Calcitonin Gene-related Peptide Receptor Research Articles

Raynaud's phenomenon associated with calcitonin gene-related peptide receptor antagonists case report.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator that regulates the cerebrovascular and peripheral circulation. A new class of migraine therapies decreases CGRP through various mechanisms. One unknown off-target effect is the impact decreasing CGRP will have on the peripheral circulation. The following cases report new onset Raynaud's phenomenon (RP) following the use of CGRP receptor antagonists (-gepants) for both the acute and preventive treatment of migraine. These cases describe the development of RP in two individuals after using each of the currently available gepant medications. To our knowledge these are the first cases reported of RP associated with the use of gepants. RP has previously been reported in association with monoclonal antibodies to the CGRP ligand and CGRP receptor indicated in the prevention of migraine. One case involved oral CGRP receptor antagonists for acute treatment inducing RP. In this case, rimegepant and ubrogepant used separately for different migraine attacks each led to RP in the digits. The other case involved oral CGRP receptor antagonist, atogepant, used as a preventive treatment and induced RP in the digits. This patient had a prior history of areolar tissue RP while breastfeeding, but never in her fingers. In both cases, the offending medications were discontinued, and the patients reported no further episodes of RP. Two cases are reported of people with migraine with new onset digital RP while taking CGRP receptor antagonists (rimegepant, ubrogepant, atogepant) for acute and preventive treatment.

Different dosage regimens of erenumab for the treatment of migraine: A systematic review and meta-analysis of the efficacy and safety of randomized controlled trials.

Migraine is a worldwide epidemic neurological disorder that has a significant influence on the quality of life. Migraine attacks are considered to be related to a calcitonin gene-related peptide (CGRP) signaling molecule, and anti-CGRP medications are used to abort and prevent migraine attacks. Erenumab, a monoclonal antibody that targets the CGRP receptor, is the first migraine preventive medication approved by the US Food and Drug Administration. In the present study, we evaluate the efficacy and safety of erenumab. This study aims to systematically assess the efficacy and safety of erenumab as a migraine preventive treatment compared to a placebo. Randomized, placebo-controlled, single or double-blind trials were searched through MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov up to May 2022. The efficacy outcomes we collected include changes from baseline on monthly migraine days, monthly acute migraine-specific medication days, ≥50% responder rate, ≥75% responder rate, and 100% responder rate at week 12. Safety outcomes include treatment emergent adverse events, serious adverse events, and any adverse event that leads to discontinuation of treatment. The study was registered with PROSPERO (Registry number: CRD42022338861). In all eight included trials, we found that erenumab (28, 70, and 140 mg) is very effective and has a significantly greater reduction in baseline monthly migraine days (28 mg: mean difference [MD]=-1.1, 95% confidence interval [CI]: -2.0 to -0.2, p=0.020; 70 mg: MD=-1.4, 95% CI: -1.8 to -1.1, p < 0.001, I2 =26%; 140 mg: MD=-1.8, 95% CI: -2.1 to -1.4, p < 0.001, I2 =0%) than placebo at week 12, especially with 140 mg. Otherwise, we found that there were no statistical differences in the occurrence of adverse events (7mg: risk ratio [RR]=0.9, 95% CI: 0.7 to 1.2, p=0.570; 21 mg: RR=1.0, 95% CI: 0.8 to 1.2, p=0.730; 28 mg: RR=0.9, 95% CI: 0.7 to 1.1, p=0.340; 70 mg: RR=1.0, 95% CI: 0.9 to 1.0, p=0.230, I2 =0%; 140 mg: RR=1.0, 95% CI: 0.9 to 1.1, p=0.880, I2 =40%) between the erenumab and placebo groups. In our study, we found that erenumab, especially at the dose of 140 mg, is an effective and well-tolerated preventive treatment for migraine.

Calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraines in adults.

Migraine headaches are widespread, debilitating and considered a main cause of disability worldwide. Symptoms of migraines include unilateral, pulsating pain that can last for hours to days, frequently associated with photophobia and phonophobia, nausea, or vomiting, and often aggravated by physical activity. The Canadian Headache Society and American Headache Society guidelines suggest strong evidence of the efficacy of triptans, acetaminophen, aspirin, diclofenac sodium, naproxen and ibuprofen for the acute treatment of migraines. The use of calcitonin gene-related peptide (CGRP) antagonists for the treatment and prevention of migraines has been gaining utilization since the approval of the first agent in this class in 2018. There are increasing available options for the acute treatment of migraines. The purpose of this article is to provide a narrative review of the pharmacological and clinical characteristics of ubrogepant and rimegepant and to discuss their implications for use.

Application of a new biological pathogenetic therapy of migraine in clinical practice: expert consensus of the Russian Headache Research Society

This consensus reviewed the main current issues of clinical application and integration into everyday practice of a new targeted preventive therapy for migraine using monoclonal antibodies (mAbs) to the calcitonin gene related peptide (CGRP) ligand or receptor. These recommendations are based on current scientific and clinical studies and an analysis of the results of several years of clinical use. The main purpose of the consensus is to assist practitioners in prescribing effective prophylactic treatment of migraine using anti-CGRP mAbs and to improve care for patients with various forms of the disease.

Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode.

The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 (3) and HTL0029882 (4), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that 3 binds to the CGRP receptor in a precedented manner but that 4 binds in an unprecedented, unexpected, and radically different manner. The observation of this phenomenon is noteworthy and may open novel avenues for CGRP receptor antagonist design.

Elucidating the Ability of CGRP to Modulate Microvascular Events in Mouse Skin.

Oedema formation and polymorphonuclear leukocyte (neutrophil) accumulation are involved in both acute and chronic inflammation. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that is released from stimulated sensory nerves. CGRP is a potent vasodilator neuropeptide, especially when administered to the cutaneous microvasculature, with a long duration of action. Here, we have investigated the ability of vasodilator amounts of CGRP to modulate oedema formation and neutrophil accumulation induced in the cutaneous microvasculature of the mouse. To learn more about the mechanism of action of endogenous CGRP, we have investigated the response to the inflammatory stimulants tumour necrosis factor alpha (TNFα) and carrageenan in three different murine models: a model where sensory nerves were depleted by resiniferatoxin (RTX); a pharmacological method to investigate the effect of a selective CGRP receptor antagonist; and a genetic approach using wildtype (WT) and αCGRP knockout (KO) mice. Our results show that exogenous CGRP potentiates oedema formation induced by substance P (SP) and TNFα. This is further supported by our findings from sensory nerve-depleted mice (in the absence of all neuropeptides), which indicated that sensory nerves are involved in mediating the oedema formation and neutrophil accumulation induced by TNFα, and also carrageenan in cutaneous microvasculature. Furthermore, endogenous CGRP was shown to contribute to this inflammatory response as carrageenan-induced oedema formation is attenuated in WT mice treated with the CGRP receptor antagonist, and in αCGRPKO mice. It is therefore concluded that CGRP can contribute to inflammation by promoting oedema formation in skin, but this response is dependent on the pro-inflammatory stimulus and circumstance.

Rimegepant for the treatment of migraine.

Migraine is a common form of primary headache, affecting up to 1 in every 6 Americans. The pathophysiology is an intricate interplay of genetic factors and environmental influence and is still being elucidated in ongoing studies. The trigeminovascular system is now known to have a significant role in the initiation of migraines, including the release of pain mediators such as CGRP and substance P. Traditional treatment of migraine is usually divided into acute and preventive treatment. Acute therapy includes non-specific therapy, such as NSAIDs and other analgesics, which may provide relief in mild to moderate migraines. 5-HT1 agonists may provide relief in severe migraine, but are not universally effective and carry a significant side-effect profile with frequent redosing requirement. Prophylactic therapy may reduce the occurrence of acute migraine attacks in selected patients, but does not completely eliminate it. More recently, CGRP antagonism has been studied and shown to be effective in both abortion and prevention of migraine. Novel medications, targeting CGRP, divide into CGRP antibodies and receptor antagonists (gepants). Rimegepant, a second-generation gepant, has shown efficacy in several clinical trials in treating acute migraine. Ongoing trials are also evaluating its role in migraine prophylaxis, and results are promising. It is also generally safer for use than existing options, does not appear to increase the chance of developing chronic migraines, and carries a very tolerable side effects profile. It is a part of a growing arsenal in migraine treatment, and may present the silver bullet for treatment of this disease.

Focus on zavegepant: the first intranasal third-generation gepant.

Migraine is the leading cause of years lived with disability in people under 50 and its burden is increased by calcitonin gene-related peptide (CGRP)-driven chronicity. Newly approved small molecules that antagonize theCGRP receptor, gepants, have advancedfrom the hepatotoxic first-generation telcagepant tothird-generation intranasal zavegepant;during this process of drug development, rimegepant, ubrogepant and atogepant, which are orally administered, have been launched and approved for clinical usewith no warning for hepatotoxicity. Real-world, long-term postmarketingdata about the efficacy and safety of gepants areawaited. The aim of the present drug evaluation study was to provide an overview of the novel, third-generation intranasal zavegepant, encompassing its development andfuture perspectives.

S539 Systematic Review and Meta-Analysis of the Prevalence of Constipation and Nausea Among Adults Using Calcitonin Gene-Related Peptide (CGRP) Inhibitors for Preventative Treatment of Cluster Headache or Migraine

Introduction: Constipation and nausea are frequently encountered medication-associated side effects. Calcitonin gene-related peptide (CGRP) inhibitor use may be potential cause of constipation and nausea, but the magnitude of this impact in patients with cluster headaches or migraines has not been well characterized. Methods: We conducted a systematic review using PUBMED and ClinicalTrials.Gov to identify randomized, placebo-controlled clinical trials using anti-CGRP antibodies or CGRP receptor antagonists for the prevention of cluster headaches or chronic migraine. We extracted data including CGRP inhibitor dose, dose frequency, and the reported proportions of patients in these trials with constipation and nausea. We compared the prevalence of these symptoms in those on medication to those on placebo, using two-tailed paired t-tests. The risk of a specific adverse event was assessed using odds ratios with 95% confidence intervals. Results: We identified an initial pool of 449 studies to which we applied a priori criteria to yield 27 studies for nausea and 15 studies for constipation analyses. In the anti-CGRP antibody-treated group, the pooled prevalence of constipation was 2.69% (N=3,574) and nausea was 2.03% (N=9,231), compared with 1.39% (N=4,520, p=0.004) and 2.47% (N=11,680, p=0.0095) in placebo-treated groups, respectively. In the CGRP receptor antagonist-treated group, the prevalence of constipation was 5.20% (N=1,847) and nausea was 6.04% (N=1,689), compared to 1.46% (N=1,852, p=0.002) and 3.05% (N=1,967, p=0.0001) in placebo-treated groups, respectively. CGRP receptor antagonist use demonstrated greater risks of constipation (OR=3.71 [2.41, 5.71], p< 0.0001) and nausea (OR=2.04 [1.48, 2.83], p< 0.0001) than anot-CGRP antibody use (constipation: OR=1.96 [1.41, 2.72], p=0.0001; nausea: OR=0.82, [0.68, 0.99], p = 0.0343). Anti-CGRP antibody use did not appear to be associated with an increased risk of nausea. Conclusion: Constipation and nausea are associated with CGRP inhibitor use in those with cluster headache or migraine. With the increased prevalence of CGRP inhibitor use, CGRP inhibitor-associated constipation and nausea cases could grow substantially. Gastroenterologists should consider CGRP inhibitor use as a medication-induced cause of nausea and constipation. CGRP receptor antagonist use is associated with higher rates of these gastrointestinal side effects than the use of anti-CGRP antibodies.

A narrative review of the calcitonin peptide family and associated receptors as migraine targets: Calcitonin gene-related peptide and beyond.

To summarize the pharmacology of the calcitonin peptide family of receptors and explore their relationship to migraine and current migraine therapies. Therapeutics that dampen calcitonin gene-related peptide (CGRP) signaling are now in clinical use to prevent or treat migraine. However, CGRP belongs to a broader peptide family, including the peptides amylin and adrenomedullin. Receptors for this family are complex, displaying overlapping pharmacologic profiles. Despite the focus on CGRP and the CGRP receptor in migraine research, recent evidence implicates related peptides and receptors in migraine. This narrative review summarizes literature encompassing the current pharmacologic understanding of the calcitonin peptide family, and the evidence that links specific members of this family to migraine and migraine-like behaviors. Recent work links amylin and adrenomedullin to migraine-like behavior in rodent models and migraine-like attacks in individuals with migraine. We collate novel information that suggests females may be more sensitive to amylin and CGRP in the context of migraine-like behaviors. We report that drugs designed to antagonize the canonical CGRP receptor also antagonize a second CGRP-responsive receptor and speculate as to whether this influences therapeutic efficacy. We also discuss the specificity of current drugs with regards to CGRP isoforms and how this may influence therapeutic profiles. Lastly, we emphasize that receptors related to, but distinct from, the canonical CGRP receptor may represent underappreciated and novel drug targets. Multiple peptides within the calcitonin family have been linked to migraine. The current focus on CGRP and its canonical receptor may be obscuring pathways to further therapeutics. Drug discovery schemes that take a wider view of the receptor family may lead to the development of new anti-migraine drugs with favorable clinical profiles. We also propose that understanding these related peptides and receptors may improve our interpretation regarding the mechanism of action of current drugs.

The CGRP Receptor Antagonist MK0974 Induces EVI1high AML Cell Apoptosis by Disrupting ERK Signaling.

Acute myeloid leukemia (AML) with high expression of the oncogenic transcription factor ecotropic viral integration site-1 (EVI1) (EVI1high AML) is refractory, and there is an urgent need to develop treatment for EVI1high AML. We previously showed that calcitonin receptor-like receptor (CRLR)/receptor activity modifying protein 1 (RAMP1) is highly expressed in EVI1high AML and participates in calcitonin gene-related peptide (CGRP)-induced stress hematopoiesis. This study examined whether MK0974 (a CGRP antagonist) acts as a therapeutic agent in CRLR/RAMP1high AML cell lines. An in vitro experimental system was used to determine the effect of MK0974 on EVI1high AML cell lines. The expression of CRLR and RAMP1-3 in EVI1high and EVI1low AML lines was evaluated by reverse-transcription polymerase chain reaction (RT-PCR). Next, MK0974 was added to the AML cell lines, and cell proliferation, cell cycle and apoptosis assays were carried out using flow cytometry (FCM). Proteins were evaluated using western blot analysis. We also generated AML cell lines with CRLR knockdown and evaluated whether the effect of MK0974 was reduced. Apoptosis was induced by adding MK0974 to the EVI1high AML cell line. In the EVI1high AML cell line, the addition of MK0974 attenuated the phosphorylation of ERK and p38. These effects were also attenuated by CRLR knockdown. MK0974, a CGRP receptor antagonist, inhibits the CRLR/RAMP1 complex and induces apoptosis, making it a potential therapeutic agent for CRLR/RAMP1high AML.

Antagonism of CGRP Receptor: Central and Peripheral Mechanisms and Mediators in an Animal Model of Chronic Migraine.

Calcitonin-gene-related peptide (CGRP) plays a key role in migraine pathophysiology and more specifically in the mechanisms underlying peripheral and central sensitization. Here, we explored the interaction of CGRP with other pain mediators relevant for neuronal sensitization in an animal model of chronic migraine. Male Sprague-Dawley rats were exposed to nitroglycerin (NTG, 5 mg/kg, i.p.) or vehicle co-administered with the CGRP receptor antagonist olcegepant (2 mg/kg i.p.), or its vehicle, every other day over a 9-day period. Twenty-four hours after the last injection of NTG (or vehicle), behavioral test and ex vivo analysis were performed. Olcegepant attenuated NTG-induced trigeminal hyperalgesia in the second phase of the orofacial formalin test. Interestingly, it also reduced gene expression and protein levels of CGRP, pro-inflammatory cytokines, inflammatory-associated miRNAs (miR-155-5p, miR-382-5p, and miR-34a-5p), and transient receptor potential ankyrin channels in the medulla–pons area, cervical spinal cord, and trigeminal ganglia. Similarly, olcegepant reduced the NTG-induced increase in CGRP and inflammatory cytokines in serum. The findings show that the activation of the CGRP pathway in a migraine animal model was associated to the persistent activation of inflammatory pathways, which was paralleled by a condition of hyperalgesia. These molecular events are relevant for informing us about the mechanisms underlying chronic migraine.

A c-Fos activation map in nitroglycerin/levcromakalim-induced models of migraine

BackgroundChronic migraine is a common and highly disabling disorder. Functional MRI has indicated that abnormal brain region activation is linked with chronic migraine. Drugs targeting the calcitonin gene-related peptide (CGRP) or its receptor have been reported to be efficient for treating chronic migraine. The CGRP signaling was also shared in two types of chronic migraine models (CMMs). However, it remains unclear whether the activation of specific brain regions could contribute to persistent behavioral sensitization, and CGRP receptor antagonists relieve migraine-like pain in CMMs by altering specific brain region activation. Therefore, it’s of great interest to investigate brain activation pattern and the effect of olcegepant (a CGRP receptor-specific antagonist) treatment on alleviating hyperalgesia by altering brain activation in two CMMs, and provide a reference for future research on neural circuits.MethodsRepeated administration of nitroglycerin (NTG) or levcromakalim (LEV) was conducted to stimulate human migraine-like pain and establish two types of CMMs in mice. Mechanical hypersensitivity was evaluated by using the von Frey filament test. Then, we evaluated the activation of different brain regions with c-Fos and NeuN staining. Olcegepant was administered to explore its effect on mechanical hyperalgesia and brain region activation.ResultsIn two CMMs, acute and basal mechanical hyperalgesia was observed, and olcegepant alleviated mechanical hyperalgesia. In the NTG-induced CMM, the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and the caudal part of the spinal trigeminal nucleus (Sp5c) showed a significant increase of c-Fos expression in the NTG group (p < 0.05), while pre-treatment with olcegepant reduced c-Fos expression compared with NTG group (p < 0.05). No significant difference of c-Fos expression was found in the paraventricular thalamic nucleus (PVT) and ventrolateral periaqueductal gray (vlPAG) between the vehicle control and NTG group (p > 0.05). In the LEV-induced CMM, mPFC, PVT, and Sp5c showed a significant increase of c-Fos expression between vehicle control and LEV group, and olcegepant reduced c-Fos expression (p < 0.05). No significant difference in c-Fos expression was found in vlPAG and ACC (p > 0.05).ConclusionsOur study demonstrated the activation of mPFC and Sp5c in two CMMs. Olcegepant may alleviate hyperalgesia of the hind paw and periorbital area by attenuating brain activation in CMMs.

Safety and efficacy of erenumab in patients with trigeminal neuralgia in Denmark: a double-blind, randomised, placebo-controlled, proof-of-concept study

Trigeminal neuralgia is a severe facial pain disorder that is difficult to treat. Erenumab, a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, has proven efficacy in migraine. Erenumab modulates sensory processing in peripheral trigeminal pain pathways in mice and was reported to be effective for patients with trigeminal neuralgia in open-label studies. We aimed to evaluate the efficacy of erenumab in patients with trigeminal neuralgia. We did a randomised, double-blind, placebo-controlled trial in adults (aged 18-85 years) with idiopathic or classic trigeminal neuralgia as defined by the 3rd edition of the International Classification of Headache Disorders. The trial was based at the Danish Headache Center, Copenhagen University Hospital. Eligible participants had no clinically significant cerebrovascular or cardiovascular disease, had self-reported pain intensity of at least 4 on the 11-point Numeric Rating Scale (0=no pain, 10=worst pain imaginable), and had at least three daily pain paroxysms. After a 1-week pre-screening period, patients entered a 4-week baseline period. Participants who met pain inclusion criteria at the end of the baseline period were randomly assigned (1:1) to receive subcutaneous injections of either erenumab 140 mg or placebo and entered the 4-week follow-up period. Randomisation was done in blocks of 10 using a computer-generated schedule by a third-party company. Participants and assessors were masked to treatment allocation, and erenumab and placebo were packed in identical prefilled syringes. The primary outcome was the number of responders, defined as patients who had a reduction of at least 30% in mean average daily pain intensity during the follow-up period compared with during the baseline period, analysed in the intention-to-treat population. This trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT number 2019-000848-95. We assessed 860 patients for suitability and excluded 741 between Oct 28, 2019, and Sept 13, 2021. 119 participants entered a 1-week pre-screening period and 26 were excluded, 93 participants entered a 4-week baseline period with 13 excluded before randomisation, and 80 participants were randomly assigned to erenumab 140 mg (n=40) or placebo (n=40). There was no difference between groups in the number of responders at 4 weeks in the intention-to-treat population (14 [35%] of 40 with erenumab vs 18 [45%] of 40 with placebo; estimated effect size -10% [95% CI -31 to 11]; p=0·36). 20 (50%) of 40 participants reported adverse events in each group. The most common adverse events were constipation (28%) and headache (10%) in the erenumab group, and headache (13%), constipation (10%), and abdominal pain (10%) in the placebo group. Erenumab did not reduce pain intensity compared with placebo in patients with trigeminal neuralgia and CGRP probably does not have an important role in paroxysmal pain. Well tolerated, effective treatments in trigeminal neuralgia are still needed. Novartis.

Plasma Clearance of Intravenously Infused Adrenomedullin in Rats with Acute Renal Failure.

Plasma adrenomedullin concentrations are reportedly elevated in patients with renal failure; however, the underlying mechanism is unclear. In this study, we investigated the plasma clearance of synthetic human adrenomedullin (AM) in two models of rats with renal dysfunction; one was induced by subcutaneous injection of mercury chloride (RD-Ag) and the other by completely blocking bilateral renal blood flow (RD-Bl). Sixty minutes after starting intravenous AM infusion, AM levels in RD-Ag, RD-Bl, and rats with normal renal function (NF) were still increased slightly; however, plasma AM levels in RD-Ag rats were approximately three times as high as in RD-Bl and NF rats. Plasma AM disappearance after the end of treatment was similar among the three groups. Pharmacokinetic analysis revealed that elevated plasma AM in RD-Ag rats may be caused by a reduced volume of distribution. The adrenomedullin functional receptor is composed of heterodimers, including GPCR, CLR (calcitonin receptor-like receptor, CALCRL), and the single transmembrane proteins, RAMP2 or RAMP3 (receptor activity modifying protein). Calcrl expression was downregulated in the lungs and kidneys of RD-Ag rats. Furthermore, the plasma concentration of exogenous AM was elevated in mice deficient in vascular endothelium-specific Ramp2. These results suggest that decreased plasma AM clearance in RD-Ag is not due to impaired renal excretion but to a decreased volume of distribution caused by a reduction in adrenomedullin receptors.

Efficacy and safety of monoclonal antibody against calcitonin gene-related peptide or its receptor for migraine patients with prior preventive treatment failure: a network meta-analysis

ObjectiveThe relative effects of monoclonal antibody against calcitonin gene-related peptide (CGRP) or its receptor for adult migraine patients with prior treatment failure remains uncertain. Therefore, this study systematically assessed the comparative effectiveness of different CGRP binding monoclonal antibodies (mAbs) for these patients.MethodsSeveral online databases including Ovid MEDILNE, Ovid EMBASE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to June 15, 2022. We included randomized clinical trials (RCT) of adult migraine patients with previous treatment failure that assessed any CGRP monoclonal antibody. The primary efficacy outcome was change in monthly migraine days (MMDs), and the primary safety outcome was treatment-emergent adverse events (TEAEs).ResultsOverall, seven studies totaling 3, 052 patients were included. Three-node analysis showed that CGRP mAbs was superior to CGRP receptor mAbs in reducing MMDs (MD: -1.55, 95% CrI: − 2.43 to − 0.44) and improving at least 50% response rates (RR: 1.52, 95% CrI: 1.04 to 2.21). Nine-node analysis showed galcanezumab 240 mg ranked first in reducing MMDs (MD -4.40, 95% CrI − 7.60 to − 1.19) and improving 50% response rates (RR: 4.18, 95% CrI: 2.63 to 6.67). Moreover, treatment with fremanezumab or eptinezumab 300 mg provides a significant advantage over erenumab 140 mg regarding an improved response rate of at least 50%. The analysis did not show difference in incidences of TEAEs and serious adverse events in any of the comparisons.ConclusionsIt appears that CGRP mAbs, especially galcanezumab 240 mg, monthly fremanezumab, and eptinezumab 300 mg, seem to be the best choice for the treatment of migraine patients with previous treatment failures. This finding also calls for future research that examine the associations between these medications in migraine therapy among the same patient group to testify the present findings.

Sensory Nerve Maintains Intervertebral Disc Extracellular Matrix Homeostasis Via CGRP/CHSY1 Axis.

Sensory nerves are long being recognized as collecting units of various outer stimuli; recent advances indicate that the sensory nerve also plays pivotal roles in maintaining organ homeostasis. Here, this study shows that sensory nerve orchestrates intervertebral disc (IVD) homeostasis by regulating its extracellular matrix (ECM) metabolism. Specifically, genetical sensory denervation of IVD results in loss of IVD water preserve molecule chondroitin sulfate (CS), the reduction of CS bio‐synthesis gene chondroitin sulfate synthase 1 (CHSY1) expression, and dysregulated ECM homeostasis of IVD. Particularly, knockdown of sensory neuros calcitonin gene‐related peptide (CGRP) expression induces similar ECM metabolic disorder compared to sensory nerve denervation model, and this effect is abolished in CHSY1 knockout mice. Furthermore, in vitro evidence shows that CGRP regulates nucleus pulposus cell CHSY1 expression and CS synthesis via CGRP receptor component receptor activity‐modifying protein 1 (RAMP1) and cyclic AMP response element‐binding protein (CREB) signaling. Therapeutically, local injection of forskolin significantly attenuates IVD degeneration progression in mouse annulus fibrosus puncture model. Overall, these results indicate that sensory nerve maintains IVD ECM homeostasis via CGRP/CHSY1 axis and promotes IVD repair, and this expands the understanding concerning how IVD links to sensory nerve system, thus shedding light on future development of novel therapeutical strategy to IVD degeneration.

34568 What a headache: Erenumab-provoked urticarial drug eruption

Erenumab is a calcitonin gene-related peptide receptor antagonist monoclonal antibody indicated for migraine prophylaxis in treatment resistant patients first approved in 2018. In the pivotal trials, the only reported cutaneous adverse effect was injection site pain. Here, we report a 40-year-old Caucasian woman who presented with a polymorphic eruption of the extremities and trunk that initially presented in the days following her first injection of erenumab. The eruption was urticarial on the trunk and papulosquamous on the extremities.

A short review on atogepant: recently approved first oral calcitonin gene-related peptide receptor antagonist

Migraine is the second leading cause of disability in terms of ‘years lived with disability’ and it affects globally about 12% of the general population. Currently available preventive therapies are not specific to migraine. After the discovery of calcitonin gene-related peptide’s (CGRP’s) role in migraine pathophysiology, CGRP receptor antagonist drugs were developed specifically for migraine. Atogepant is the only oral, selective, potent, second-generation CGRP receptor antagonist approved in September 2021 by Food and Drug Administration (FDA) for prophylaxis of episodic migraines and chronic migraines. It acts by blocking the α-CGRP receptor present on the vascular smooth muscle cell membrane of cranial arteries. It has the added advantage of oral administration, less hepatotoxicity, minimal drug–drug interactions (DDIs) with better efficacy, safety, and tolerability profile compared to the other CGRP receptor antagonists. This present review summarizes the physicochemical properties, pharmacokinetics-pharmacodynamics (PK-PD) parameters, uses, and drug-food interactions with the help of available current evidence.

Efficacy and Safety of Erenumab, Galcanezumab, and Fremanezumab in the Treatment of Drug-Resistant Chronic Migraine: Experience in Real Clinical Practice.

Due to the recent introduction of new biologic drugs for chronic migraine, a global evaluation in real clinical practice is necessary. The objective was to evaluate the effectiveness and safety in real clinical practice of drugs targeting the calcitonin gene-related peptide receptor (CGRPr) in patients with chronic migraine. Single-center, restrospective study (2019-2022), including patients with chronic migraine treated with erenumab, galcanezumab, or fremanezumab. Effectiveness variables were recorded, namely, number of migraine headache days per month (MHD), Migraine Disability Assessment Scale (MIDAS) score, and Headache Impact Test-6 (HIT-6) score, assessing changes at week 12, 24 from baseline. Toxicity was recorded following the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. In all, 104 patients were included (46.2% erenumab, 41.3% galcanezumab, 12.5% fremanezumab). A reduction in MHD, MIDAS, and HIT-6 was achieved at weeks 12 and 24 with erenumab (p75% at week 24 than those intensified; P = 0.041). There was no difference in efficacy (P = 0.154) or improvement in quality of life (P = 0.783, P = 0.150), but there was greater toxicity (P < 0.001) among nonresponders with erenumab 70 mg versus erenumab 140 mg. The results confirm the effectiveness and safety of anticalcitonin gene-related peptide (CGRP) drugs in real clinical practice. However, the study shows little benefit from erenumab intensification, with similar effectiveness and worse tolerability than the standard dose.