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Background. Migraine is the second most incapacitating disease and is accompanied by multiple comorbidities, especially in chronic migraines. Migraine treatment and improvement of the patients’ quality of life are an important clinical issue. The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are the first target therapy for migraine. To date, there are no published data on the duration of effect after using mAbs. Aim. To determine the effect duration after cessation of erenumab treatment in patients with migraine. Methods. The study included 64 patients with migraine, who received at least three doses of erenumab; treatment was stopped when reduction of the headache frequency by at least 30% was achieved. The frequency of headache and migraine were assessed 1, 3 and 6 months after the end of treatment. Results. There was a significant increase in the frequency of headache compared to the values reported at the end of treatment, however, the rates were still significantly lower compared to the baseline values. In some patients, no increase in headache frequency following discontinuation of treatment was observed.

Abstract 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.

Background and Purpose: Multiple drugs targeting the calcitonin gene‐related peptide (CGRP) receptor have been developed for migraine treatment. Here, the effect of the monoclonal antibody erenumab on CGRP‐induced vasorelaxation was investigated in human isolated blood vessels, as well as the effect of combining erenumab with the small molecule drugs, namely rimegepant, olcegepant, or sumatriptan. Experimental Approach: Concentration–response curves to CGRP, adrenomedullin or pramlintide were constructed in human coronary artery (HCA) and human middle meningeal artery (HMMA) segments, incubated with or without erenumab and/or olcegepant. pA2 or pKb values were calculated to determine the potency of erenumab in both tissues. To study whether acutely acting antimigraine drugs exerted additional CGRP‐blocking effects on top of erenumab, HCA segments were incubated with a maximally effective concentration of erenumab (3 μM), precontracted with KCl and exposed to CGRP, followed by rimegepant, olcegepant, or sumatriptan in increasing concentrations. Key Results: Erenumab shifted the concentration‐response curve to CGRP in both vascular tissues. However, in HCA, the Schild plot slope was significantly smaller than unity, whereas this was not the case in HMMA, indicating different CGRP receptor mechanisms in these tissues. In HCA, rimegepant, olcegepant and sumatriptan exerted additional effects on CGRP on top of a maximal effect of erenumab. Conclusions and Implications: Gepants have additional effects on top of erenumab for CGRP‐induced relaxation and could be effective in treating migraine attacks in patients already using erenumab as prophylaxis. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene–related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date.Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration).Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double‐blind treatment period. In addition, migraine‐related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non‐reverters using the Headache Impact Test‐6 (HIT‐6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS).Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1–2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT‐6 total score for reverters versus non‐reverters compared to placebo (erenumab: −9.5 [0.6] vs. −5.1 [0.5]; placebo: −8.9 [0.7] vs. −4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: −22.1 [1.2] vs. −6.3 [1.8]; placebo: −19.9 [1.3] vs. −7.9 [1.6]). Substantial improvements were reported in MPFID‐Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non‐reverters in erenumab treatment groups (MPFID‐PI: −5.9 [0.3] vs. −1.9 [0.6]; MPFID‐EA: −7.9 [0.4] vs. −3.4 [0.6]) and in placebo (MPFID‐PI: −5.4 [0.4] vs. −1.0 [0.5]; MPFID‐EA: −7.1 [0.5] vs. −3.2 [0.5]).This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient‐reported outcomes in the erenumab group. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Phase II/III randomized clinical trials (RCTs) are vulnerable to many types of bias beyond randomization. Insights into the reporting quality of RCTs involving migraine patients treated with monoclonal antibodies targeting the calcitonin gene-related peptide system (anti-CGRP MAbs) are currently lacking. Our aim was to analyze the reporting quality of phase II/III RCTs involving migraine patients treated with anti-CGRP MAbs. Methods: A systematic search was performed on the PubMed and EMBASE databases, according to PRISMA guidelines, for relevant RCTs in either episodic or chronic migraine prevention. Additionally, an adapted version of the 2010 CONSORT statement checklist was utilized. The ROBvis online tool was used to document the risk of bias. Results: From the initially identified 179 articles, we finally found 31 RCTs that were eligible for evaluation. The average CONSORT compliance was 88.7% (69.7–100%), while 93.5% (N = 29) of the articles had a compliance greater than 75%. Twenty-eight CONSORT items were reported in more than 75% of the articles. The average compliance of the analyzed RCTs was 93.9% for Galcanezumab, 91.3% for Fremanezumab, followed by 85.4% for Erenumab and Eptinezumab studies. Implementation of the ROB2 tool showed some concerning "missing information" arising from the inadequate reporting. Specifically, 50% of the studies (N = 16) were categorized as having inadequate information regarding the randomization process. Conclusions: Adequate reporting quality was disclosed in the evaluated RCTs with anti-CGRP MAbs in migraine prevention. However, some methodological issues need to be highlighted to be addressed in future studies assessing the efficacy of new molecules targeting CGRP or other candidate pathways implicated in migraine pathophysiology. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of cerebral small vessel disease, caused by a mutation in the NOTCH3 gene on chromosome 19. The main clinical features include migraine (often with aura), early onset, recurrent subcortical ischemic strokes, mood disturbances, and cognitive impairment, frequently leading to dementia and disability with a reduction in life expectancy. Cerebral chronic global hypoperfusion, due to impaired cerebrovascular reactivity, seems to play a primary role in CADASIL. Migraine is the most common early feature of the disease, and to date, there are no consensus guidelines for treatment. Given the vasomodulatory influence of many antimigraine drugs, there is concern about their use in this disease. In particular, the calcitonin gene-related peptide (CGRP) system serves as a vasodilatory protective mechanism during cerebral and cardiac ischemia. Blocking this system could exacerbate ischemic events. Herein, we describe two CADASIL patients who were treated with the calcitonin gene-related peptide (CGRP) receptor antagonist erenumab for chronic migraine, reporting a significant reduction in the frequency of attacks and intensity of pain, and an improvement in quality of life without adverse effects. [ABSTRACT FROM AUTHOR]

Objectives: Migraine is a neurological disease with a high frequency of incidence. The new monoclonal antibodies selective for the calcitonin gene-related peptide and its ligand (anti-CGRP mAbs) have been marketed both in the USA and EU based on the positive efficacy results in the prevention of migraine. This search has been carried out with the aim of collecting real-world evidence on the effectiveness of anti-CGRP mAbs, performing a cost-savings analysis, and comparing performances among anti-CGRP mAbs medicines marketed in the American and European market. Methods: The literature review has been performed in PubMed database on 31 December 2022; the cost of the unitary dose of anti-CGRP mAbs has been extracted consulting an American national database. Results: The results confirm efficacy and good tolerability of anti-CGRP mAbs, determining a difference in the purchase price. In fact, all extracted studies showed a protective risk factor exposure in monthly migraine days reduction for all the anti-CGRP mAbs, whereas the cost analysis showed that using eptinezumab, in a quarter there is a cost saving of at least $425 per patient, compared with the other anti-CGRP mAbs. Conclusions: With equal efficacy and equal safety, anti-CGRP mAbs should be prescribed also regard to the cost established at the negotiation, making sure to guarantee the best treatment to the patients, but at the same time impacting as little as possible to the healthcare services resources. [ABSTRACT FROM AUTHOR]

Background: About 15% to one third of migraineurs experience aura symptoms. Aura is a reversible focal neurological phenomenon involving visual, sensory, speech, and motor symptoms that usually precede migraine pain. Monoclonal antibodies against calcitonin-related peptide (anti- CGRP mAbs) are effective in preventing chronic and episodic migraine, but little is known about their effectiveness on specifically preventing migraine with aura. Methods: This is a pilot prospective observational cohort study, aiming at evaluating the effectiveness and safety of Erenumab, Fremanezumab or Galcanezumab for the treatment of migraine aura. We enrolled 14 patients at the Headache Centre of University Federico II of Naples. Duration of follow-up was 12 months. We assessed mean monthly days with aura symptoms, with or without subsequent headache, as well as mean monthly days with headache and mean monthly MIDAS score, by reviewing standardized paper patient headache diaries every three months. Results: A significant decrease in mean monthly aura days was observed throughout the observation period (median baseline: 13, interquartile range: 4–16; after 12 months: 1, interquartile range: 0–3, p < 0.001). We observed a statistically significant decrease in mean monthly headache days as well (median baseline 21, interquartile range: 16–30; after 12 months: 5, interquartile range: 4–7, p < 0.001). During the 12-month treatment period, none of the 14 patients reported mild or serious adverse events. Conclusion: Our findings suggest that anti-CGRP mAbs are highly effective in migraine with aura, both in reducing mean monthly aura days and mean monthly days with headache. [ABSTRACT FROM AUTHOR]

Objective: To explore the rate of hypertension incoming in patients treated with monoclonal antibodies against the calcitonin gene-related peptide. Background: The monoclonal antibodies blocking the calcitonin gene-related peptide are unquestionable effective in the prevention of migraine. Despite this, the development of hypertension has been detected in some patients. Methods: This was a retrospective study conducted at the University Hospital of Modena. Patients were visited quarterly up to 1 year. Results: Globally, no significant increase in the blood pressure was detected. The 5.7% of the patients developed a significant increase in their blood pressure. In particular, patients with a pre-existing hypertension were more likely to have a significant increase in the blood pressure. Conclusion: The risk of developing hypertension during a treatment with anti-calcitonin gene-related peptide monoclonal antibodies seems low. Anyway, patients with a pre-existing hypertension should be cautiously monitored because they are more likely to develop hypertension. [ABSTRACT FROM AUTHOR]

To describe long-term (24-month) treatment patterns of patients initiating galcanezumab versus standard of care (SOC) preventive migraine treatments including anticonvulsants, beta-blockers, antidepressants, and onabotulinumtoxinA using administrative claims data. This retrospective cohort study, which used Optum de-identified Market Clarity data, included adults with migraine with ≥1 claim for galcanezumab or SOC preventive migraine therapy (September 1, 2018 − March 31, 2020) and continuous database enrollment for 12 months before (baseline) and 24 months after (follow-up) the index date (date of first claim). Baseline patient demographics, clinical characteristics, and treatment patterns were analyzed after 24-month follow-up, including adherence (measured as the proportion of days covered [PDC]), persistence, discontinuation (≥60-day gap), restart, and treatment switch. Propensity score matching (1:1) was used to balance the galcanezumab and SOC cohorts. The study included 2307 matched patient pairs with 24-month follow-up. The mean age across cohorts was 44.5 years (females: ∼87%). Patients in the galcanezumab versus SOC cohort demonstrated greater treatment adherence (PDC: 48% vs. 38%), with more patients considered adherent (PDC ≥80%: 26.6% vs. 20.7%) and persistent (322.1 vs. 236.4 d) (all p <.001). After 24-month follow-up, fewer galcanezumab-treated patients had discontinued compared with SOC-treated patients (80.1% vs. 84.7%; p <.001), of which 41.3% and 39.6% switched to a non-index medication, respectively. The most prevalent medication patients switched to in both cohorts was erenumab. Significantly greater proportions of patients who initiated galcanezumab versus SOC medications switched to fremanezumab (p <.001) and onabotulinumtoxinA (p =.016). Patients who initiated galcanezumab for migraine prevention had higher treatment adherence and persistence compared with those who initiated SOC medications after 24-month follow-up. Only few patients (3 − 13%) with migraine, who qualify for preventive treatment, are using them. Conventional preventive treatments have not been developed specifically for migraine treatment, and more than half of the patients stop using them prematurely. Calcitonin gene-related peptide monoclonal antibodies such as galcanezumab, fremanezumab, and erenumab are newer treatments that provide migraine-specific preventive treatment. Prior studies have compared 6- to 12-month migraine medication use by patients starting galcanezumab versus those starting traditional standard of care (SOC) migraine preventive medications. We compared long-term (24-month) migraine medication use in patients starting galcanezumab versus those starting SOC migraine preventive medications to confirm if the results are sustained over a longer period. Over 24 months, patients who used galcanezumab followed the prescribed treatment regimen to a greater extent compared with those who used SOC medications (48% vs. 38%, respectively). Additionally, patients using galcanezumab continued treatment for a longer time compared with those using SOC. Over 24 months, about 85% of patients stopped taking SOC medications, while around 80% of patients stopped taking galcanezumab. Our findings indicate that patients with migraine are more likely to continue using galcanezumab as a preventive treatment for a longer period compared with SOC medications. This study helps identify gaps in the preventive treatment of migraine and provides insights on how they are not being used enough. [ABSTRACT FROM AUTHOR]

Background: Chronic migraine (CM) is a disabling and hard-to-treat condition, associated with high disability and high cost. Among the preventive treatments, botulinum toxin A (BoNT-a) and monoclonal antibodies against the calcitonin gene-related protein (anti-CGRP mAbs) are the only disease-specific ones. The assessment of the disease burden is complex, and among others, tools such as the allodynia symptoms checklist (ASC-12) and headache impact test (HIT-6) are very useful. This exploratory study analysed the impact of these two therapies on migraine burden. Methods: The RAMO study was a multicentre, observational, retrospective investigation conducted in two headache centres: the Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan) and the Fondazione Policlinico Campus Bio-Medico (Rome). This study involved patients with chronic migraine treated with mAbs or BoNT-A. We conducted a subgroup exploratory analysis on HIT-6 and ASC-12 scores in the two groups. The Wilcoxon rank-sum test, Fisher's exact test, and ANOVA were performed. Results: Of 126 patients, 36 on mAbs and 90 on BoNT-A had at least one available follow-up. mAbs resulted in a mean reduction of −11.1 and −11.4 points, respectively, in the HIT-6 at 6 and 12 months, while BoNT-A was reduced −3.2 and −3.6 points, respectively; the mAbs arm resulted in mean reductions in ASC-12 at 6 and 12 months of follow-up of −5.2 and −6.0 points, respectively, while BoNT-A showed lesser mean changes of −0.5 and −0.9 points, respectively. The adjusted analysis confirmed our results. Conclusions: In this exploratory analysis, anti-CGRP mAbs showed superior effectiveness for HIT-6 and ASC12 compared to BoNT-A. Reductions in terms of month headache days (MHD), migraine disability assessment test (MIDAS), and migraine acute medications (MAM) were clinically relevant for both treatments. [ABSTRACT FROM AUTHOR]

Introduction: The introduction of clacitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) has revolutionized the treatment of migraines. In clinical practice gepants might be considered as a valid option to treat acute attacks in patients with migraine who are treated with mAbs. However, the safety and tolerability of such a combination is not well addressed in the real-world setting. We designed this study to evaluate the safety and tolerability of combining CGRP mAbs with gepants in the management of migraines. Methods: This was a retrospective, real-world, exploratory study. The participants included within the study were adult (≥ 18 years) patients diagnosed with migraine. Screening for patients who were treated with at least one GCRP mAbs was done. Data was collected from one site, the American Center for Psychiatry and Neurology, Abu Dhabi UAE. A total of 516 patients taking CGRP mAbs were identified. Extracted data from patients' electronic medical records included patient demographics, migraine characteristics, prescribed treatments, and adverse events (AEs). The tolerability and safety of the combination therapy was evaluated on the basis of documented AEs. Results: Among the identified 516 patients, 234 were administered gepants in addition to the CRGP mAb (215, rimegepant; 19, ubrogepant). Eleven of the 234 patients switched from rimegepant to urogepant as a result of lack of efficacy; one patient switched from urogepant to zolmitriptan because of the lack of insurance coverage of the former medication. Among all the patients included in this study, three AEs were documented. These AEs were generally mild and transient and hence did not lead to discontinuation of treatment. Moreover, 42 of the 234 (17.9%) patients were switched from one class of CGRP mAbs to another at least once while continuing treatment with the assigned gepants. Conclusion: The findings of this study demonstrate that combining CGRP mAbs with gepants is a safe and well-tolerated treatment approach for migraine. Future studies are warranted to further validate these findings and explore long-term outcomes. [ABSTRACT FROM AUTHOR]

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Abstract Background The reimbursement of erenumab in Spain and other European countries is currently restricted because of the cost of this novel therapy to patients with migraine who have experienced previous failures to traditional preventive treatments. However, this reimbursement policy should be preferably based on cost-effectiveness studies, among other criteria. This study performed a cost-effectiveness analysis of erenumab versus topiramate for the prophylactic treatment of episodic migraine (EM) and versus placebo for chronic migraine (CM). Methods A Markov model with a 10-year time horizon, from the perspective of the Spanish National Healthcare System, was constructed based on data from responder and non-responder patients. A responder was defined as having a minimum 50% reduction in the number of monthly migraine days (MMD). A hypothetical cohort of patients with EM with one or more prior preventive treatment failures and patients with CM with more than two treatment failures was considered. The effectiveness score was measured as an incremental cost per quality-adjusted life year (QALY) gained and cost per migraine day (MD) avoided. Data from clinical outcomes and patient characteristics were obtained from erenumab clinical trials (NCT02066415, STRIVE, ARISE, LIBERTY and HER-MES). Deterministic and probabilistic sensitivity analyses were performed to validate the robustness of the model. Results After a 10-year follow-up, the estimated QALYs were 5.88 and 6.11 for patients with EM treated with topiramate and erenumab, respectively. Erenumab showed an incremental cost per patient of €4,420 vs topiramate. For CM patients, erenumab resulted in 0.756 QALYs gained vs placebo; and an incremental cost of €1,814. Patients treated with erenumab achieved reductions in MD for both EM and CM (172 and 568 MDs, respectively). The incremental cost per QALY gained with erenumab was below the Spanish threshold of €30,000/QALY for both health and societal perspectives (EM €19,122/QALY and CM €2,398/QALY). Conclusions Erenumab is cost-effective versus topiramate as a preventive treatment for EM and versus placebo for patients with CM from the perspective of the Spanish National Health System.

Abstract Introduction The introduction of clacitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) has revolutionized the treatment of migraines. In clinical practice gepants might be considered as a valid option to treat acute attacks in patients with migraine who are treated with mAbs. However, the safety and tolerability of such a combination is not well addressed in the real-world setting. We designed this study to evaluate the safety and tolerability of combining CGRP mAbs with gepants in the management of migraines. Methods This was a retrospective, real-world, exploratory study. The participants included within the study were adult (≥ 18 years) patients diagnosed with migraine. Screening for patients who were treated with at least one GCRP mAbs was done. Data was collected from one site, the American Center for Psychiatry and Neurology, Abu Dhabi UAE. A total of 516 patients taking CGRP mAbs were identified. Extracted data from patients’ electronic medical records included patient demographics, migraine characteristics, prescribed treatments, and adverse events (AEs). The tolerability and safety of the combination therapy was evaluated on the basis of documented AEs. Results Among the identified 516 patients, 234 were administered gepants in addition to the CRGP mAb (215, rimegepant; 19, ubrogepant). Eleven of the 234 patients switched from rimegepant to urogepant as a result of lack of efficacy; one patient switched from urogepant to zolmitriptan because of the lack of insurance coverage of the former medication. Among all the patients included in this study, three AEs were documented. These AEs were generally mild and transient and hence did not lead to discontinuation of treatment. Moreover, 42 of the 234 (17.9%) patients were switched from one class of CGRP mAbs to another at least once while continuing treatment with the assigned gepants. Conclusion The findings of this study demonstrate that combining CGRP mAbs with gepants is a safe and well-tolerated treatment approach for migraine. Future studies are warranted to further validate these findings and explore long-term outcomes.

Abstract Background Chronic migraine (CM) is a disabling condition with high prevalence in the general population. Until the recent approval of monoclonal antibodies targeting the calcitonin gene-related peptide (Anti-CGRP mAbs), OnabotulinumtoxinA (BoNT-A) was the only treatment specifically approved for CM prophylaxis. Direct comparisons between the two treatments are not available so far. Methods We performed an observational, retrospective, multicenter study in Italy to compare the real-world effectiveness of Anti-CGRP mAbs and BoNT-A. Patients with CM who had received either treatment according to Italian prescribing regulations were extracted from available clinical databases. Efficacy outcomes included the change from baseline in monthly headache days (MHD), MIgraine Disability ASsessment test (MIDAS), and monthly acute medications (MAM) evaluated at 6 and 12 months of follow-up. The primary outcome was MHD change from baseline at 12 months. Safety outcomes included serious adverse events (SAE) and treatment discontinuation. Unadjusted and adjusted models were used for the analyses. Results Two hundred sixteen potentially eligible patients were screened; 183 (86 Anti-CGRP mAbs; 97 BoNT-A) were included. One hundred seventy-one (80 Anti-CGRP mAbs; 91 BoNT-A) and 154 (69 Anti-CGRP mAbs; 85 BoNT-A) patients were included in the efficacy analysis at 6 and 12 months of follow-up, respectively. Anti-CGRP mAbs and BoNT-A both resulted in a mean MHD reduction at 6 (-11.5 and -7.2 days, respectively; unadjusted mean difference -4.3; 95%CI -6.6 to -2.0; p = 0.0003) and 12 months (-11.9 and -7.6, respectively; unadjusted mean difference -4.4; 95%CI -6.8 to -2.0; p = 0.0002) of follow-up. Similar results were observed after adjusting for baseline confounders. Anti-CGRP mAbs showed a significant MIDAS (-31.7 and -19.2 points, p = 0.0001 and p = 0.0296, respectively) and MAM reduction (-5.1 and -3.1 administrations, p = 0.0023 and p = 0.0574, respectively) compared to BoNT-A at 6 and 12 months. No SAEs were reported. One patient receiving fremanezumab discontinued treatment due to arthralgia. Treatment discontinuations, mainly for inefficacy, were comparable. Conclusion Both Anti-CGRP mAbs and BoNT-A were effective in CM patients with Anti-CGRP mAbs presenting higher effect magnitude, with comparable safety. Still, BoNT-A remains a valuable option for CM patients with contraindications to Anti-CGRP mAbs or for frail categories who are candidates to local therapy with limited risk of systemic administration. Graphical Abstract

Oralee J Varnado,1 Brenna L Brady,2 Anthony J Zagar,1 Yvonne P Robles,2 Margaret Hoyt1 1Eli Lilly and Company, Indianapolis, IN, USA; 2Merative, Ann Arbor, MI, USACorrespondence: Oralee J VarnadoValue, Evidence, and Outcomes, Eli Lilly and Company, Lilly Corporate Center, 893 Delaware Street, Indianapolis, IN, 46285, USA, Tel +1 317 277 0599, Email varnado_oralee_johnson@lilly.comBackground: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are indicated for migraine prevention in the United States. Limited data comparing real-world treatment patterns for CGRP mAbs are available.Objective: To compare the treatment patterns among patients with migraine initiating galcanezumab, fremanezumab, and erenumab.Methods: This retrospective study included adult patients with one or more claims for a self-injectable CGRP mAb (galcanezumab, fremanezumab, or erenumab), with continuous enrollment in medical and pharmacy benefits for 12 months pre-index and 6 and 12 months post-index using MerativeTM MarketScan® Commercial and Medicare databases from May 2017 through March 2021. Propensity-score matching was used to address confounding by observed covariates. Outcomes analyzed included proportion of days covered (PDC), medication-possession ratio (MPR), persistence (≤ 60-day gap), treatment discontinuation, and switch to a non-index drug. Descriptive X2 and t-test analyses were conducted.Results: At the 12-month follow-up, matched galcanezumab and fremanezumab cohorts each comprised 2674 patients and the galcanezumab and erenumab cohorts 3503 each. The mean (SD) PDC and MPR were both 0.6 (0.3) across all cohorts. Based on PDC ≥ 0.80 and MPR ≥ 0.80, a greater proportion of galcanezumab vs fremanezumab (46.2% vs 43.7%, p=0.053; 46.8% vs 44.3%, p=0.053) and galcanezumab vs erenumab (46.2% vs 44%, p=0.156; 46.7% vs 44.5%, p=0.262), respectively, initiators were adherent. Compared to galcanezumab, fremanezumab (248.0 days vs 236.5 days, p=0.001), and erenumab (247.8 days vs 241.7 days, p=0.061) initiators had lower mean persistence. Galcanezumab initiators were less likely to discontinue treatment than fremanezumab (47.8% vs 51.7%, p=0.005) and erenumab (47.7% vs 50.2%, p=0.040) initiators. Across cohorts, most switchers initiated onabotulinum toxin A as subsequent treatment. Similar results were observed for 6-month follow-up cohorts.Conclusion: Patients with migraine who initiated treatment with galcanezumab showed higher persistence and lower treatment discontinuation rates than those initiating either fremanezumab or erenumab.Plain Language Summary: What was known before? Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are medicines developed for migraine prevention. CGRP mAbs bind to the CGRP ligand or receptor and limit pain associated with migraine attacks. Currently, three self-injectable CGRP mAbs are approved for prevention: erenumab, fremanezumab, and galcanezumab. Use of erenumab, fremanezumab, and galcanezumab can slow or stop migraine-related symptoms and reduce migraine-related disability.What does this study add? This study describes how migraine medications are used in the US by patients with migraine who started using galcanezumab, fremanezumab, or erenumab for migraine treatment. Over a period of 12 months, patients who started treatment for migraine with galcanezumab were more likely to continue their treatment than those who started using either fremanezumab or erenumab. At 12 months, fewer patients who started galcanezumab were likely to discontinue their treatment than patients who started using either fremanezumab or erenumab. Among patients who discontinued and switched, most patients switched to Botox A, a non-CGRP treatment. Among patients who switched to a different CGRP mAb, most patients in the fremanezumab and erenumab groups switched to galcanezumab, while most patients in the galcanezumab group switched to erenumab.Interpretation: These findings suggest that patients remained on galcanezumab longer and were less likely to discontinue.Keywords: CGRP mAb, erenumab, fremanezumab, galcanezumab, treatment patterns, migraine

Background and Objectives: Migraine is a chronic neurological disorder affecting approximately 14% of the global population. Beyond physical pain, migraines significantly impact individuals’ quality of life, influencing education, employment, and income levels. Topiramate, a second-generation antiepileptic medication, has demonstrated notable efficacy in reducing the occurrence of chronic migraine. Over the past three decades, extensive research has implicated the neuropeptide calcitonin gene-related peptide (CGRP) in migraine pathogenesis. Erenumab, the first FDA-approved CGRP inhibitor, received approval in 2018. This study aims to compare the clinical efficacy of Erenumab and Topiramate for migraine prevention. Materials and Methods: We conducted a retrospective cohort study of adults with episodic or chronic migraine over a 12-month period, comparing Erenumab (n = 52) and Topiramate (n = 56). Outcomes assessed included changes in the Migraine Disability Assessment (MIDAS) scores from baseline over the last three months of treatment and the proportion of patients achieving a ≥50% reduction in MIDAS scores by the end of the study. Results: The Erenumab group showed significant improvement, with nearly 79% of patients achieving a 50% reduction in their MIDAS score, with a mean reduction of 3.76. Notably, only two patients (3.8.5) discontinued treatment due to adverse events. In contrast, the Topiramate group had over 15% of patients achieve a 50% reduction in MIDAS scores, with a mean reduction of 5.89, and a had discontinuation rate of 14.2% due to adverse events. Conclusions: Both Topiramate and Erenumab are effective for migraine prevention. However, Topiramate has lower tolerability and more side effects, while Erenumab offers better tolerability and safety at a higher cost. Treatment decisions should be individualized based on patient needs, efficacy, safety, and cost considerations.

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. [ABSTRACT FROM AUTHOR]

Erenumab, a fully human monoclonal antibody targeting the calcitonin gene‐related peptide receptor, is efficacious and safe for prevention of attacks of migraine in adults. This phase I, randomized, open‐label, multiple‐dose study evaluated the safety, tolerability, and pharmacokinetics (PK) of erenumab in children and adolescents with migraine. The initial treatment phase lasted 12 weeks, followed by an optional 40‐week extension phase for adolescents. Primary end points were PK of erenumab, incidence of treatment‐emergent adverse events (TEAEs), and changes in clinical and laboratory assessments. Participants received erenumab 35 mg (n = 4), 70 mg (n = 17), or 140 mg (n = 32) q4w. The mean age was 14.1 years. Of the 53 participants, 48 (90.6%) completed the initial treatment phase and 36 (67.9%) received erenumab during the extension phase. Mean exposures to erenumab based on the maximum observed concentration and the area under the drug concentration–time curve during the dosing interval increased approximately dose‐proportionally. A total of 42 participants (79.2%) reported TEAEs (307.2 per 100 participant‐years); and four (7.5%) reported serious TEAEs not considered treatment‐related. The most common TEAEs were upper respiratory tract infection, headache, and vomiting. No clinically significant changes were reported in vital signs, electrocardiograms, and laboratory and neurological assessments. Overall, the observed PK profile of erenumab in children and adolescents with migraine is consistent with that in adults when body weight differences are taken into consideration. The safety profile of erenumab in children and adolescents is consistent with that in adults. [ABSTRACT FROM AUTHOR]

Background: Migraine imposes a substantial global burden, impacting patients and society. Pharmacotherapy, as a primary treatment, entails specific adverse reactions. Emphasizing these reactions is pivotal for improving treatment strategies and enhancing patients' well-being. Thus, we conducted a comprehensive bibliometric and visual analysis of relevant literature. Methodology: We conducted a comprehensive search on the Science Citation Index Expanded within the Web of Science, restricting the literature for analysis based on criteria such as document type, publication date, and language. Subsequently, we utilized various analytical tools, including VOSviewer, Scimago Graphica, the R package 'bibliometrix', CiteSpace, and Excel programs, for a meticulous examination and systematic organization of data concerning journals, authors, countries/regions, institutions, keywords, and references. Results: By August 31, 2023, the literature was distributed across 379 journals worldwide, authored by 4,235 individuals from 1726 institutions. It featured 2,363 keywords and 38,412 references. 'HEADACHE' led in publication count, with 'SILBERSTEIN S' as the most prolific author. The United States ranked highest in publication volume, with 'UNIV COPENHAGEN' leading among institutions. Conclusion: Our research findings indicate that researchers in the field continue to maintain a focus on the calcitonin gene-related peptide (CGRP) system and explore diverse mechanisms for drug development through the application of novel biotechnological approaches. Furthermore, it is imperative to enhance the assessment of clinical trial outcomes, consistently monitor the efficacy and safety of prominent drugs such as Erenumab and Fremanezumab. There is a need for further evaluation of acute and preventive treatments tailored to different populations and varying types of migraine. [ABSTRACT FROM AUTHOR]

Background: Migraine is a neurological disorder characterized by attacks of head pain with prevalent unilateral localization, moderate to high intensity and specifically associated accompanying symptoms. Methods: In this retrospective observational study, we analyzed data regarding 209 patients who had previously been diagnosed with migraine and who were prescribed, between 2019 and 2022, subcutaneous injections of anti-CGRP monoclonal antibodies (mAbs) fremanezumab or galcanezumab or anti-CGRP receptors mAb erenumab regardless of the concomitant assumption of any other acute-phase or prophylactic migraine medication. Results: Regarding efficacy, in the 205 analyzed patients, the change from baseline in terms of MIDAS, HIT-6, MMDs and MAD scores was statistically significant for erenumab and galcanezumab, while for fremanezumab a statistical significance was not achieved likely due to the small sample size. In the treated population, 36 patients (17.5%) reported AEs (pain during injection, transient injection site erythema, nausea, constipation and fatigue). Only 5 patients (2.4%) discontinued the treatment for AEs while 15 patients (7.3%) left for lack of efficacy. Conclusions: this retrospective study comes out in favor of both significant efficacy and safety of anti-CGRP and anti-CGRP receptors mAbs in migraine patients. Further methodologically stronger studies are necessary to validate our observation. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) have shown promising effectiveness in migraine management compared to other preventative treatment options. Many questions remain regarding switching between antibody classes as a treatment option in patients with migraine headaches. This preliminary retrospective real-world study explored the treatment response of patients who switched between CGRP mAb classes due to lack of efficacy or poor tolerability. A total of 53 patients with migraine headache switched between three of the CGRP mAbs types due to lack of efficacy of the original prescribed CGRP mAbs, specifically eptinezumab, erenumab, and galcanezumab. Fremanezumab was not included due to unavailability in the UAE. Galcanezumab and eptinezumab target the CGRP ligand (CGRP/L), while erenumab targets CGRP receptors (CGRP/R). The analysis of efficacy demonstrated that some improvements were seen in both class switch cohorts (CGRP/R to CGRP/L and CGRP/L to CGRP/R). The safety of switching between CGRP classes was well observed, as any adverse events presented before the class switch did not lead to the discontinuation of treatment following the later switch. The findings of this study suggest that switching between different classes of CGRP mAbs is a potentially safe and clinically viable practice that may have some applications for those experiencing side effects on their current CGRP mAb or those witnessing suboptimal response. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim was to evaluate the effect of anti‐calcitonin gene related peptide (CGRP) (ligand or receptor) antibodies on depressive symptoms in subjects with migraine and to determine whether depressive symptoms predict treatment response. Methods: Patients with migraine treated with erenumab and fremanezumab at the Leiden Headache Centre completed daily E‐headache diaries. A control group was included. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Center for Epidemiological Studies Depression Scale (CES‐D) questionnaires at baseline (T0) and after 3 months (T1). First, the effect of treatment on the reduction in HADS‐D and CES‐D scores was assessed, with reduction in depression scores as the dependent variable and reduction in monthly migraine days (MMD) and treatment with anti‐CGRP medication as independent variables. Second, depression as a predictor of treatment response was investigated, using the absolute reduction in MMD as a dependent variable and age, gender, MMD, active depression, impact, stress and locus of control scores as independent variables. Results: In total, n = 108 patients were treated with erenumab, n = 90 with fremanezumab and n = 68 were without active treatment. Treatment with anti‐CGRP medication was positively associated with a reduction in the HADS‐D (β = 1.65, p = 0.01) compared to control, independent of MMD reduction. However, the same effect was not found for the CES‐D (β = 2.15, p = 0.21). Active depression predicted poorer response to erenumab (p = 0.02) but not to fremanezumab (p = 0.09). Conclusion: Anti‐CGRP (ligand or receptor) monoclonals lead to improvement of depressive symptoms in individuals with migraine, independent of migraine reduction. Depression may predict treatment response to erenumab but not to fremanezumab. [ABSTRACT FROM AUTHOR]

Introduction: Limited clinical evidence is available regarding the potential effectiveness of anti‐CGRP monoclonal antibodies for the preventive treatment of migraine with aura. Aim of the Study: This observational study involved a series of migraine patients affected by either migraine with or without aura, who were investigated for any changes in their frequencies and their migraine aura attack characteristics observed during treatment with anti‐CGRP Mabs over a 1‐year period. Patients and Methods: Twelve migraine patients were included, seven of whom were treated with erenumab, 2 with fremanezumab, and 3 with galcanezumab. Clinical data were collected at baseline, which were defined as 3 months prior to the initiation of treatment, and thereafter at each trimester, over the 1‐year treatment period. The parameters included the number of headache and migraine days/month, the frequency of aura episodes, the number of days with acute drug intakes/month, and the scores from the migraine disability status scale (MIDAS), and the Headache Impact Test 6 (HIT‐6). Results: Anti‐CGRP Mbs antibodies induced significant decreases in mean headache and migraine without aura days per month, the number of days with medication intake, as well as MIDAS and HIT‐6 scores (p < 0.0001). In contrast, the anti‐CGRP Mab treatment did not appear to impact the frequency of migraine with aura attacks but seemed to reduce both the intensity and the duration of headache phases of migraine aura. Furthermore, some migraine patients referred to having aura attacks without headache over the course of the treatment period. Conclusions: Based on the above findings, we hypothesize that anti‐CGRP Mabs did not influence neuronal and vascular events related to cortical spreading depression (CSD) which is considered the pathophysiological substrate of aura. Conversely, these antibodies are able to counteract, via their peripheral mechanisms of action, the sensitization of the trigemino‐vascular pathway which is triggered by CSD. This aforementioned might explain why in our patients, migraine aura attacks remained unchanged in their frequencies, but the headache phases were either reduced or absent. [ABSTRACT FROM AUTHOR]

Background: Anti-Calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) have shown significant efficacy in preventing migraine. However, there have been limited reports of adverse events (AEs) after marketing, particularly for eptinezumab launched in 2020. The study aimed to mine and analyze the AE signals with four anti-CGRP mAbs from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to gain insights into the safety profile of these medications post-marketing. Methods: All AE reports on the four anti-CGRP mAbs (erenumab, galcanezumab, fremanezumab, and eptinezumab) were retrieved from the FAERS database from the first quarter (Q1) of 2018 to Q1 of 2023. Disproportionality analysis was measured by reporting odd ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) to identify potential AE signals. Comparisons were made between the four drugs in terms of AEs. Results: A total of 38,515 reports of erenumab, 19,485 reports of galcanezumab, 5,332 reports of fremanezumab, and 2,460 reports of eptinezumab were obtained, mostly reported in the second to third year after launch in the market. The common AEs to erenumab included constipation (17.93%), injection site pain (14.08%), and alopecia (7.23%). The AEs that occurred more frequently with galcanezumab included injection site pain (24.37%), injection site erythema (5.35%), and injection site haemorrhage (4.97%). Common AEs related to fremanezumab were injection site pain (13.10%), injection site erythema (7.02%), and injection site pruritus (5.47%). Fatigue (13.54%), throat irritation (9.02%), and pruritus (8.20%) were the most common AEs with eptinezumab. In addition, there are new AEs that were not listed in the drug instructions but occurred concurrently with multiple drugs, such as Raynaud's phenomenon, weight increase, menstrual disorders, throat tightness, and paraesthesia oral. Conclusion: Common AE signals of the four anti-CGRP mAbs and new AE signals were found to provide a reference for clinical drug selection in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Although randomized controlled trials (RCTs) have shown that calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (CGRP mAbs) are an efficacious and safe therapeutic modality for migraine prevention, their clinical benefits have not been well validated in Japanese patients in the real-world setting. The present study aimed to evaluate the real-world efficacy and safety of galcanezumab, fremanezumab, and erenumab in Japanese patients with migraine. Methods: This observational retrospective cohort study was conducted at two headache centers in Japan. Patients with migraine who had experienced treatment failure with at least one traditional oral migraine preventive agent were treated with a CGRP mAb de novo. The primary efficacy endpoints were the changes from baseline in monthly migraine days (MMDs) and Headache Impact Test-6 (HIT-6) score after 3 dosing intervals (V3). We explored whether demographic and clinical characteristics predicted therapeutic outcomes at V3. Results: Sixty-eight patients who completed three doses of a CGRP mAb (85.3% female [58/68], mean age: 46.2 ± 13.1 years) were included in the analysis. There were 19 patients with chronic migraine. The baseline MMDs were 13.4 ± 6.0. After 3 doses, the MMDs significantly decreased to 7.4 ± 5.5 (p < 0.0001), and the 50% response rate was 50.0%. HIT-6 score was significantly reduced from 66.7 ± 5.4 to 56.2 ± 8.7 after 3 doses (P = 0.0001). There was a positive correlation between the changes in MMDs and HIT-6 score from baseline after 2 doses (p = 0.0189). Those who achieved a ≥ 50% therapeutic response after the first and second doses were significantly more likely to do so at V3 (crude odds ratio: 3.474 [95% CI: 1.037 to 10.4], p = 0.0467). The most frequent adverse event was constipation (7.4%). None of the adverse events were serious, and there was no need for treatment discontinuation. Conclusions: This real-world study demonstrated that CGRP mAbs conferred Japanese patients with efficacious and safe migraine prevention, and an initial positive therapeutic response was predictive of subsequent favorable outcomes. Concomitant measurement of MMDs and HIT-6 score was useful in evaluating the efficacy of CGRP mAbs in migraine prevention. [ABSTRACT FROM AUTHOR]

Background: The present study investigates the wearing-off effect in adults with chronic migraine treated with erenumab or fremanezumab. Methods: This real-world observational study was based on pre-collected headache diaries from chronic migraine patients in treatment with either monthly injections of 140 mg of erenumab or 225 mg of fremanezumab. Consistent wearing-off was defined as an increase of ≥2 weekly migraine days in the last week compared to the second week over two consecutive 4-week treatment periods. The primary endpoint was wearing-off in the total population. The secondary endpoints were difference in wearing-off in (i) a subgroup of patients treated with erenumab and fremanezumab and (ii) consistent wearing-off in patients with a ≥30% reduction in monthly migraine days, compared to baseline, in the two consecutive treatment months. Results: In total, 100 patients (erenumab: n =60, fremanezumab: n =40) were included. Sixty-two out of 100 (62%) patients had consistent ≥30% treatment response on antibody therapy in both months (erenumab: n =36, fremanezumab: n =26). There was no consistent wearing-off over the two consecutive months from week 2 to week 4 (3.04%, p =0.558). There was no wearing-off within the erenumab (p =0.194) or the fremanezumab (p =0.581) groups. Among the ≥30% treatment responders, there was no consistent wearing-off over the two consecutive months (2.6%, p =0.573). Conclusions: There was no wearing-off in treatment responders, which is in alignment with premarketing data from placebo-controlled phase III studies. These data suggest that patients should be informed upfront that no wearing-off effect is expected because anxiety for attacks at the end of the month per se may generate migraine attacks. [ABSTRACT FROM AUTHOR]

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 βCGRP. 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. [ABSTRACT FROM AUTHOR]

Background: Migraine is often associated with depression and anxiety, leading to a diminished quality of life. Calcitonin gene‐related peptide (CGRP) antagonists have shown promise in treating migraines, but their effects on concurrent depression and anxiety have not been clarified. Methods: A literature review was conducted on ClinicalTrials.gov, PubMed, Ovid Medline, and EMBASE focusing on phase 3 clinical trials, post-hoc analysis studies, and real-world evidence (RWE) published in the past 5 years. The review primarily utilized patient-reported outcome tools, such as the Patient Health Questionnaire-9, Hamilton Depression Rating Scale, Beck Depression Inventory-II, generalized anxiety disorder (GAD)-7, and Hamilton Anxiety Rating Scale (HARS), to assess anxiety and depression in relation to CGRP-targeted monoclonal antibodies. Results: Out of 260 studies, 17 met the inclusion criteria. Eptinezumab lacked sufficient evidence regarding its impact on depression and anxiety. While sufficient evidence on its effect on comorbid anxiety was not available, fremanezumab was shown to significantly improve comorbid depression in one study while not achieving statistical significance in another. Erenumab and galcanezumab showed significant improvement in comorbid depression, implying possible benefits in patients with migraine. Galcanezumab showed faster relief from depressive symptoms than other injectable CGRP antagonists. Galcanezumab also exhibited improvements in GAD-7 scores for anxiety, although not statistically significant, whereas RWE showed promising HARS scores for both galcanezumab and erenumab. Conclusions: Galcanezumab and erenumab appear to be more effective in improving concurrent depressive and anxiety symptoms in migraine patients than fremanezumab. Notably, these psychometric questionnaires were not the primary outcome measures of the trials and were not specifically designed to investigate the effects of these medications on depression or anxiety. Further research is needed to fully understand the impact of CGRP antagonists on mental health disorders associated with migraines. These findings have implications for enhancing the overall well-being and quality of life in individuals with migraines and comorbid psychiatric conditions.

Abstract Background Randomized clinical trials have demonstrated efficacy and safety of erenumab. The aim of this study is to evaluate the effectiveness and safety of erenumab in a real-world setting in French patients with migraine associated with extreme unmet needs. Methods This is a one year-prospective real-word study with enrolment of all consecutive adult patients included in the FHU InovPain registry who participated in a compassionate erenumab use program. Results Of 144 patients included, 140 patients (82.1% female / mean age of 50.9 ± 11.4) received at least one dose of erenumab and were concerned by effectiveness and safety assessment. All patients had failed 11 oral preventive treatments. Most of them suffered from chronic migraine (88.6%) and presented a medication overuse (90.7%) at baseline. Thirty-eight (27.1%) discontinued treatment during the 12-month follow-up, with 22 (15.7%), 11 (7.9%) and 5 (3.6%) patients before 3, 6 or 9 months of treatment. The proportion of ≥ 50% responders at M3, M6, M9 and M12 was 74/140 (52.9%), 69/118 (58.5%), 61/107 (57.0%) and 60/102 (58.8%) respectively. At M3, the rate of reversion from chronic migraine to episodic migraine was 57.3% and the rate of transition from medication overuse to non-overuse was 46.5%. For monthly migraine days, the median (IQR) was 18.0 (13.0–26.0), 9.0 (5.0–17.0), 7.5 (5.0–14.0), 8.0 (5.0–12.5) and 8.0 (5.0–12.0) at M0, M3, M6, M9 and M12 respectively. For HIT-6 score, the median (IQR) was 68.0 (63.8–73.3), 60.0 (54.0–65.0), 60.0 (50.3–53.0), 59.0 (50.0–63.0) and 58.0 (50.0–62.9) at M0, M3, M6, M9 and M12 respectively. Fifty-three (37.9%) patients reported at least one of the following adverse events: cutaneous erythema and/or pain at the injection site for 42 (30%) patients, constipation for 22 (15.7%) patients, muscle spasm for 2 (1.4%) patients, alopecia for one (0.7%) patient and blood pressure increase in one (0.7%) patient. There was no serious adverse event. One female patient became pregnant after 5 months of exposure to erenumab with a safe evolution after treatment discontinuation. Conclusion This first French real-world study related to migraine prevention with CGRP-mAbs confirms effectiveness and safety of erenumab in patients with extreme unmet needs.