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Calcitonin gene-related peptide receptor antagonist
Calcitonin gene-related peptide receptor antagonist
Calcitonin gene-related peptide receptor antagonist
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Calcitonin gene-related peptide (CGRP) receptor antagonists, commonly known as gepants, are a class of drugs that act as antagonists of the calcitonin gene-related peptide receptor (CGRPR).[1]

Several monoclonal antibodies that bind to the CGRP receptor or peptide have been approved for prevention of migraine.[2] Nerve activation triggers the release of CGRP and other neuropeptides, leading to inflammation, pain, and swelling. Three small molecule CGRPR antagonists are approved in the U.S. as antimigraine agents.[3][4][5] Drugs of this class have also been investigated for use in osteoarthritis.[6]

Examples

[edit]

Non-peptide small molecules

[edit]
  • Ubrogepant is approved for acute treatment of migraines[7][4]
  • Rimegepant (BMS-927711) is approved for acute and preventative treatment of migraines[8][3]
  • Atogepant (AGN-241689) is approved for preventative treatment of migraines[5]
  • Zavegepant (BHV- 3500) is a nasal spray approved for acute treatment of migraines.[9][10]
  • Telcagepant (MK-0974), reached phase III clinical trials; development discontinued in 2011.[11]
  • Olcegepant (BIBN-4096BS) is a drug candidate[12]
  • BI 44370 TA (BI 44370)[13]
  • MK-3207[14]
  • SB-268262

Monoclonal antibodies targeting the CGRP receptor

[edit]
  • Erenumab (AMG-334) is approved for prevention of migraine.[15]

Monoclonal antibodies targeting the CGRP molecule

[edit]

Necrotizing fasciitis

[edit]

A study has found botox effective against necrotizing fasciitis caused by S. pyogenes in mice.[20] Its mechanism of action is by blocking CGRP receptor of nerve cells, which trigger intense pain and activate CGRP cascade, which prevents the immune system attacks to control the pathogen.[21] Botox blocks the CGRP cascade of nerve cells.[22]

Migraine

[edit]

As of 2018, erenumab, brand name Aimovig, was approved in the U.S. for use for migraines. It interacts by blocking the CGRP receptor.[23] As of 2018, fremanezumab, brand name Ajovy, was approved in the U.S. for use for migraines. It interacts with the CGRP protein expressed during an attack.[24] The third approved treatment, as of 2018, galcanezumab, brand name Emgality, was approved in the U.S. for use in migraines. It also interacts with the protein.[25]

As of February 2020, eptinezumab (Vyepti) was approved by the FDA for the treatment of migraine via intravenous infusion as well.[26]

Three small-molecule antagonists have been approved for treatment of migraine: ubrogepant, rimegepant, and atogepant.[4][3][5] Ubrogepant and rimegepant are approved for acute treatment.[4][3] Atogepant and rimegepant are approved for preventative treatment.[5][3]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Calcitonin gene-related peptide receptor antagonist

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from Grokipedia
Calcitonin gene-related peptide (CGRP) receptor antagonists, commonly referred to as gepants, are a class of small-molecule drugs that selectively block the receptor, a key mediator in , to provide acute or preventive treatment for migraines without causing . These antagonists target the heterodimeric receptor complex consisting of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), inhibiting CGRP-induced , neurogenic , and in the trigeminovascular . By preventing CGRP binding, they reduce neuronal activation and associated symptoms such as , , and , offering a migraine-specific mechanism distinct from traditional treatments like . CGRP, a 37-amino acid released from trigeminal sensory nerves, plays a central role in initiation and propagation, with elevated levels observed in jugular during attacks and of CGRP triggering migraine-like symptoms in susceptible individuals. The development of CGRP receptor antagonists began in the late , with early intravenous agents like olcegepant demonstrating efficacy in phase II trials by achieving up to 66% pain relief at two hours, though oral candidates like telcagepant faced setbacks due to concerns. Subsequent advancements led to FDA approvals for safer oral formulations, including (December 2019) and (February 2020) for acute treatment, and (2021) and rimegepant (May 2021) for prevention, alongside intranasal zavegepant (2023). Clinical trials have established their efficacy, with and yielding 19-22% and 20-21% pain freedom at two hours post-dose, respectively, compared to 12-14% and 11-12% for , alongside significant relief from most bothersome symptoms. These agents are well-tolerated, with common adverse effects limited to mild issues like (2-4%), , and dry mouth, and no evidence of cardiovascular risks, making them suitable for patients contraindicated for vasoconstrictors. Ongoing research explores their potential in cluster headaches and other disorders, underscoring their role as a transformative advance in management.

Background

(CGRP) is a 37-amino acid that serves as a key regulator in various physiological processes. It was first discovered in through studies on alternative RNA processing of the calcitonin , revealing that tissue-specific splicing produces distinct mRNA transcripts encoding either calcitonin or CGRP. CGRP exists in two primary isoforms, αCGRP and βCGRP, which share over 90% and exhibit similar biological potency; αCGRP is encoded by the CALCA (primarily expressed in the central and peripheral nervous systems), while βCGRP arises from the separate CALCB (more prominent in the ), with the human forms differing by three at positions 3, 22, and 25. Structurally, CGRP features an N-terminal ring formed by a bridge between residues 2 and 7, followed by an α-helical region, a β-turn, and a C-terminal group, which collectively contribute to its stability and bioactivity. CGRP is biosynthesized primarily in peptide-containing C-fiber and Aδ sensory neurons, including those in the dorsal root ganglia, trigeminal ganglia, and perivascular nerves. The peptide is produced as part of a larger precursor protein via of the CALCA or CALCB genes, located on human , and is processed into its mature form with an amidated . Release occurs from peripheral nerve terminals through calcium-dependent , often stored in dense-core vesicles, and is triggered by stimuli such as nerve activation, inflammation, or activation of transient receptor potential vanilloid 1 () channels (e.g., by ). This release mechanism supports an pathway, allowing CGRP to act locally in tissues like , blood vessels, and viscera. Physiologically, CGRP functions as the most potent known microvascular vasodilator, surpassing prostaglandins by a factor of 10 in efficacy, which promotes sustained increases in blood flow and in responsive tissues such as and mesenteric arteries. It contributes to neurogenic inflammation by enhancing plasma protein extravasation, potentiating the effects of , and facilitating formation and immune cell recruitment at sites of sensory nerve activation. In pain transmission, CGRP released from sensory afferents amplifies nociceptive signaling, promoting through interactions that enhance release and central sensitization in pathways involved in inflammatory and neuropathic pain.90453-2) Additionally, CGRP exerts cardioprotective effects, particularly in models, by improving myocardial circulation, reducing cardiac and , and mitigating vascular cell proliferation under hypertensive or ischemic conditions.

CGRP receptor

The (CGRP) receptor is a heterodimeric complex composed of the calcitonin receptor-like receptor (CLR), a class B G-protein-coupled receptor (GPCR), and receptor activity-modifying protein 1 (RAMP1). RAMP1 is essential for the receptor's trafficking to the cell surface and modulates its ligand-binding properties, forming a functional unit that specifically recognizes CGRP as its primary endogenous ligand. This structural arrangement distinguishes the CGRP receptor from related complexes, such as the 1 (AMY1) receptor, which pairs the calcitonin receptor (CTR) with RAMP1 but exhibits different selectivity profiles despite sharing the RAMP1 component. Upon activation by CGRP, the receptor couples to the stimulatory (Gs), which activates adenylate cyclase and elevates intracellular (cAMP) levels. This cAMP increase subsequently activates (PKA), promoting downstream physiological effects such as in vascular cells and enhanced neuronal excitability through mechanisms. The receptor demonstrates high-affinity binding to CGRP, with dissociation constants (Kd) typically in the picomolar to low nanomolar range (e.g., 0.2–3.3 nM), enabling sensitive detection of the ligand at physiological concentrations. The CGRP receptor is predominantly expressed in sensory neurons of the trigeminal ganglia, endothelial and cells of blood vessels, and regions of the including the trigeminal nucleus caudalis. This distribution supports its roles in neurovascular regulation and , with receptor components like CLR and RAMP1 co-localized in these tissues to facilitate localized signaling.

Pathophysiology

Role in migraine

Calcitonin gene-related peptide (CGRP) plays a central role in pathophysiology through its release from trigeminal sensory nerves, which innervate the cranial vasculature and . During attacks, activation of the trigeminovascular system leads to CGRP release, promoting meningeal , neurogenic , and subsequent central in the trigeminal nucleus caudalis. This aberrant signaling amplifies transmission and contributes to the throbbing characteristic of , building on CGRP's normal physiological role as a potent vasodilator and neuromodulator. Clinical evidence strongly supports CGRP's involvement, with studies demonstrating elevated CGRP levels in during spontaneous attacks compared to interictal periods. In migraineurs, CGRP concentrations in plasma rise significantly during headache phases, correlating with pain intensity, and normalize after treatment with , indicating a direct link to the acute attack. Further substantiating this, intravenous infusion of CGRP in susceptible individuals triggers migraine-like headaches. A seminal 2002 randomized, double-blind, -controlled study by Lassen et al. showed that CGRP infusion induced delayed attacks in 33% (4/12) of migraine patients without aura, mimicking the time course and symptoms of spontaneous migraines, whereas did not. This human provocation model highlights CGRP's sufficiency in initiating migraine pathophysiology. In chronic migraine, sustained CGRP receptor activation is implicated in maintaining central and trigeminal . Persistent elevation of CGRP in the cranial circulation during frequent attacks may perpetuate a cycle of neurogenic , lowering the threshold for subsequent episodes and contributing to the transformation from episodic to chronic forms.

Involvement in other conditions

(CGRP) has been implicated in the of (OA), where it promotes joint and contributes to . Studies have demonstrated elevated levels of CGRP in the of OA patients, correlating with increased intensity and disease severity. For instance, a 2015 investigation found higher CGRP expression in synovial tissues from individuals with knee OA, suggesting its role in driving inflammatory processes and nociceptive signaling within affected . This elevation is thought to exacerbate degradation and synovial , highlighting CGRP's pro-inflammatory effects in this degenerative condition. In cardiovascular disorders, CGRP exerts protective vasodilatory effects, helping to maintain vascular tone and mitigate ischemic damage. Its deficiency or blockade has been associated with exacerbated and worsened outcomes in , as CGRP infusion in affected patients improves and reduces without significantly altering . Research indicates that endogenous CGRP levels rise in response to cardiac stress, such as during , to counteract and support cardioprotection against remodeling and ischemia. These actions underscore CGRP's beneficial role in preserving endothelial function and preventing hypertensive crises. Beyond these conditions, CGRP is under investigation for its involvement in neurogenic inflammation, including Raynaud's phenomenon, where its vasodilatory properties may counteract episodic . In Raynaud's, CGRP in cutaneous blood flow has been observed, with infusions showing prolonged vasodilatory responses that alleviate symptoms in affected patients. Additionally, CGRP contributes to neurogenic inflammation in cluster headaches, where its release during attacks parallels that in , and experimental infusions can provoke episodes in susceptible individuals, supporting its role in trigeminovascular activation. Regarding COVID-19-associated lung inflammation, 2023 research has explored CGRP receptor antagonists as a means to attenuate (ARDS) by modulating excessive inflammatory responses in the pulmonary vasculature, though protective effects of endogenous CGRP on viral clearance have also been noted in bronchial epithelial models.

Mechanism of action

Receptor antagonism

Receptor antagonism involves the direct blockade of the (CGRP) receptor, a heterodimeric complex composed of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), by competitive antagonists that prevent CGRP binding and subsequent downstream signaling. These antagonists occupy the orthosteric at the extracellular domain interface of the CLR/RAMP1 complex, thereby inhibiting the ligand-induced conformational changes necessary for receptor activation. This blockade specifically prevents the coupling of the receptor to the stimulatory (Gs), which would otherwise activate and elevate intracellular (cAMP) levels in target cells. The simplified binding equilibrium for receptor antagonism can be represented as: Antagonist+Receptor⇌Antagonist-Receptor complex\text{Antagonist} + \text{Receptor} \rightleftharpoons \text{Antagonist-Receptor complex} In this complex, no Gs protein activation occurs, halting the cAMP signaling cascade. Pharmacodynamically, receptor antagonism attenuates CGRP-mediated effects in the trigeminovascular system, including reduced neurogenic vasodilation of cranial blood vessels and decreased neuronal hyperexcitability and firing in trigeminal ganglia and the spinal trigeminal nucleus. By interrupting these pathways, antagonists mitigate the inflammatory and pain signaling associated with migraine pathogenesis without affecting vascular tone in other systems to the same extent. Erenumab serves as the prototype , binding directly to the CLR/RAMP1 interface with high affinity to competitively block CGRP access, as elucidated by crystallographic studies of the complex. In contrast, small-molecule gepants demonstrate varied antagonism modes: orthosteric competitive binding, as seen with , directly competes at the CGRP orthosteric site, while exhibits a non-competitive profile, potentially involving allosteric modulation to inhibit receptor activation.

Clinical applications

Migraine prevention

Calcitonin gene-related peptide (CGRP) receptor antagonists, including monoclonal antibodies (mAbs) and small-molecule gepants, are indicated for the preventive treatment of episodic migraine (4–14 migraine days per month) and chronic migraine (≥15 headache days per month, with at least half being migraine days) in adults, and for episodic migraine in pediatric patients aged 6–17 years weighing at least 45 kg (fremanezumab only), particularly those with moderate to severe disability. According to the 2024 American Headache Society (AHS) position statement, these therapies are recommended as a first-line option for migraine prevention, alongside traditional agents like beta-blockers or topiramate, without requiring prior failure of other preventives. This shift acknowledges their favorable efficacy and tolerability profiles in patients who have not responded adequately to conventional prophylactics. Clinical trials have demonstrated that CGRP antagonists significantly reduce the frequency of attacks, with many patients achieving at least a 50% reduction in monthly days (MMDs). For instance, pivotal phase 3 trials of mAbs such as , , , and showed mean reductions of 4 to 7 MMDs over in episodic , while chronic studies reported 7 to 8 fewer headache days per month. Similarly, gepants like (10–60 mg daily) reduced MMDs by 1.2 to 1.7 days more than over 12 weeks in episodic , with 56–61% of patients achieving ≥50% reduction compared to 29% on . (75 mg every other day) has also shown comparable efficacy in reducing MMDs by approximately 4.3 days versus 3.5 days for . These outcomes highlight the therapies' role in long-term strategies to decrease burden and improve . Administration routes vary by class: mAbs are given via subcutaneous injection monthly (erenumab 70–140 mg, fremanezumab 225 mg, galcanezumab 120 mg after ) or intravenous quarterly (eptinezumab 100–300 mg), offering convenience for patients preferring infrequent dosing. In contrast, gepants like and are oral formulations, taken daily or every other day, respectively, providing a non-injectable alternative for preventive use. All are FDA-approved specifically for adults with episodic or chronic whose condition is inadequately controlled by prior therapies, and fremanezumab for pediatric episodic (ages 6–17 years, ≥45 kg), though the AHS guidance supports broader first-line application.

Acute migraine treatment

Calcitonin gene-related peptide (CGRP) receptor antagonists, known as gepants, are approved for the acute treatment of with or without in adults, targeting moderate-to-severe attacks where patients experience significant pain and associated symptoms. These agents provide on-demand symptomatic relief without the vasoconstrictive effects associated with , making them suitable for patients with cardiovascular risk factors. Ubrogepant (Ubrelvy), approved by the FDA in December 2019, is administered as an oral tablet in doses of 50 mg or 100 mg, taken as needed at onset, with a maximum of 200 mg per 24 hours and no more than 8 doses in 30 days. (Nurtec ODT), approved by the FDA in February 2020, is given as a 75 mg , also as needed, with a maximum of 75 mg per 24 hours and safety not established beyond 18 doses in 30 days. Zavegepant (Zavzpret), approved by the FDA in March 2023, is administered as a 10 mg in one , as needed, with a maximum of 10 mg (one dose) per 24 hours and safety not established for more than 8 migraines in 30 days. Clinical trials demonstrate efficacy in achieving pain freedom at 2 hours post-dose, a key endpoint for acute relief. In the phase 3 ACHIEVE I trial, 50 mg and 100 mg resulted in pain freedom rates of 19.2% and 21.2%, respectively, compared to 11.8% for . Similarly, in a phase 3 trial, 75 mg achieved a 21% pain freedom rate at 2 hours versus 11% for . For zavegepant, phase 3 trials showed pain freedom rates of 23.6% and 22.5% at 2 hours versus 14.9% and 15.5% for . These outcomes highlight the rapid blockade of CGRP signaling to abort attacks, with both drugs showing superior relief of the most bothersome symptom (e.g., or ) at 2 hours compared to .

Emerging indications

Research into calcitonin gene-related peptide (CGRP) receptor antagonists has expanded beyond to explore their therapeutic potential in various conditions involving neurogenic and pain. While no approvals have been granted for these emerging uses as of November 2025, preclinical and early clinical data suggest roles in modulating inflammatory pathways. Safety profiles from trials, including low rates of cardiovascular events, are often extrapolated to these investigational applications, though dedicated studies are needed to confirm tolerability. In (OA), CGRP receptor antagonists have been investigated for pain relief due to CGRP's involvement in joint inflammation and . A phase II trial initiated by in 2015 evaluated a targeting CGRP in OA patients, aiming to reduce pain through blockade of this . However, subsequent phase II results with showed no significant pain reduction compared to in knee OA, highlighting challenges in translating preclinical efficacy to clinical outcomes. Despite these mixed findings, ongoing interest persists in targeting CGRP for OA symptom management. For respiratory conditions, particularly (ARDS) associated with , CGRP antagonists have garnered attention for their potential to mitigate excessive lung inflammation. Trials investigating CGRP receptor antagonists for ARDS were authorized by the FDA starting in 2020 (e.g., phase 2 for intranasal vazegepant), based on evidence that CGRP blockade could dampen immune overactivation without compromising protective . Preclinical models support this approach, showing reduced and cytokine storms, though human trial data remain preliminary and no full approvals have followed. Beyond these, potential applications include and Raynaud's . Phase 3 trials of for chronic (published June 2025) and for episodic (published May 2025) did not demonstrate significant reductions in attack frequency over (erenumab: -7.3 vs. -5.9 weekly attacks; eptinezumab: -4.0 vs. -4.6), with no regulatory endorsements as of November 2025. In Raynaud's , where CGRP normally promotes , antagonists are not pursued as therapy due to exacerbation risks; a 2021 of 169 patients confirmed microvascular complications (e.g., digital ulcers) occur in only 5.3% of those with preexisting Raynaud's on CGRP antagonists. However, as of August 2024, the FDA required label updates for CGRP antagonists to warn of Raynaud's risk and potential worsening of or circulation issues, supported by a February 2025 disproportionality analysis showing association in post-marketing data; this underscores the need for cautious use in comorbid cases. Overall, these investigational pursuits underscore the need for larger, condition-specific trials to establish efficacy and delineate risks.

Pharmacological classes

Small-molecule gepants

Small-molecule gepants represent a class of non-peptide, orally or nasally administered (CGRP) receptor antagonists designed for the treatment of . These compounds act as competitive antagonists at the CGRP receptor, blocking the binding of CGRP and thereby inhibiting downstream signaling pathways involved in pathophysiology. Unlike peptide-based inhibitors, gepants are small molecules with favorable pharmacokinetic profiles, including half-lives ranging from 5 to 11 hours and primary metabolism via the hepatic enzyme CYP3A4. This allows for flexible dosing regimens, such as on-demand use for acute attacks or daily administration for prevention, without the need for injections. The of gepants enables rapid absorption and , typically within 1-2 hours, making them suitable for acute relief. They exhibit high selectivity for the CGRP receptor, with minimal off-target effects on related receptors like or adrenomedullin. Metabolism primarily through necessitates caution with strong inducers or inhibitors of this , which can alter drug exposure. Unlike , gepants lack vasoconstrictive properties and thus carry no cardiovascular contraindications, broadening their applicability in patients with comorbidities. Approved gepants include ubrogepant, rimegepant, atogepant, and zavegepant, all receiving U.S. Food and Drug Administration (FDA) approval between 2019 and 2023. Ubrogepant (Ubrelvy), approved in December 2019, is an oral tablet indicated for acute treatment of migraine in adults, with doses of 50 mg or 100 mg taken as needed. Rimegepant (Nurtec ODT), approved in February 2020 for acute use and expanded in May 2021 for prevention, is available as an oral disintegrating tablet (75 mg) for both indications, offering convenience without water. Atogepant (Qulipta), approved in September 2021, is an oral tablet (10 mg, 30 mg, or 60 mg daily) specifically for preventive treatment of episodic migraine. Zavegepant (Zavzpret), approved in March 2023, is the first nasal spray formulation (10 mg as a single spray in one nostril) for acute migraine treatment, providing an alternative for patients with nausea or gastrointestinal issues. Early development of gepants faced challenges, as seen with first-generation agents. Olcegepant, the inaugural , was limited to intravenous administration due to poor oral and never progressed to widespread clinical use. Telcagepant, an oral candidate, demonstrated in phase III trials for acute but was discontinued in 2011 following observations of liver , including elevated levels with repeated dosing. These setbacks informed the design of second-generation gepants, which incorporate structural modifications to enhance safety and reduce hepatotoxic potential while maintaining .

Monoclonal antibodies

Monoclonal antibodies targeting the (CGRP) pathway represent a class of biologic therapies designed for the preventive treatment of , acting either by directly antagonizing the CGRP receptor or by binding to the CGRP itself. These agents are fully humanized or human (IgG) antibodies, engineered for high specificity and prolonged duration of action due to their pharmacokinetic properties, including half-lives ranging from 21 to 31 days, which support monthly or quarterly dosing regimens. Unlike small-molecule antagonists, these biologics undergo minimal and are primarily eliminated through proteolytic degradation, resulting in low and sustained therapeutic levels. Erenumab (Aimovig) is the only that functions as a direct CGRP , binding to the receptor complex on the cell surface to prevent CGRP-induced signaling. Approved by the FDA on May 17, 2018, for prevention in adults, erenumab is administered as a subcutaneous injection (70 mg or 140 mg) once monthly, with a of approximately 21 days. Its unique receptor-targeting mechanism distinguishes it from ligand-binding antibodies, potentially offering broader blockade of CGRP-related pathways. Ligand-targeting monoclonal antibodies, such as fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti), neutralize CGRP before it binds to the receptor and are not direct receptor antagonists; they are addressed in related articles on CGRP inhibitors.

Safety profile

Common adverse effects

Calcitonin gene-related peptide (CGRP) receptor antagonists, encompassing both monoclonal antibodies (mAbs) and small-molecule gepants, are generally well-tolerated in clinical use, with low rates of treatment discontinuation observed across trials. In phase 3 studies, discontinuation due to adverse events occurred in less than 5% of participants for both classes, indicating a favorable safety profile for long-term management of conditions like migraine. For mAbs such as , , and , the most frequently reported adverse effect is injection-site reactions, including , pain, and induration, with rates varying from approximately 5% to 47% depending on the agent and trial, often mild, transient, and comparable to . These reactions are typically mild and transient, resolving without intervention in the majority of cases. In contrast, gepants like and are associated with gastrointestinal symptoms, notably (2-7%) and constipation (up to 6% for , higher for at ~17%), occurring during acute or preventive dosing regimens. Second-generation gepants, including and , demonstrate no evidence of in clinical evaluations, a marked improvement over earlier compounds like telcagepant that were discontinued due to liver elevations. All adverse effects across the class are predominantly mild and self-limiting, often not requiring medical intervention beyond routine monitoring. No black-box warnings have been issued by regulatory authorities for these agents.

Cardiovascular and other concerns

Calcitonin gene-related peptide (CGRP) plays a vasodilatory role in the cardiovascular system, and its inhibition raises theoretical concerns about increased risk of or exacerbation of conditions like Raynaud's phenomenon due to reduced . A 2018 review highlighted CGRP's cardioprotective effects, including its role in preventing , ischemia, and by promoting and reducing . Despite these theoretical risks, long-term data from open-label extension studies up to 5 years have shown no excess cardiovascular events with CGRP receptor antagonists compared to placebo or active comparators, confirmed by real-world analyses including Medicare beneficiaries as of 2025. In patients with Raynaud's phenomenon, a 2021 of adults with found no increased microvascular complications associated with CGRP antagonists, alleviating some concerns about peripheral . However, emerging data suggest a potential signal for Raynaud's aggravation in susceptible individuals; in August 2024, the FDA required label updates for CGRP inhibitors to include warnings about Raynaud's phenomenon and potential based on post-marketing reports, though causality remains unestablished. CGRP antagonists are not absolutely contraindicated in but require caution in severe cases, such as recent , due to potential impacts on vascular tone; monitoring is recommended during initiation. Expert consensus advises avoiding these agents in patients with active cerebrovascular or ischemic events until further safety data accumulate. Beyond cardiovascular effects, possible impacts on have been raised, given CGRP's role in promoting tissue repair via sensory neurons and immune modulation, though clinical evidence is limited to case reports and no widespread complications have been observed. Early concerns linking CGRP inhibition to severe infections like have been addressed, with a 2025 meta-analysis indicating no significant elevated infection risk overall, though some mAbs may mildly increase general infection rates. Long-term effects on remain understudied, as CGRP influences activity, but initial cross-sectional cohorts over 1 year report no significant changes in bone mineral density with anti-CGRP therapy as of 2024.

Development history

Early discovery

The (CGRP) was first identified in 1982 through studies that revealed of the calcitonin gene, producing a 37-amino-acid distinct from calcitonin itself. This discovery, led by Amara et al., highlighted CGRP's potential as a potent vasodilator and neuromodulator, with expression noted in neural tissues and endocrine cells. Subsequent research in the and early confirmed its widespread distribution in sensory neurons, particularly those involved in pain transmission, setting the stage for exploring its role in neurological disorders. By the early 2000s, attention turned to CGRP's involvement in , driven by the limitations of existing treatments like , which are ineffective in approximately 30-40% of patients and contraindicated in those with cardiovascular risks due to their vasoconstrictive effects. studies in 2002 demonstrated that intravenous CGRP provoked delayed migraine-like headaches in migraineurs but not in controls, establishing a causal link and positioning CGRP as a promising non-vasoconstrictive therapeutic target. This evidence built on earlier observations of elevated CGRP levels in during spontaneous attacks, further underscoring the peptide's role in neurogenic inflammation. In the 1990s, the CGRP receptor was pharmacologically characterized and molecularly cloned, revealing it as a heterodimer comprising the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), which enabled targeted antagonist development. A key milestone came in 2004 with the Phase II trial of olcegepant (BIBN 4096 BS), the first selective small-molecule CGRP receptor antagonist, which showed significant headache relief in 66% of acute migraine patients without cardiovascular effects. Building on this, a 2010 study by Hansen et al. confirmed CGRP's migraine-inducing potential specifically in patients with aura, where infusions triggered attacks in 71% of participants, reinforcing the peptide's centrality in migraine mechanisms across subtypes.

Regulatory milestones

The first regulatory milestone for (CGRP) receptor antagonists was the U.S. Food and Drug Administration (FDA) approval of (Aimovig) on May 17, 2018, marking it as the inaugural (mAb) targeting the CGRP receptor for the preventive treatment of in adults. This approval was based on phase 3 trials demonstrating significant reductions in monthly migraine days compared to . Shortly thereafter, the (EMA) granted approval for erenumab on July 30, 2018, aligning closely with the FDA timeline and establishing early international regulatory support for this class of agents. Subsequent approvals expanded the availability of small-molecule CGRP receptor antagonists, known as gepants, for acute treatment. (Ubrelvy) received FDA approval on December 23, 2019, as the first oral gepant for acute treatment in adults, supported by evidence of pain freedom within two hours in clinical trials. (Nurtec ODT) was approved by the FDA on February 27, 2020, initially for acute treatment, and expanded on May 27, 2021, to include preventive use in episodic , making it the first agent approved for both indications. (Qulipta) gained FDA approval on September 28, 2021, specifically for preventive treatment of episodic , further broadening oral options. EMA approvals for in 2022 and in 2023 for preventive uses mirrored these FDA decisions, facilitating broader European access. In 2023, regulatory progress continued with the FDA approval of zavegepant (Zavzpret) on March 9 for acute treatment, offering a non-oral alternative with rapid onset via intranasal delivery. Post-market developments that year included the publication of long-term safety data from analyses, such as the FDA Adverse Event Reporting System (FAERS), which reported no new safety signals beyond known mild effects like injection-site reactions for mAbs and for gepants across over 65,000 reports from 2018 to early 2023. No major product recalls have been issued for any CGRP receptor antagonists to date. By 2024, clinical guidelines elevated the status of these agents. The American Headache Society (AHS) issued a position statement on March 11, 2024, endorsing CGRP-targeted therapies, including receptor antagonists, as a first-line option for prevention alongside traditional treatments, without requiring prior failure of other therapies. As of 2025, these antagonists are widely prescribed, with from large cohorts confirming sustained efficacy and tolerability over multiple years.

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