Case reports: Could sexual dysfunction in women with migraine be a side effect of CGRP inhibition?

BACKGROUND: The development and approval of antibodies targeting calcitonin gene-related peptide or its receptor mark a revolutionary era for preventive migraine treatment. Real-world evidence sheds light on rare, stigmatized or overlooked side effects of these drugs. One of these potential side effects is sexual dysfunction. CASE REPORTS: We present two cases of one 42-year-old and one 45-year-old female patient with chronic migraine who both reported sexual dysfunction as a possible side effect of treatment with galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide. DISCUSSION: As calcitonin gene-related peptide is involved in vaginal lubrication as well as genital sensation and swelling, inhibiting the calcitonin gene-related peptide pathway may lead to sexual dysfunction as a potential side effect. CONCLUSION: Sexual dysfunction in female migraine patients might be a rare and overlooked side effect of monoclonal antibodies targeting the calcitonin gene-related peptide pathway. Considering the discomfort and stigma surrounding both migraine and sexual dysfunction, we advocate for an open attitude and awareness among clinicians toward such side effects.

Sustained response to atogepant in episodic migraine: post hoc analyses of a 12-week randomized trial and a 52-week long-term safety trial.

BACKGROUND: Atogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment. METHODS: These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated. RESULTS: In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8-81.1% following an initial ≥50% response, 47.3-61.9% following an initial ≥75% response, and 34.8-41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4. CONCLUSION: Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).

MicroRNA profiling in women with migraine: effects of CGRP-targeting treatment.

BACKGROUND: Migraine lacks biomarkers that can trace the biological pathways of the disease and predict the effectiveness of treatments. Monoclonal antibodies targeting calcitonin gene-related peptide pathway - including erenumab - offer the opportunity of investigating potential migraine biomarkers due to their specific mechanism of action in preventing both episodic (EM) and chronic (CM) migraine. Our study aims at evaluating the expression levels of circulating microRNAs (miRNAs) according to migraine type, before and after treatment with erenumab and based on treatment response, in order to identify miRNAs with potential role as epigenetic biomarkers. METHODS: The study included women aged 25-50 years with EM or CM treated with erenumab according to clinical indications. MiRNAs expression levels were assessed before (baseline) and after a 16-week treatment with erenumab, 140 mg every four weeks (post-treatment). An extensive miRNAs profiling was performed by qRT-PCR in small, pooled groups of ≤ 8 women each, classified according to migraine frequency (EM and CM) and the degree of response to erenumab. The expression levels of selected miRNAs were also validated using single miRNA assays in each woman with EM and CM. RESULTS: During the study, 36 women with migraine (19 with EM and 17 with CM) out of 40 who were initially screened, performed the assessment of miRNA expression at baseline and post-treatment, Erenumab treatment significantly improved migraine burden in both EM and CM. MiRNA profiling revealed differential expression levels of a wide set of miRNAs (hsa-let-7d-3p, hsa-miR-106b-3p, hsa-miR-122-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-16-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-25-3p, hsa-miR-29b-2-5p, hsa-miR-326, miR-363-3p, hsa-miR-424-5p, hsa-miR-485-3p, hsa-miR-532-5p, hsa-miR-543, hsa-miR-629-5p, hsa-miR-660-5p, hsa-miR-92a-3p) depending on treatment response. Among them, single miRNA assays confirmed the progressive decrease of hsa-miR-143-3p expression levels in relation to increasing response to erenumab in women with EM (7 with low, 6 with medium, and 6 with high response; p = 0.02). Additionally, single assays showed higher hsa-miR-34a-5p and hsa-miR-382-5p expression levels at baseline in women with CM compared with those with EM (p = 0.0002 and p = 0.0007, respectively), as well as their expression level decrease in women with CM from baseline to follow-up (p = 0.04 and p = 0.02, respectively). CONCLUSIONS: Our study suggests that targeting the CGRP pathway in migraine changes the expression levels of certain miRNAs. These miRNA levels are linked to the levels of response to CGRP receptor blockage. Future research challenges include assigning specific functions to the modulated miRNAs to unravel pathways modulated by the disease and the treatment. TRIAL REGISTRATION: The study was registered in clinicaltrials.gov with code NCT04659226 and in the Novartis database with code CAMG334AIT05T.

Effectiveness and tolerability of eptinezumab in treating patients with migraine resistant to conventional preventive medications and CGRP (receptor) antibodies: a multicentre retrospective real-world analysis from Germany.

BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. METHODS: We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). RESULTS: After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects. CONCLUSIONS: The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results.

Reduction of plasma CGRP levels in migraine patients treated with erenumab or galcanezumab. / Reducción de los niveles plasmáticos de CGRP en pacientes con migraña tratados con erenumab o galcanezumab.

TITLE: Reducción de los niveles plasmáticos de CGRP en pacientes con migraña tratados con erenumab o galcanezumab.

Zavegepant for Acute Treatment of Migraine: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: Evaluate the safety and efficacy of zavegepant (BHV-3500), a recently approved nasal spray containing a third-generation calcitonin gene-related peptide receptor antagonist, for treating acute migraine attacks. METHODS: A comprehensive search was conducted across various databases up to 06/26/2023 to identify relevant randomized clinical trials (RCTs) on zavegepant's efficacy and safety in treatment of acute migraine attacks. Primary outcome: freedom from pain at 2 hours postdose. Safety outcomes were evaluated based on adverse events (AEs), with zavegepant 10 mg and placebo groups compared for incidence of AEs. RESULTS: Two RCTs, involving 2061 participants (1014 receiving zavegepant and 1047 receiving placebo), were quantitatively analyzed. An additional trial was included for qualitative synthesis. Zavegepant 10 mg exhibited a significantly higher likelihood of achieving freedom from pain at 2 hours postdose compared with the placebo group (risk ratio [RR] 1.54, 95% confidence interval [CI] 1.28 to 1.84). It also showed superior relief from the most bothersome symptoms at 2 hours postdose compared with placebo (RR 1.26, 95% CI 1.13 to 1.42). However, the zavegepant 10 mg group experienced a higher incidence of AEs compared with placebo (RR 1.78, 95% CI 1.5 to 2.12), with dysgeusia being the most reported AE (RR 4.18, 95% CI 3.05 to 5.72). CONCLUSION: Zavegepant 10 mg is more effective than placebo in treating acute migraine attacks, providing compelling evidence of its efficacy in relieving migraine pain and most bothersome associated symptoms. Further trials are necessary to confirm its efficacy, tolerability, and safety in diverse clinic-based settings with varied patient populations.

A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine.

BACKGROUND: The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. METHODS: This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN). RESULTS: Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified. CONCLUSIONS: Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.Trial registration: Clinicaltrials.gov: NCT03266588.

An update on migraine: Current and new treatment options.

ABSTRACT: Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both.

Efficacy and Safety of Erenumab in Participants With Episodic Migraine in Whom 2-4 Prior Preventive Treatments Had Failed: LIBERTY 3-Year Study.

BACKGROUND AND OBJECTIVES: The LIBERTY study assessed the efficacy and safety of erenumab in participants with episodic migraine (EM) and 2-4 prior preventive treatment failures. The results have been presented after 3 years of erenumab exposure in its open-label extension phase (OLEP). METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could enter the OLEP and receive 140 mg of erenumab once monthly for 3 years. The main outcomes included the proportion of participants achieving ≥50% reduction in monthly migraine days (MMDs), the mean MMD change from baseline, and tolerability and safety. RESULTS: Overall, 240/246 (97.6%) participants entered the OLEP and 168/240 (70.0%) completed the study (85/118 continuing erenumab [n = 1 lost during follow-up]; 83/122 switching from placebo [n = 2 lost during follow-up]). In the overall population, 79/151 participants (52.3%) with valid data points achieved ≥50% reduction in MMDs at week 168 (i.e., responders). In the continuous erenumab group, 35/117 participants (29.9%) were ≥50% responders at week 12 of the DBTP and 26/35 (74.3%) remained ≥50% responders in at least half of OLEP visits. Of the 82/117 participants (70.1%) not achieving responder status at week 12 in the continuous erenumab group, 17/82 (20.7%) converted to ≥50% responders in at least half of OLEP visits. Of 103/120 participants (85.8%) not achieving responder status at week 12 in the placebo-erenumab group, 42/103 (40.8%) converted to ≥50% responders in at least half of OLEP visits after switching to erenumab. Overall, the mean (SD) MMD change from baseline showed sustained improvement over 3 years (-4.4 [3.9] days at week 168). The most common treatment-emergent AEs (per 100 person-years) were nasopharyngitis (28.8), influenza (7.5), and back pain (5.8). Overall, 9.6% (3.9 per 100 person-years) and 6.7% (2.7 per 100 person-years) of participants reported events of treatment-emergent hypertension and constipation, respectively. The safety and tolerability profile remained consistent with earlier studies. DISCUSSION: Erenumab (140 mg) showed sustained efficacy over 3 years in participants with EM and 2-4 prior preventive treatment failures. No new safety signals were observed. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03096834.

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.

Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies in Migraine: Focus on Drug Interactions.

Calcitonin gene-related peptide neurotransmission was the target for recent development of monoclonal antibodies that effectively prevent attacks of both episodic and chronic migraine. The aim of this narrative review was to offer deeper insight into drug-drug, drug-food and drug-disease interactions of monoclonal antibodies approved for prevention of migraine attacks. For this narrative review, relevant literature was searched for in MEDLINE and Google Scholar databases, covering the 1966-2023 and 2006-2023 periods, respectively. The ClinicalTrials.gov database was also searched for relevant clinical studies whose results had not been published previously in medical journals, covering 2000-2023. Monoclonal antibodies (erenumab, fremanezumab, galcanezumab and eptinezumab) augment prophylactic action of gepants and onabotulinumtoxin A and somewhat increase efficacy of triptans used to abort migraine attacks; however, their adverse reactions may also be augmented. Pharmacokinetic interactions and interactions in general with drugs used for other indications except migraine are negligible, as are drug-food interactions. However, monoclonal antibodies may worsen diseases with already weakened CGRP neurotransmission, Raynaud phenomenon and constipation. Monoclonal antibodies used for prevention of migraine do not engage in significant pharmacokinetic interactions with other drugs; however, they do engage in pharmacodynamic interactions with other anti-migraine drugs, additively augmenting their prophylactic action, but also increasing frequency and severity of adverse reactions, which are a consequence of the CGRP neurotransmission interruption.

Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial.

Importance: Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. Objective: To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. Design, Setting, and Participants: The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Interventions: Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). Main Outcomes and Measures: The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. Results: A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Conclusions and Relevance: Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. Trial Registration: ClinicalTrials.gov Identifier: NCT03927144.

Evaluation of outcomes of calcitonin gene-related peptide (CGRP)-targeting therapies for acute and preventive migraine treatment based on patient sex.

BACKGROUND: Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. METHODS: We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. RESULTS: In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: -2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group.Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

CGRP receptor antagonists (gepants).

Small molecule calcitonin gene-related peptide (CGRP) receptor antagonists are commonly referred to as gepants. The first generation of gepants provided the first line of evidence of CGRP-mediated antimigraine medication in 2004-2011. However, further development was halted due to either lack of oral availability or concerns of hepatotoxicity. More than 15 years later, the first second generation of gepants, ubrogepant and rimegepant, are now approved for the acute treatment of migraine with or without aura. Furthermore, a novel and promising third-generation gepant, zavegepant, has recently been approved as well. In this chapter, we review the evidence supporting the effectiveness, safety, and tolerability of gepants for the acute treatment of migraine. Furthermore, we discuss the potential limitations and future directions of this class of migraine-specific medication.

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.

Update on gepants for the treatment of chronic migraine.

Chronic migraine (CM) is a profoundly debilitating condition that has detrimental clinical and social outcomes. Over the past two decades, novel small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, known as gepants, and CGRP monoclonal antibodies (mAbs) have been developed, ushering in a new era of migraine-specific treatment. In this review, we discuss the literature investigating the role of gepants for the treatment of CM. Numerous completed and ongoing clinical studies have conclusively demonstrated the safety, tolerability, and efficacy of several gepants for the acute treatment of migraine. However, preventive trials involving gepants have focused on patients with episodic migraine, with atogepant being the only gepant approved for CM prevention by the US Food and Drug Administration at the time of writing. Although some preliminary positive results have been reported, further research is still required to achieve additional advancements in the future. In summary, the effectiveness of gepants for treating individuals with CM are highly expected. This review highlights the development and current progress of gepants for the treatment of CM, focusing both on their role as acute abortive agents and preventive measures and on their concomitant use with other antimigraine medications, such as CGRP mAbs or triptans.

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.

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.

CGRP Antagonism and Ketogenic Diet in the Treatment of Migraine.

The study of migraine is based on the complexity of the pathology, both at the pathophysiological and epidemiological levels. Although it affects more than a billion people worldwide, it is often underestimated and underreported by patients. Migraine must not be confused with a simple headache; it is a serious and disabling disease that causes considerable limitations in the daily life of afflicted people, including social, work, and emotional effects. Therefore, it causes a daily state of suffering and discomfort. It is important to point out that this pathology not only has a decisive impact on the quality of life of those who suffer from it but also on their families and, more generally, on society as a whole. The clinical picture of migraine is complex, with debilitating unilateral or bilateral head pain, and is often associated with characteristic symptoms such as nausea, vomiting, photophobia, and phonophobia. Hormonal, environmental, psychological, dietary, or other factors can trigger it. The present review focuses on the analysis of the physiopathological and pharmacological aspects of migraine, up to the correct dietary approach, with specific nutritional interventions aimed at modulating the symptoms. Based on the symptoms that the patient experiences, targeted and specific therapy is chosen to reduce the frequency and severity of migraine attacks. Specifically, the role of calcitonin gene-related peptide (CGRP) in the pathogenesis of migraine is analyzed, along with the drugs that effectively target the corresponding receptor. Particularly, CGRP receptor antagonists (gepants) are very effective drugs in the treatment of migraine, given their high diffusion in the brain. Moreover, following a ketogenic diet for only one or two months has been demonstrated to reduce migraine attacks. In this review, we highlight the diverse facets of migraine, from its physiopathological and pharmacological aspects to prevention and therapy.