Developments in targeting calcitonin gene-related peptide.

INTRODUCTION: Calcitonin Gene-Related Peptide (CGRP)-targeted therapy has revolutionized migraine treatment since its first approval in 2018. CGRP-targeted therapy includes monoclonal antibodies (mAbs) and gepants, which modulate trigeminal nociceptive and inflammatory responses, alleviating pain sensitization involved in migraine pathogenesis. CGRP-targeted therapy is effective not only for migraine but also for other chronic headache disorders that share the CGRP pathway. AREAS COVERED: The authors review the latest developments and evidence for CGRP-targeted therapy for episodic migraine and chronic migraine. In addition, the authors discuss the emerging evidence on response prediction, menstrual migraine, vestibular migraine, idiopathic intracranial hypertension, post-traumatic headache, and the relationship between selected migraine comorbidities and CGRP. EXPERT OPINION: Since the launch of CGRP-targeted therapy, many practical issues have been raised. Generally, it's safe to combine CGRP-targeted mAbs and gepants; this is an excellent option for patients with partial response. When considering stopping CGRP-targeted therapy, although a disease-modifying effect is likely, the optimal time for discontinuation remains unknown. Finally, beyond migraine, CGRP-targeted therapy may be used for other chronic pain disorders and psychological comorbidities.

CGRP-targeted medication in chronic migraine - systematic review.

BACKGROUND: Chronic migraine is a highly debilitating condition that is often difficult to manage, particularly in the presence of medication overuse headache. Drugs targeting the calcitonin gene-related peptide (CGRP), or its receptor have shown promising results in treating this disorder. METHODS: We searched Pubmed and Embase to identify randomized clinical trials and real-world studies reporting on the use of medication targeting the calcitonin gene-related peptide in patients with chronic migraine. RESULTS: A total of 270 records were identified. Nineteen studies qualified for the qualitative analysis. Most studies reported on monoclonal antibodies targeting CGRP (anti-CGRP mAbs), that overall prove to be effective in decreasing monthly migraine days by half in about 27.6-61.4% of the patients. Conversion from chronic to episodic migraine was seen in 40.88% of the cases, and 29-88% of the patients stopped medication overuse. Obesity seems to be the main negative predictor of response to anti-CGRP mAbs. There is no evidence to suggest the superiority of one anti-CGRP mAb. Despite the lack of strong evidence, the combination of anti-CGRP medication with onabotulinumtoxinA in chronic migraine is likely to bring benefits for resistant cases. Atogepant is the first gepant to demonstrate a significant decrease in monthly migraine days compared to placebo in a recent trial. Further, anti-CGRP mAb and gepants have a good safety profile. CONCLUSION: There is strong evidence from randomized trials and real-world data to suggest that drugs targeting CGRP are a safe and effective treatment for chronic migraine.

Activation of CGRP receptor-mediated signaling promotes tendon-bone healing.

Calcitonin gene-related peptide (CGRP), an osteopromotive neurotransmitter with a short half-life, shows increase while calcitonin receptor-like (CALCRL) level is decreased at the early stage in bone fractures. Therefore, the activation of CALCRL-mediated signaling may be more critical to promote the tendon-bone healing. We found CGRP enhanced osteogenic differentiation of BMSCs through PKA/CREB/JUNB pathway, contributing to improved sonic hedgehog (SHH) expression, which was verified at the tendon-bone interface (TBI) in the mice with Calcrl overexpression. The osteoblast-derived SHH and slit guidance ligand 3 were reported to favor nerve regeneration and type H (CD31hiEMCNhi) vessel formation, respectively. Encouragingly, the activation or inactivation of CALCRL-mediated signaling significantly increased or decreased intensity of type H vessel and nerve fiber at the TBI, respectively. Simultaneously, improved gait characteristics and biomechanical performance were observed in the Calcrl overexpression group. Together, the gene therapy targeting CGRP receptor may be a therapeutic strategy in sports medicine.

The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota.

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. The neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.

Blood pressure elevation in erenumab-treated patients with migraine: A retrospective real-world experience.

BACKGROUND: Erenumab is a monoclonal antibody that targets the calcitonin gene-related peptide (CGRP) receptor and is approved for the preventative treatment of migraine in adults. CGRP is involved in the regulation of vasomotor tone under physiologic and pathologic conditions, including hypertension. While there has not been evidence of hypertension in preclinical models or clinical trials, post-marketing data suggest erenumab may be associated with hypertension. This led to a warning in the United States Food and Drug Administration prescribing information for erenumab. OBJECTIVE: To determine the frequency of worsening blood pressure (BP) after initiation of erenumab in patients with migraine and how this is associated with hypertension. METHODS: This is an observational retrospective cohort study evaluating patients at a tertiary headache or neurology department. Systolic and diastolic BPs were compared between the initial visit prior to initiation of erenumab, and follow-up visit while on erenumab. Worsening BP was defined as moving from a lower stage to a higher stage of BP, as defined by the American Heart Association. Serious adverse vascular events were also recorded. RESULTS: A total of 335 patients were included in the final analysis (mean [SD] age of 45.7 [14.40] years, 83.9% [281/335] female). At baseline, 20.9% (70/335) of patients had a prior diagnosis of hypertension. The median (interquartile range) time to follow-up appointment from initial appointment was 20.5 (13.3-35.3) weeks. The mean (SD) BP at baseline was systolic 124.7 (15) mmHg and diastolic 77 (11) mmHg, and at follow-up was systolic 124.0 (15) mmHg and diastolic 77.8 (9) mmHg. Overall, 23.3% (78/335) of all patients had worsening BP, whereas 13/225 (3.9%) patients had improvement in their BP. Patients with atrial fibrillation were more likely to develop worsening BP (odds ratio, 4.9, 95% confidence interval 1.12-21.4; p = 0.035). There was no association between worsening BP and pre-existing hypertension, sex, body mass index, or age. One patient had non-ST elevation myocardial infarction attributed to a hypertensive emergency while on erenumab. CONCLUSION: We found that 23.3% of patients initiated on erenumab may have developed worsening BP, suggesting the need for BP monitoring in patients initiated on erenumab.

CGRP monoclonal antibodies and CGRP receptor antagonists (Gepants) in migraine prevention.

Migraine is a prevalent and disabling neurological disease. Its preventive treatment for decades has been rather limited due to the absence of disease-specific therapies with limited efficacy and tolerability. The advances made in migraine research have led to the discovery of the calcitonin gene-related peptide (CGRP) and its role in migraine pathophysiology. CGRP is a neuropeptide that acts as potent vasodilator and is involved in pain processing. Increased levels of plasma CGRP have been observed during migraine attacks as well as interictally when comparing patients with migraine and healthy controls. In the last years, two classes of drugs antagonizing CGRP have therefore been developed as the first migraine-specific preventive treatments: anti-CGRP monoclonal antibodies (mAbs) and gepants. Four mAbs have been approved: erenumab, galcanezumab, fremanezumab, and eptinezumab. Gepants are small molecules that antagonize the CGRP receptor; currently only rimegepant and atogepant have been approved for migraine prevention. These new drugs have demonstrated efficacy and safety in clinical trials for both episodic and chronic migraine, and results from their real-world experience are being increasingly reported in literature. In this review, we provide an overview of anti-CGRP drugs and their placement in migraine prevention.

Pharmacotherapies for Migraine and Translating Evidence From Bench to Bedside.

Migraine is a ubiquitous neurologic disorder that afflicts more than 1 billion people worldwide. Recommended therapeutic strategies include the use of acute and, if needed, preventive medications. During the past 2 decades, tremendous progress has been made in better understanding the molecular mechanisms underlying migraine pathogenesis, which in turn has resulted in the advent of novel medications targeting signaling molecule calcitonin gene-related peptide or its receptor. Here, we provide an update on the rational use of pharmacotherapies for migraine to facilitate more informed clinical decision-making. We then discuss the scientific discoveries that led to the advent of new medications targeting calcitonin gene-related peptide signaling. Last, we conclude with recent advances that are being made to identify novel drug targets for migraine.

Activation of ATP-sensitive potassium channels triggers migraine attacks independent of calcitonin gene-related peptide receptors: a randomized placebo-controlled trial.

BACKGROUND: The present study aimed to investigate whether levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody. METHODS: In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0.05 mg/ml levcromakalim or placebo on two experimental days separated by at least one week (between days 8 and 21). The primary endpoint was the difference in the incidence of migraine attacks between levcromakalim and placebo during the 12-hour post-infusion period. RESULTS: In total, 16 participants completed the study. During the 12-hour observation period, 14 (88%) of 16 participants experienced migraine attacks after levcromakalim, compared to two (12%) after placebo (p < 0.001). The area under the curve for median headache intensity was greater after levcromakalim than placebo (p < 0.001). Levcromakalim elicited dilation of the superficial temporal artery during the first hour after infusion, a response absent following placebo (p < 0.001). CONCLUSIONS: The induction of migraine attacks via opening of KATP channels appears independent of CGRP receptor activation.Trial Registration: ClinicalTrials.gov, Identifier NCT05889442.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist.

BACKGROUND: The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis. METHODS: In vitro and in vivo studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using 125I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant in vivo potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats. RESULTS: Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats. CONCLUSIONS: Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.

Quantal size increase induced by the endocannabinoid 2-arachidonoylglycerol requires activation of CGRP receptors in mouse motor synapses.

In mouse motor synapses, the exogenous application of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG) increases acetylcholine (ACh) quantal size due to the activation of CB1 receptors and the stimulation of ACh vesicular uptake. In the present study, microelectrode recordings of miniature endplate potentials (MEPP) revealed that this effect of 2-AG is independent of brain-derived neurotrophic factor (BDNF) signaling but involves the activation of calcitonin gene-related peptide (CGRP) receptors along with CB1 receptors. Potentiation of MEPP amplitude in the presence of 2-AG was prevented by blockers of CGRP receptors and ryanodine receptors (RyR) and by inhibitors of phospholipase C (PLC) and Ca2+ /calmodulin-dependent protein kinase II (CaMKII). Therefore, we suggest a hypothetical chain of events, which starts from the activation of presynaptic CB1 receptors, involves PLC, RyR, and CaMKII, and results in CGRP release with the subsequent activation of presynaptic CGRP receptors. Activation of CGRP receptors is probably a part of a complex molecular cascade leading to the 2-AG-induced increase in ACh quantal size and MEPP amplitude. We propose that the same chain of events may also take place if 2-AG is endogenously produced in mouse motor synapses, because the increase in MEPP amplitude that follows after prolonged tetanic muscle contractions (30 Hz, 2 min) was prevented by the blocking of CB1 receptors. This work may help to unveil the previously unknown aspects of the functional interaction between ECs and peptide modulators aimed at the regulation of quantal size and synaptic transmission.

Pharmacological characterisation of erenumab, Aimovig, at two calcitonin gene-related peptide responsive receptors.

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) is involved in migraine pathophysiology. CGRP can signal through two receptors. The canonical CGRP receptor comprises the calcitonin receptor-like receptor and receptor activity-modifying protein 1 (RAMP1); the AMY1 receptor comprises the calcitonin receptor with RAMP1. Drugs that reduce CGRP activity, such as receptor antagonists, are approved for the treatment and prevention of migraine. Despite being designed to target the canonical CGRP receptor, emerging evidence suggests that these antagonists, including erenumab (a monoclonal antibody antagonist) can also antagonise the AMY1 receptor. However, it is difficult to estimate its selectivity because direct comparisons between receptors under matched conditions have not been made. We therefore characterised erenumab at both CGRP-responsive receptors with multiple ligands, including αCGRP and ßCGRP. EXPERIMENTAL APPROACH: Erenumab antagonism was quantified through IC50 and pKB experiments, measuring cAMP production. We used SK-N-MC cells which endogenously express the human CGRP receptor, and HEK293S and Cos7 cells transiently transfected to express either human CGRP or AMY1 receptors. KEY RESULTS: Erenumab antagonised both the CGRP and AMY1 receptors with an ~20-120-fold preference for the CGRP receptor, depending on the cells, agonist, analytical approach and/or assay format. Erenumab antagonised both forms of CGRP equally, and appeared to act as a competitive reversible antagonist at both receptors. CONCLUSION AND IMPLICATIONS: Despite being designed to target the CGRP receptor, erenumab can antagonise the AMY1 receptor. Its ability to antagonise CGRP activity at both receptors may be useful in better understanding the clinical profile of erenumab.

What to do with non-responders to CGRP(r) monoclonal antibodies: switch to another or move to gepants?

In this editorial we aim to provide potential therapeutic options in patients who do not benefit from treatment with CGRP(r) monoclonal antibodies. Based on current real-life studies and analysis of practical and economic aspects, we will analyze the potential benefits of changing CGRP-targeted treatment.

New drugs targeting calcitonin gene-related peptide for the management of migraines.

INTRODUCTION: Significant advances in migraine research have contributed to the development of new drugs for the treatment of migraine. Monoclonal antibodies (mAbs) against Calcitonin Gene-Related Peptide (CGRP) or its receptor and CGRP receptor antagonists (gepants) have been associated with a good safety profile and resulted in an overall efficacy in reducing the number of monthly migraine days both in episodic and chronic forms of migraine. AREAS COVERED: The results from main investigation studies (phase 2 or 3) of CGRP-targeting drugs (both anti-CGRP mAbs and gepants) are reported in this expert-opinion review. EXPERT OPINION: The introduction of new drugs targeting CGRP is a significant breakthrough in the migraine field, and represents a new generation of therapeutic agents that are available to manage migraine. The evaluation of efficacy and safety in the long-term follow-up and the development of trials comparing the available drugs could improve the current knowledge. The economic sustainability of these drugs remains to be clarified, and a cost-cutting campaign should be promoted based on the high burden of migraine.

Efficacy and safety of monoclonal antibodies targeting CGRP in migraine prevention. GRADE tables elaborated by the ad hoc working group of the International Headache Society.

OBJECTIVES: Grading of Recommendations, Assessment Development and Evaluation (GRADE) tables were created using a standardized and independent assessment of the efficacy and side effects of treatments with monoclonal antibodies (mAb) against calcitonin gene-related peptide (CGRP) or the CGRP receptor for the prevention of migraine. We hope to provide support for author groups writing national or regional treatment or management guidelines for migraine prevention. METHODS: We formulated patient/population, intervention, comparison and outcomes (PICO) questions for the efficacy and safety of mAb against CGRP or the CGRP-receptor for the prevention of migraine attacks. We performed a systematic literature research for randomized studies with eptinezumab, erenumab, fremanezumab and galcanezumab and a pooled analysis was done, using RevMan 5.4 software. For dichotomous outcomes we used risk ratio, and for continuous outcomes we used the mean difference to compare and summarize the evidence between groups. The evidence across studies, for each outcome, except serious adverse events, was assessed using GRADE evidence tables. Additionally, we report the serious adverse effects in the tables of the characteristics of the studies. RESULTS: All mAb are superior to placebo for the reduction in monthly migraine days (days in which a headache consistent with migraine occurred) in participants with episodic and chronic migraine. There are no major differences between the mAb. CONCLUSIONS: The GRADE evidence summary tables provided will support author groups to write treatment guidelines for the prevention of migraine with mAb.

Antinociceptive effect of the calcitonin gene-related peptide receptor antagonist BIBN4096BS in mice with bacterial cystitis.

Patients with urinary tract infections (UTIs) suffer from urinary frequency, urgency, dysuria, and suprapubic pain, but the mechanisms by which bladder afferents sense the presence of uropathogens and encode this information is not well understood. Calcitonin gene-related peptide (CGRP) is a 37-mer neuropeptide found in a subset of bladder afferents that terminate primarily in the lamina propria. Here, we report that the CGRP receptor antagonist BIBN4096BS lessens lower urinary tract symptoms and prevents the development of pelvic allodynia in mice inoculated with uropathogenic Escherichia coli (UPEC) without altering urine bacterial loads or the host immune response to the infection. These findings indicate that CGRP facilitates the processing of noxious/inflammatory stimuli during UPEC infection. Using fluorescent in situ hybridization, we identified a population of suburothelial fibroblasts in the lamina propria, a region where afferent fibers containing CGRP terminate, that expresses the canonical CGRP receptor components Calcrl and Ramp1. We propose that these fibroblasts, in conjunction with CGRP+ afferents, form a circuit that senses substances released during the infection and transmit this noxious information to the central nervous system.NEW & NOTEWORTHY Afferent C fibers release neuropeptides including calcitonin gene-related peptide (CGRP). Here, we show that the specific CGRP receptor antagonist, BIBN409BS, ameliorates lower urinary tract symptoms and pelvic allodynia in mice inoculated with uropathogenic E. coli. Using fluorescent in situ hybridization, we identified a population of suburothelial fibroblasts in the lamina propria that expresses the canonical CGRP receptor. Our findings indicate that CGRP contributes to the transmission of nociceptive information arising from the bladder.

The Anti-Calcitonin Gene-Related Peptide (Anti-CGRP) Antibody Fremanezumab Reduces Trigeminal Neurons Immunoreactive to CGRP and CGRP Receptor Components in Rats.

Treatment with the anti-CGRP antibody fremanezumab is successful in the prevention of chronic and frequent episodic migraine. In preclinical rat experiments, fremanezumab has been shown to reduce calcitonin gene-related peptide (CGRP) release from trigeminal tissues and aversive behaviour to noxious facial stimuli, which are characteristic pathophysiological changes accompanying severe primary headaches. To further decipher the effects of fremanezumab that underlie these antinociceptive effects in rats, immunohistochemistry and ELISA techniques were used to analyse the content and concentration of CGRP in the trigeminal ganglion, as well as the ratio of trigeminal ganglion neurons which are immunoreactive to CGRP and CGRP receptor components, 1-10 days after subcutaneous injection of fremanezumab (30 mg/kg) compared to an isotype control antibody. After fremanezumab treatment, the fraction of trigeminal ganglion neurons which were immunoreactive to CGRP and the CGRP receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) was significantly lowered compared to the control. The content and concentration of CGRP in trigeminal ganglia were not significantly changed. A long-lasting reduction in CGRP receptors expressed in trigeminal afferents may contribute to the attenuation of CGRP signalling and antinociceptive effects of monoclonal anti-CGRP antibodies in rats.