Calcitonin Gene-related Peptide Inhibitors Research Articles

Effect of CGRP inhibitors on interictal cerebral hemodynamics in individuals with migraine.

Calcitonin gene-related peptide (CGRP) plays an important role in cerebral vasodilation, so here we aim to quantify the impact of CGRP monoclonal antibody (mAb) therapy on cerebral hemodynamics. In 23 patients with chronic and episodic migraine, cerebral hemodynamic monitoring was performed (1) prior to and (2) 3-months into CGRP-mAb therapy. Transcranial Doppler monitored cerebral blood flow velocity (CBFv) in the middle cerebral artery (MCA) and posterior cerebral artery (PCA), from which cerebrovascular reactivity (CVR) and cerebral autoregulation (CA; Mx-index) were calculated. CA was similar off and on treatment, in the MCA (p = 0.42) and PCA (p = 0.72). CVR was also unaffected by treatment, in the MCA (p = 0.38) and PCA (p = 0.92). CBFv and blood pressure were also unaffected. The subgroup of clinical responders (>50% reduction in migraine frequency) exhibited a small reduction in MCA-CBFv (6.0 cm/s; IQR: 1.1-12.4; p = 0.007) and PCA-CBFv (8.9 cm/s; IQR: 6.9-10.3; p = 0.04). Dynamic measures of cerebrovascular physiology were preserved after 3 months of CGRP-mAb therapy, but a small reduction in CBFv was observed in patients who responded to treatment. Subgroup findings should be interpreted cautiously, but further investigation may clarify if CBFv is dependent on the degree of CGRP inhibition or may serve as a biomarker of drug sensitivity.

AMPK/MTOR/TP53 Signaling Pathway Regulation by Calcitonin Gene-Related Peptide Reduces Oxygen-Induced Lung Damage in Neonatal Rats through Autophagy Promotion.

Our previous studies indicated that calcitonin gene-related peptide (CGRP) alleviates hyperoxia-induced lung injury and suggested the possible involvement of autophagy in this process. Herein, we aimed to further explore the potential involvement of tumor protein p53 (TP53) and autophagy in the mode of action of CGRP against hyperoxia-induced lung injury in vitro and in vivo. The study conducted tests on type II alveolar epithelial cells (AECII) and rats that were subjected to hyperoxia treatment or combined treatment of hyperoxia with CGRP, CGRP inhibitor, rapamycin (an autophagy agonist), 3-methyladenine (3-MA, an autophagy inhibitor), TP53 silencing/inhibitor (pifithrin-α), or expression vector/activator (PRIMA-1 (2,2-bis(hydroxymethyl)-3-quinuclidinone)) and their corresponding controls. We found that oxidative stress, apoptosis, and autophagy were all increased by hyperoxia treatment in vitro. However, treating AECII cells with CGRP reversed hyperoxia-induced oxidative stress and apoptosis but further promoted autophagy. In addition, the combined treatment with rapamycin or TP53 silencing with CGRP promoted the effect of CGRP, while contrary results were obtained with combined therapy with 3-MA or TP53 overexpression. In vivo, the number of hyperoxia-induced autophagosomes was promoted in the lung tissue of neonatal rats. Furthermore, hyperoxia increased the expression levels of AMP-activated protein kinase (AMPK) alpha 1 (also known as protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1)) but inhibited TP53 and mechanistic target of rapamycin (MTOR); these expression trends were regulated by CGRP treatment. In conclusion, we showed that CGRP can attenuate hyperoxia-induced lung injury in neonatal rats by enhancing autophagy and regulating the TP53/AMPK/MTOR crosstalk axis.

Atogepant (Qulipta)


 CADTH recommends that Qulipta be reimbursed by public drug plans for the prevention of episodic migraine, if certain conditions are met.
 Qulipta should only be reimbursed for adults with episodic migraine, according to the criteria used by public drug plans for other calcitonin gene-related peptide (CGRP) inhibitors for the prevention of episodic migraine.
 In addition to following the pre-existing criteria for other CGRP inhibitors, Qulipta should not be used in combination with other CGRP inhibitors. Qulipta should only be reimbursed if the cost is reduced such that the total treatment cost of Qulipta does not exceed the total treatment cost of the least costly CGRP inhibitor reimbursed for the preventive treatment of episodic migraine in adults.

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

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

Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain

Migraine and neuropathic pain (NP) are both painful, disabling, chronic conditions which exhibit some symptom similarities and are thus considered to share a common etiology. The calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant the search for more effective therapeutic targets for pain management. This scoping review focuses on human studies of common pathogenic factors in migraine and NP, with reference to available preclinical evidence to explore potential novel therapeutic targets. CGRP inhibitors and monoclonal antibodies alleviate inflammation in the meninges; targeting transient receptor potential (TRP) ion channels may help prevent the release of nociceptive substances, and modifying the endocannabinoid system may open a path toward discovery of novel analgesics. There may exist a potential target in the tryptophan-kynurenine (KYN) metabolic system, which is closely linked to glutamate-induced hyperexcitability; alleviating neuroinflammation may complement a pain-relieving armamentarium, and modifying microglial excitation, which is observed in both conditions, may be a possible approach. Those are several potential analgesic targets which deserve to be explored in search of novel analgesics; however, much evidence remains missing. This review highlights the need for more studies on CGRP modifiers for subtypes, the discovery of TRP and endocannabinoid modulators, knowledge of the status of KYN metabolites, the consensus on cytokines and sampling, and biomarkers for microglial function, in search of innovative pain management methods for migraine and NP.

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.

Alopecia signals associated with calcitonin gene-related peptide inhibitors in the treatment or prophylaxis of migraine: A pharmacovigilance study.

Although rarely observed in clinical trials, alopecia has been reported in migraine patients treated with calcitonin gene-related peptide (CGRP) inhibitors during the postmarketing period. This study sought to assess whether CGRP inhibitors are associated with disproportionate alopecia reporting relative to other drugs including those indicated for migraine treatment or prophylaxis in a real-world setting. Retrospective disproportionality analysis. Spontaneous adverse events reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) through the fourth quarter of 2021. Thirteen Medical Dictionary for Regulatory Activities preferred terms were used to define alopecia cases in FAERS. Disproportionality was measured by calculating proportional reporting ratios (PRR) and 95% confidence intervals (CI). A PRR >2.0 with a lower 95% CI >1.0 and ≥3 cases was considered a positive signal. During the study period, CGRP inhibitors were reported as suspect products in 55,994 adverse events including 1827 (3.26%) alopecia cases. Compared with all other drugs across FAERS, alopecia signals were detected for the collective CGRP inhibitor class (PRR 4.06; 95% CI 3.88-4.25) and fremanezumab (PRR 5.42; 95% CI 4.66-6.29), erenumab (PRR 4.29; 95% CI 4.05-4.54), galcanezumab (PRR 4.11; 95% CI 3.78-4.48), and eptinezumab (PRR 2.06; 95% CI 1.25-3.40) individually. CGRP inhibitors were consistently associated with alopecia signals relative to triptans (PRR 12.46; 95% CI 10.22-15.18) and celecoxib (PRR 3.50; 95% CI 3.19-3.83), but not in comparison with anticonvulsants, onabotulinumtoxinA, or beta-blockers across analyses. Within the CGRP inhibitor class, an alopecia signal was observed for biologics relative to drugs (PRR 6.11; 95% CI 3.79-9.87). Significant alopecia signals were identified for CGRP inhibitors relative to all other drugs and certain comparator migraine therapies based on adverse events reported to FAERS, with CGRP-targeting biologics primarily driving disproportionate reporting. Future observational data will be necessary to better characterize the potential association between real-world use of CGRP inhibitors and incident alopecia in patients with migraine.

Management of Migraine: An Overview

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

Erenumab Decreases Headache-Related Sick Leave Days and Health Care Visits: A Retrospective Real-World Study in Working Patients with Migraine.

IntroductionThe prevalence of migraine is highest among working age individuals, and this disease is associated with an increased number of sick leaves and health care visits, as well as lost productivity. Erenumab, the first monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) pathway, is effective in decreasing the monthly number of migraine days, but evidence of its impact on the number of sick leave days and health care visits in patients with migraine is limited.MethodsThis retrospective registry study focused on occupationally active patients with migraine treated with erenumab at a Finnish private health care provider, Terveystalo. Erenumab responders, defined as patients who had at least two unique prescriptions of erenumab and no prescription of other CGRP inhibitor (CGRPi), were followed for 12 months prior to and after erenumab treatment initiation (index), and the change in the number of headache-related and all-cause sick leave days, health care visits and prescriptions for other medications during this period were assessed from the registry data. The same outcomes were assessed in an age- and sex-matched control group of migraine patients not receiving CGRPi to control for potential changes in patient behavior and health care practices during the COVID-19 pandemic.ResultsAltogether, 162 patients who were entitled to employer-sponsored health care received erenumab and met the 12-month follow-up requirements. In the responder group (n = 82; 50.1%) headache-related sick leave days were reduced by 73.9% (p = 0.035) and health care visits by 44.6% (p < 0.001) in the 12 months following treatment initiation compared to the period of 12 months prior to treatment. All-cause sick leave days were reduced by 19.4% and all-cause health care visits by 13.5%, but these changes were not statistically significant. Triptan prescriptions decreased by 30.4% (p = 0.012) and other prophylactic treatments by 31.5% (p = 0.004). No significant changes were observed in the corresponding outcomes in the migraine control group during the same period.ConclusionsThe results of this registry study suggest that in addition to the effect on the monthly number of migraine days documented in clinical trials, erenumab can significantly reduce the number of headache-related sick leave days and health care visits in employed patients with migraine managed in routine clinical practice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00303-x.

Biologics for episodic and chronic migraines.

What is the efficacy of calcitonin gene-related peptide (CGRP) inhibitors in migraine prophylaxis? Treating 5 to 8 patients with CGRP inhibitors will lead to 1 patient having at least a 50% reduction in monthly migraine days (MMD) compared with placebo. From baseline, a decrease of 1 to 2 MMD may

CGRP Inhibitors and Oxidative Stress Biomarkers in Resistant Migraine: A Real-Life Study with Erenumab, Fremanezumab, and Galcanezumab

Patients with high-frequency resistant migraine and medication-overuse headache are still the main clinical challenge in tertiary headache centers. The approval of targeted antibodies against the calcitonin gene-related peptide (CGRP) and its receptor represents a powerful instrument. In this study, we observed how biological and clinical features of resistant migraineurs responded to erenumab, fremanezumab, or galcanezumab. We found a reduction in advanced oxidation protein products (AOPP) as a biomarker of improved redox state after six months of treatment. We also found that treatment efficacy was precocious and maintained with high individual responder rates. In particular, seven out of ten patients achieved a reduction of 50% from the baseline at three months, which was maintained at six months, while about one out of our patients experienced a 75% reduction in headache frequency from the first month of treatment. The migraine disability assessment (MIDAS) and the associated fatigue, anxiety, and sleep quality also significantly improved. The allodynia symptom dropped from moderate/severe to mild/absent as a sign of central sensitization reduction. Our study confirmed the safety and efficacy of CGRP inhibition in real-life, high-challenging patients. Additional evidence is needed to understand the role of oxidative stress as a migraine biomarker.

Effectiveness of dual migraine therapy with CGRP inhibitors and onabotulinumtoxinA injections: case series.

Clinical trials for calcitonin gene-related peptide (CGRP) inhibitors excluded the concomitant use of onabotulinumtoxinA; thus, there is a lack of efficacy and safety data of the combined therapies. Our study aims to examine the effectiveness of CGRP inhibitors with onabotulinumtoxinA by evaluating migraine reductions in headache days and severity. Seventeen patients with chronic migraines were identified who had a partial or poor response to onabotulinumtoxinA, and were placed on dual therapy with a CGRP inhibitor. Patients' initial headache days and severity ratings were compared to final values taken 1-6months after adding the CGRP inhibitor to their treatment regime. Comparisons between headache days and severity ratings prior to and during dual treatment were performed utilizing the Kruskal-Wallis test. The significance was set at p < 0.05. Of 17 patients (16F/1M), n = 9 were taking fremanezumab, n = 4 were taking erenumab, and n = 4 were taking galcanezumab. Patients' average headache days per month was reduced from 27.6 ± 4.8 initially to 18.6 ± 9.4 post-treatment (p = 0.00651), and their average pain level was reduced from 8.4 ± 1.4 out of 10 to 5.4 ± 2.5 (p = 0.00074). No serious adverse side effects were reported from patients on dual therapy. Patients with suboptimal response to onabotulinumtoxinA may benefit from CGRP inhibitors' addition to their migraine regimens. Placebo-controlled randomized studies are advised to corroborate this finding.

Abstract P643: Incidence of Ischemic Stroke Among Migraineurs on Calcitonin Gene-Related Peptide Inhibitors

Introduction: Migraine is common and often disabling. Recent research has focused on a new class of treatments targeting the pain-signaling molecule calcitonin-gene-related peptide (CGRP). CGRP inhibitors are the first preventive therapies designed specifically for migraine. However, CGRP also induces vasodilation, and plays a role in cerebral blood flow autoregulation. The clinical cerebrovascular effects of long-term blockade of CGRP are not yet known. Methods: We analyzed a retrospective cohort of migraine patients from a large administrative dataset in the United States (OPTUM) that covers patients with commercial insurance and Medicare Advantage, during 2018 and 2019, using ICD-10 codes for all types of migraines. Migraine patients were divided into two groups based on their use of CGRP inhibitors (erenumab, fremanezumab, galcanezumab). We determined the incidence of stroke during 2018 and 2019 among both groups. For the group of migraine patients who used CGRP inhibitors, we focused on the incidence of stroke after these medications were initiated. Results: We identified 646,404 migraine patients; 18, 692 (2.9%) of them had used a CGRP inhibitor. Among the users of CGRP inhibitors, 86% were females, and 58% of patients were in the 41 to 65-year-old range. The average time of follow-up was 197 days after initiation of the medication. A total of 1.3 % of patients who used CGRP inhibitors had an ischemic stroke during the follow-up period versus 2.4% of patients who did not use CGRP inhibitors. The lower rate of stroke in the CGRP antibody group was found in both sexes and all age groups. Conclusions: These preliminary results suggest that CGRP inhibitors are not associated with a higher frequency of stroke in the initial months of use. This could be related to the avoidance of these medications in patients with known cardiovascular risk factors. Further analyses will be completed on vascular risk factor incidence in these populations as well as multiple regression. Prospective, long term studies are needed to confirm these results.

Understanding the migraine treatment landscape prior to the introduction of calcitonin gene-related peptide inhibitors: Results from the Assessment of TolerabiliTy and Effectiveness in MigrAINe Patients using Preventive Treatment (ATTAIN) study.

BackgroundCalcitonin gene‐related peptide (CGRP) inhibitors were introduced in the United States (US) in 2018. To understand the changing patterns of preventive treatment following the introduction of these new agents, we must first characterize the patterns which preceded their introduction.ObjectiveTo characterize the burden, unmet need, and treatment patterns in patients with migraine initiating preventive migraine medications before the introduction of CGRP inhibitors in the US.MethodsBetween March 2016 and October 2017, we enrolled episodic (EM) and chronic migraine (CM) patients initiating or changing preventive treatment at primary care or neurology clinic visits in the US, in a real‐world observational study using a prospective cohort design. At baseline and monthly thereafter for 6 months, we collected data from study sites and patients on migraine frequency, treatment modifications, migraine impact on functioning, and work productivity for a descriptive analysis of migraine patient experience and treatment patterns.ResultsFrom the sample of 234 completers, 118 had EM (50.4%) and 116 had CM (49.6%). Mean age at enrollment was 41 years (SD = 12) and mean age at first migraine diagnosis was 22 years (SD = 11). Most participants were females (n = 204/234; 87.2%) and white (n = 178/234; 76.1%). The majority (n = 164/234; 70.1%) had not used preventive migraine treatment in the 5 years prior to enrollment (treatment naïve). At baseline, mean monthly migraine days were 9.6 days (SD = 5.0) for the preventive treatment naïve group and 12.4 days (SD = 7.0) for treatment experienced patients. The majority had severe Migraine Disability Assessment (Grade IV, total score ≥21), including 67.1% (n = 110/164) of the preventive treatment naïve and 77.1% (n = 54/70) of the preventive treatment experienced patients. Headache Impact Test total scores indicating severe impairment (score >59) occurred in 88.4% (n = 145/164) of the treatment naïve and 88.6% (n = 62/70) of treatment experienced patients. Mean work productivity loss as measured by the Work Productivity and Activity Impairment questionnaire in the subsample of employed patients was 53.3% loss. The most used acute medications at baseline were nonsteroidal anti‐inflammatory agents (n = 124/234; 53.0%), acetaminophen‐based products (n = 112/234; 47.9%), and triptans (n = 105/234; 44.9%). The most commonly initiated preventive treatments were topiramate (n = 100/234; 42.7%), tricyclic antidepressants (n = 39/234; 16.7%), beta‐blockers (n = 26/234; 11.1%), and onabotulinumtoxinA (n = 24/234; 10.3%). Over the 6‐month follow‐up period, almost half of patients (n = 116/234, 49.6%) modified their preventive treatment and discontinued treatment (n = 88/312 total modifications; 28.2%) or modified their pattern of use by increasing, decreasing, or skipping doses (n = 224/312 total modifications; 71.8%), often without seeking medical advice. Avoiding side effects was the main reason reported among patients who discontinued (n = 52/88; 59.1%), decreased frequency or dose (n = 37/89; 41.6%), and skipped doses (n = 29/86; 33.7%). Perceived lack of efficacy was another frequent reason reported among those who discontinued (n = 20/88; 22.7%), decreased frequency or dose (n = 15/89; 16.9%), and skipped doses (n = 18/86; 20.9%). Despite initiation of preventive treatment and improvements observed in number of headache and migraine days, migraine patients continued to experience substantial disability, headache impact, and reduced productivity throughout the 6‐month follow‐up period.ConclusionsPrior to 2018, the burden of migraine was high for patients initiating preventive treatments. Despite having more than 9 days of migraine per month on average, the majority (70.1%) of patients initiating prevention had been treatment naïve, indicating underuse of preventive treatments. The preventive treatments used in this study were poorly tolerated and were reported by patients to lack efficacy, resulting in suboptimal adherence. The high discontinuation rates suggest that the preventive medications being offered during the period of the study did not meet the treatment needs of patients. In addition, the decisions by about half of patients to alter their prescribed treatment plan without consulting their provider can pose substantial health risks. These findings pertain to the broad set of preventive treatments initiated in this study and do not support inferences about individual preventive treatments, due to limitations in sample size. These findings suggest the need for more effective and better tolerated preventive treatment options.

Tolerability of eptinezumab in overweight, obese or type 1 diabetes patients.

IntroductionIn addition to its role in the pathogenesis of migraine, calcitonin gene‐related peptide (CGRP) is implicated in the regulation of insulin secretion. However, there are limited data on the use of CGRP inhibitor monoclonal antibodies in individuals who are overweight/obese and those with diabetes.MethodsTwo randomized, double‐blind, placebo‐controlled trials were conducted to assess the safety and metabolic effects of eptinezumab in non‐migraine overweight/obese patients (study 1) and patients with type 1 diabetes (T1D; study 2). The primary end‐point in overweight/obese patients was safety and changes in basal metabolic rate (BMR), defined as the energy expenditure during the fasting and resting states. In patients with T1D, the primary end‐points were safety and insulin sensitivity as assessed by the bodyweight and insulin concentration corrected glucose infusion rate (M/I).ResultsA total of 24 patients were enrolled in study 1, and 21 patients were enrolled in study 2. In overweight/obese patients, there was no significant difference in the least squares (LS) mean change in BMR between the eptinezumab‐ and placebo‐treated patients from baseline to day 7 (6.4 vs −25.2 Kcal/day; LS mean difference 31.6 [95% confidence interval −90.6, 153.8]). In patients with T1D, there was no significant difference in insulin sensitivity between the eptinezumab and placebo groups. Eptinezumab was well tolerated in both studies with a similar rate of adverse events between treatment groups, and no new safety signals were identified.ConclusionEptinezumab was well tolerated and not associated with adverse metabolic effects in patients who were overweight/obese or had T1D, providing ongoing support for the use of eptinezumab in these subgroups of patients with migraine.

Prophylactic Treatment of Pediatric Migraine: Is There Anything New in the Last Decade?

Migraine is a frequent and very disabling disease, especially at pediatric age. Despite this, there are few controlled data on the prophylactic treatment of primary headaches in this category of age. Given that the recently introduced calcitonin gene-related peptide (CGRP) inhibitors (CGRP-r) are still limited to adulthood, there is no drug with exclusive indication for migraine treatment in pediatric age. This raises several limitations in terms of adherence and effectiveness of the therapy. Moreover, the scenario is complicated by placebo response, which is larger in children and adolescents than in adults and often leads to an improvement in the attack frequency even in absence of any active pharmacological treatment. Our aim was to investigate the real evidence concerning the prophylactic therapy of pediatric migraine by reviewing the clinical studies published between 2010 and 2019.

(293) Calcitonin Gene-Related Peptide Inhibitor: Role in Treatment of Hemicrania Continua, with Potential Benefit in Controlling Diarrhea

Erenumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody, approved recently for prevention of episodic and chronic migraine. CGRP is involved in the pathogenesis of migraine, and erenumab works by blocking the CGRP receptors. Common side effects include injection site reactions and constipation. Here we present a patient with hemicrania continua (HC) who responded well to erenumab, while the medication additionally treated her debilitating diarrhea. A 61-year-old female with history of intractable, refractory, chronic, daily, left hemicranial headaches with migrainous features associated with restlessness, but without cranial autonomic symptoms, was diagnosed to have HC with 100 % response to high dose indomethacin trial. She was maintained on low dose indomethacin due to severe acid reflux, along with topiramate, and greater occipital nerve cryoanalgesia, with partial relief. The patient had additionally been complaining of chronic daily watery diarrhea of unknown etiology with intolerance to solids and liquids for 1 year prior to staring the indomethacin. She complained of about 6 loose stools per day. The patient was started on erenumab 70 mg subcutaneously and re-evaluated after 4 weeks. She reported 50% improvement in headache frequency and intensity one week after starting the medication, with no side effects. Additionally, four days after erenumab was started she noted that her stools appeared more formed and her bowel movements reduced in frequency to once daily. She denied constipation. We plan to take her off indomethacin if the favorable response continues. CGRP inhibitors are a new class of drugs that appear to show great promise in migraine prophylaxis with minimal side effects. We believe that this case demonstrates potential benefit of erenumab in other headache syndromes such as HC, as well as highlighting its effectiveness in treating diarrhea. Further studies need to be done to ascertain the full potential of these drugs.

Erenumab: A First-in-Class Monoclonal Antibody for Migraine Prevention.

Objective: To review the pharmacology, efficacy, and safety of the calcitonin gene-related peptide (CGRP) inhibitor erenumab for migraine preventive therapy. Data Sources: A MEDLINE/PubMed search (January 2000 to January 2019) was conducted using the keywords erenumab-aooe, erenumab, migraine, migraine prophylaxis, migraine prevention, and chronic migraine. Additional articles were identified by hand from references. Study Selection and Data Extraction: We included English-language articles (excluding poster presentations) evaluating erenumab pharmacology, efficacy, or safety in humans for migraine prevention. Data Synthesis: Erenumab is a CGRP inhibitor that inhibits vasodilation in response to acute migraines, which decreases pain perception during the migraine. Erenumab efficacy and safety has only been compared with placebo, but its reduction in monthly migraine days (MMDs) and medication response (≥50% reduction in MMDs) are comparable to current recommended off-label therapies for migraine prevention in short-term treatment studies. Additionally, erenumab is associated with low adverse event burden with no difference found compared with placebo per published clinical trials. Relevance to Patient Care and Clinical Practice: Erenumab is the first medication approved in the United States for the prevention of migraines in adults. No head-to-head data are available, but existing data suggest that erenumab is at least as effective as current off-label products and with reduced adverse effects. Conclusion: Erenumab is an effective once-monthly injectable agent for migraine prevention in patients with chronic or episodic migraine. It is also effective for patients who have previously failed migraine preventive therapy. Erenumab has a favorable adverse effect profile, which may improve patient adherence.

TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation

The skin is highly sensitive to the chemical warfare agent in mustard gas, sulfur mustard (SM) that initiates a delayed injury response characterized by erythema, inflammation and severe vesication (blistering). Although SM poses a continuing threat, used as recently as in the Syrian conflict, no mechanism-based antidotes against SM are available.Recent studies demonstrated that Transient Receptor Potential Ankyrin 1 (TRPA1), a chemosensory cation channel in sensory nerves innervating the skin, is activated by SM and 2‐chloroethyl ethyl sulfide (CEES), an SM analog, in vitro, suggesting it may promote vesicant injury.Here, we investigated the effects of TRPA1 inhibitors, and an inhibitor of Calcitonin Gene Related Peptide (CGRP), a neurogenic inflammatory peptide released upon TRPA1 activation, in a CEES-induced mouse ear vesicant model (CEES-MEVM). TRPA1 inhibitors (HC-030031 and A-967079) and a CGRP inhibitor (MK-8825) reduced skin edema, pro-inflammatory cytokines (IL-1β, CXCL1/KC), MMP-9, a protease implicated in skin damage, and improved histopathological outcomes.These findings suggest that TRPA1 and neurogenic inflammation contribute to the deleterious effects of vesicants in vivo, activated either directly by alkylation, or indirectly, by reactive intermediates or pro-inflammatory mediators. TRPA1 and CGRP inhibitors represent new leads that could be considered for validation and further development in other vesicant injury models.

Calcitonin Gene-Related Peptide Receptor Antagonists for Migraine Prophylaxis.

Prophylaxis is recommended for patients who experience frequent migraines. Because current drugs used for prophylaxis are not 100% effective and cause adverse effects that affect compliance, new strategies have been studied to prevent headaches. One new pharmacologic strategy is to use an inhibitor of the calcitonin gene-related peptide (CGRP). As a class, the CGRP receptor inhibitors have reduced monthly migraine days and are well tolerated. This article will briefly review CGRP inhibitors in development.