrast, monoclonal antibodies against CGRP or the CGRP receptor are beneficial for the prophylactic treatments in chronic migraine. Here I will provide a historical overview of the long path that led to their successful development. In addition, I will discuss aspects on the biology of CGRP signalling, the role of CGRP in migraine headache, the efficacy of CGRP targeted treatment, and synthesize what currently is known about the role of CGRP in the trigeminovascular system.

Future prophylactic treatments in migraine: Beyond anti-CGRP monoclonal antibodies and gepants.

Migraine is ranked as a leading cause of years lived with disability among all neurological disorders. Therapies targeting the calcitonin gene-related peptide (CGRP) signaling pathway, including monoclonal antibodies against the receptor or ligand and small molecule CGRP receptor antagonists (gepants), are today approved for migraine prophylaxis with additional compounds expected to be introduced to the market soon. In this review, we consider other putative prophylactic migraine drugs in development, including compounds targeting G-protein coupled receptors, glutamate, ion channels, and neuromodulatory devices. Emergence of these new interventions could complement our current treatment armamentarium for migraine management.