Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date.
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ABSTRACT:
SUBMITTER: Pellesi L
PROVIDER: S-EPMC5697612 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
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Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date.
Pellesi Lanfranco L Guerzoni Simona S Pini Luigi Alberto LA
Clinical pharmacology in drug development 20170414 6
Migraine, a common neurovascular brain disorder, represents a severe and widespread health problem; along with medication-induced (medication-overuse) headache, it is the third-leading cause of disability worldwide. Currently, its therapeutic management remains unsatisfactory for several reasons; up to 40% of migraineurs are eligible for prophylactic treatment, but there are issues of efficacy, safety, and adherence. In recent years the evidence on the role of calcitonin gene-related peptide (CG ...[more]
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Project description:Remarkable advancements have been made in the field of migraine pathophysiology and pharmacotherapy over the past decade. Understanding the molecular mechanism of calcitonin gene-related peptide (CGRP) has led to the discovery of a novel class of drugs, CGRP functional blocking monoclonal antibodies (mAbs), for migraine prevention. CGRP is a neuropeptide inherently involved in migraine physiology where its receptors are found dispersed throughout the central and peripheral nervous systems. CGRP-targeted mAbs are effective in the preventive treatment of both chronic and episodic migraine. The advantages of mAbs over oral migraine preventives are numerous. Favorable attributes of the mAbs include high affinity and selectivity for CGRP molecular targets, long-circulating plasma half-lives, and limited risk for nonspecific hepatic and renal toxicity. This pharmacological profile leads to fewer off-target (side) effects and drug-drug interactions rendering mAbs an attractive alternative to traditional small molecule therapies, especially for the preventive treatment of migraine. MAbs display minimal drug interaction thus are excellent for patients prescribed with multiple medications. However, the long-term safety of CGRP blockade is incompletely known, and CGRP mAbs use should be avoided during pregnancy. CGRP mAbs represent a radical shift in preventing chronic and episodic migraine.
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Project description:OBJECTIVE:Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine. BACKGROUND:The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs). METHODS:This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks. RESULTS:The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ?1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ?2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal. CONCLUSION:Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.
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Project description:BackgroundTo date, real-world evidence on persistence to anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies (mAbs) or onabotulinumtoxinA have excluded eptinezumab. This retrospective cohort study was performed to compare treatment persistency among patients with migraine on anti-CGRP mAbs (erenumab, fremanezumab, galcanezumab, or eptinezumab) or onabotulinumtoxinA.MethodsThis retrospective study used IQVIA PharmMetrics data. Adult patients with migraine treated with an anti-CGRP mAb or onabotulinumtoxinA who had 12 months of continuous insurance enrollment before starting treatment were included. A "most recent treatment episode" analysis was used in which the most recent episode was defined as the latest treatment period with the same drug (anti-CGRP mAb or onabotulinumtoxinA) without a ≥ 15-day gap in medication supply on/after June 25, 2020, to December 31, 2021. Patients were indexed at the start of their most recent episode. Patients were considered non-persistent and discontinued the therapy associated with their most recent episode if there was ≥ 15-day gap in medication supply. A Cox proportional-hazards model estimated the discontinuation hazard between treatments. The gap periods and cohort definition were varied in sensitivity analyses.ResultsThe study included 66,576 patients (median age 46 years, 88.6% female). More eptinezumab-treated patients had chronic migraine (727/1074), ≥ 3 previous acute (323/1074) or preventive (333/1074) therapies, and more prior treatment episodes (3) than other treatment groups. Based on a 15-day treatment gap, patients on subcutaneous anti-CGRP mAbs had a 32% (95% CI: 1.19, 1.49; erenumab), 42% (95% CI: 1.27, 1.61; galcanezumab), and 58% (95% CI: 1.42, 1.80; fremanezumab) higher discontinuation hazard than those receiving eptinezumab, with this relationship attenuated, but still statistically significant based on 30-day and 60-day treatment gaps. There was no significant difference in the discontinuation hazard between eptinezumab and onabotulinumtoxinA. Based on a 15-day treatment gap among patients who newly initiated therapy, the discontinuation hazard of subcutaneous anti-CGRP mAbs remained significantly higher compared to eptinezumab and onabotulinumtoxinA.ConclusionPatients treated with eptinezumab demonstrated persistency that was higher than subcutaneous anti-CGRP mAbs and similar to onabotulinumtoxinA.
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Project description:BackgroundReal-world data are accumulating on the effectiveness, tolerability and safety of anti-calcitonin gene-related peptide pathway monoclonal antibodies for the preventive treatment of migraine. We performed a systematic review of the methodology of prospective, observational, clinic-based real-world evidence studies with these drugs in both episodic and chronic migraine.MethodsThe objectives were to evaluate the definitions and reported outcomes used, and to perform a risk of bias assessment for each of the different studies. PubMed and EMBASE were systematically queried for relevant scientific articles. Study quality assessment of the included studies was conducted using the "National Heart, Lung and Blood Institute (NHLBI) Study Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group".ResultsForty-six studies fitted the criteria for the systematic review and were included in the analysis. Ten studies (21.7%) defined a migraine day for the study, while only 5 studies defined a headache day for the study (10.9%). The most common primary endpoint/objective of the studies was change in monthly migraine days (n = 16, 34.8%), followed by responder rate (n = 15, 32.6%) and change in monthly headache days (n = 5, 10.9%). Eight studies (17.4%) did not define the primary endpoint/objective. Thirty-three studies were graded as "good" quality and 13 studies were graded as "fair".ConclusionOur analysis shows rather significant heterogeneity and/or lack of predefined primary outcomes/objectives, definitions of outcomes measures and the use of longitudinal monitoring (e.g. headache diaries). Standardization of terminology, definitions and protocol procedures for real-world evidence studies of preventive treatments for migraine are recommended.Trial registrationThis study was registered with PROSPERO with ID CRD42022369366.
| S-EPMC10286407 | biostudies-literature
Project description:BackgroundCriteria, including clinical features and effective outcomes, for access and persistence of novel but costly treatments may vary between countries, thus affecting the health of patients. Monoclonal antibodies against the calcitonin gene-related peptide pathway (anti-CGRP mAbs) for migraine treatment are currently prescribed following strict criteria.ObjectiveThe aim was to assess the effectiveness and safety of three anti-CGRP mAbs (erenumab, galcanezumab, and fremanezumab) in consecutive resistant chronic migraine patients presenting at our Headache Center and the impact of criteria set by the Italian Medicines Agency to start and continue (achieving a ≥ 50% reduction in Migraine Disability Assessment [MIDAS] score) with treatment under the reimbursement program.MethodsA monocentric, prospective, cohort study was conducted, enrolling 203 severe (resistant to three or more preventive treatments) chronic migraine patients (84.7% with medication overuse) treated with erenumab (47.2%), galcanezumab (36.5%), or fremanezumab (16.3%), with up to 12 months follow-up. Patients completed a headache diary that included monthly migraine days (MMDs), number of analgesics and days with analgesic use, and patient-reported outcome questionnaires (MIDAS, Headache Impact Test 6 [HIT-6] questionnaires, and the Patient Global Impression of Change [PGIC] scale). Moreover, percentages of patients showing ≥ 50%, ≥ 75% and 100% reduction in MMDs (responder rates) were calculated at different follow-ups. A subgroup analysis was performed for patients with 12-month follow-up. Potential predictors of response were assessed at different follow-ups.ResultsIn the overall population, all three anti-CGRP mAbs were similarly effective and dropouts were 17.2%. The percentage of patients with ≥ 50% reduction in MMDs (min-max 36.4-56.8%) and in monthly analgesic consumption (51.1-75.7%) was inferior to the percentage of patients who reported a ≥ 50% reduction in MIDAS score (89.5-100%). HIT-6 score was also consistently reduced at all follow-ups. In patients with a 12-month follow-up, MIDAS and HIT-6 scores were also reduced at all follow-ups compared with baseline, with 84.4-100% of patients achieving a ≥ 50% reduction in MIDAS score, and patients with a ≥ 50% response rate ranging from 36.4 to 66.6%. No severe adverse events were recorded. Fewer migraine days at baseline were associated with ≥ 50% response rate at 1 month and fewer MMDs, years of chronic migraine, and monthly analgesic use at 6 months.ConclusionIn resistant chronic migraine patients, anti-CGRP mAbs are effective and safe. A ≥ 50% reduction in MIDAS score seems to be the most advantageous outcome measure in this setting, which allows most severe migraine patients to persist with treatment.
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Project description:Migraine is a common neurologic disorder characterized by attacks consisting of unilateral, throbbing headache accompanied by photophobia, phonophobia, and nausea which remarkably reduces the patients' quality of life. Not migraine-specific non-steroidal anti-inflammatory drugs (NSAIDs) are effective in patients affected by mild episodic migraine whilst in moderate or severe episodic migraine and in chronic migraineurs triptans and preventative therapies are needed. Since these treatments are endowed with serious side effects and have limited effectiveness new pharmacological approaches have been investigated. The demonstrated pivotal role of calcitonin gene-related peptide (CGRP) has fostered the development of CGRP antagonists, unfortunately endowed with liver toxicity, and monoclonal antibodies (mAbs) toward circulating CGRP released during migraine attack or targeting its receptor. Currently, four mAbs, eptinezumab, fremanezumab, galcanezumab for CGRP and erenumab for CGRP canonical receptor, have been studied in clinical trials for episodic and chronic migraine. Apart from the proven effectiveness, these antibodies have resulted well tolerated and could improve the compliance of the patients due to their long half-lives allowing less frequent administrations. This study aims at investigating the still poorly clear pathogenesis of migraine and the potential role of anti-CGRP mAbs in the scenario of prophylaxis of migraine.
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Project description:BackgroundIn daily practice, anti-CGRP monoclonal antibodies (MAbs) may be useful in chronic migraine (CM) with medication overuse (MO), but data is limited. We evaluated their effectiveness in a real-life clinical cohort.MethodsThis is a prospective study conducted in CM patients with and without medication overuse treated with monthly MAbs during 6 months (erenumab/galcanezumab). We collected headache characteristics, including acute medication intake, through an electronic diary. We compared patients (1) with and without MO at baseline, (2) with and without ongoing MO after treatment, defining MO resolution as < 10 or 15 days/month of acute medication intake, according to analgesic type, during the 6-month treatment.ResultsOf 139 CM patients completing 6-month treatment with anti-CGRP MAbs, 71.2% (99/139) had MO at baseline. After 6 months, patients with and without MO at baseline had significant and similar proportions of ≥50% reduction in migraine days/month (MO: 63.6% vs. non-MO: 57.5%, p = 0.500). 60.6% (60/99) no longer satisfied MO definition. Reduction in headache frequency compared to baseline occurred in both MO-ongoing and MO-resolution group, although those who stopped overusing had a greater improvement (headache days/month: - 13.4 ± 7.6 vs. -7.8 ± 7.2, p < 0.0001). No differences in MO resolution were observed according to the MAbs used. Baseline lower pain severity was associated with MO resolution (OR [95%]:0.236[0.054-0.975]; p = 0.049).ConclusionsIn real-life anti-CGRP MAbs are as effective in CM patients with MO as in patients without it and facilitate MO cessation. Reduction in headache frequency and acute medication days/month occurs regardless of whether patients stop overusing or not.
| S-EPMC8499507 | biostudies-literature
Project description:BackgroundChronic 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.MethodsWe 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.ResultsTwo 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.ConclusionBoth 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.
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