Network meta-analysis of migraine therapies: balancing efficacy and safety.

Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy. An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure-response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose-response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated. The results suggested that a 20 mg dose of MK-3207 (EC50 of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose-response would be reached around 40-100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial. The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose-response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.

Background: Rimegepant, a small molecule oral calcitonin gene-related peptide (CGRP) receptor antagonist, is approved for the acute and preventive treatment of migraine. We hypothesized that intermittent CGRP receptor blockade with rimegepant 75 mg acute treatment as needed (PRN) might result in reductions in monthly migraine days (MMD) over time, and was evaluated as the study objective. Methods: This was a post-hoc analysis of adults with ≥6 MMD at baseline who self-administered rimegepant 75 mg orally PRN for acute treatment of migraine up to 52-weeks in an open-label safety study (BHV3000-201; NCT03266588). Outcome measures (defined as median time to) and response rates (defined as proportion of patients reporting) were captured for ≥30% and ≥50% reduction of baseline MMD. Results: 1044 participants with ≥6 MMD at baseline were analyzed. Median time to ≥30% reduction in MMD was 12 weeks (IQR; 4–40 weeks); median time to ≥50% reduction was 32 weeks (IQR; 12-NR weeks). Reduction in MMD was observed over time regardless of baseline migraine frequency, however higher baseline MMD were associated with a longer time to achieving ≥30% or ≥50% MMD reduction. Conclusion: In participants presenting with ≥6 MMD, PRN acute treatment of migraine attacks over 52-weeks with oral rimegepant 75 mg was observed to confer reductions in migraine frequency. Trial registration: NCT03266588

Background: This observational study presents preliminary real-world evidence on the comparative efficacy and safety of combination therapy with onabotulinumtoxinA and the CGRP receptor antagonist atogepant versus atogepant monotherapy in patients with treatment-refractory chronic migraine. Methods: Twenty adult patients (aged 18-75) meeting ICHD-3 criteria for refractory chronic migraine - defined by 8 monthly migraine days, MIDAS ³11, and inadequate response or intolerance to ³ 3 preventive therapies - were enrolled. Ten patients received atogepant monotherapy, while ten initiated combination therapy with onabotulinumtoxinA and atogepant. Efficacy was assessed over three months using changes in monthly migraine days, headache severity (Numerical Rating Scale, NRS), and disability scores (HIT-6, MIDAS). Acute medication use and tolerability were also evaluated. Results: The combination therapy group demonstrated significantly greater reductions in monthly migraine days, headache intensity, and disability scores compared to the monotherapy group. Responders - defined as patients remaining migraine-free for 36 consecutive weeks - were more frequent in the combination cohort. Both treatments were well tolerated, with no serious adverse events reported. Chronic migraine remains a debilitating condition, often resistant to standard preventive treatments. Dual blockade of the CGRP pathway - via onabotulinumtoxinA and a CGRP receptor antagonist - may offer synergistic benefits by targeting both peripheral and central CGRP mechanisms. Conclusion: These preliminary findings support the enhanced clinical efficacy and safety of combining onabotulinumtoxinA with CGRP receptor antagonists in managing refractory chronic migraine. This multimodal strategy may provide a personalized, mechanism-based approach to care and warrants further investigation in larger, controlled studies.

BackgroundMigraine is a common neurovascular disorder that has a severe impact on the individual daily life. Atogepant (AGN-241689) is an orally ingested, small-molecule drugs belonging to calcitonin gene-related peptide receptor antagonist, which has been initiated for the prophylactic treatment of migraine. However, there is no comprehensive literature to study the efficacy and safety of atogepant for the treatment of migraine. In this article, we present a meta-analysis of the available studies.MethodsMEDLINE, Embase, Cochrane Library and ClinicalTrials.gov were searched before October 20, 2021 for any relevant literature. Eventually, three randomized clinical trials (RCTs) with 2,466 patients were included in our study.ResultsWe pooled 2,466 patients from 3 RCTs and primary outcome was mean monthly migraine days, the secondary endpoints were monthly headache days, acute medication use days per month and ≥ 50% reduction in monthly migraine days, baseline to end of trials. It was found that atogepant (10 mg, 30 mg, 60 mg once a day) led to a significant reduction in monthly migraine days (P < 0.00001, P < 0.00001, P = 0.007), monthly headache days (P < 0.00001, P < 0.00001, P = 0.001), and monthly medication use days (P < 0.00001, P < 0.00001, P = 0.0001), and an increase in the proportion of people with ≥ 50% reduction in monthly migraine days (P = 0.0008, P = 0.02, P = 0.04) in comparison with placebo. Moreover, there were no significant differences (P > 0.05) in outcomes of adverse events between atogepant and placebo.ConclusionsAtogepant has shown good efficacy and safety in the prophylactic treatment of migraine, and further studies are expected.

Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial

IntroductionWe systematically reviewed the efficacy and safety of Calcitonin Gene‐Related Peptide (CGRP) antagonists for migraine treatment.MethodsVarious databases including PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), WanFang Data were electronically searched for randomized controlled trials (RCTs) on CGRP antagonists for migraine treatment since inception to March 2021. The trials were screened for inclusion, after which the methodological quality of the included trials was assessed. Then meta‐analysis was performed using the Revman 5.3 software.ResultsA total of 26 RCTs involving 21,736 patients were included. The CGRP antagonists group included 13,635 patients while the control group included 8101 patients. Meta‐analysis showed that compared to the control group, CGRP antagonists were associated with various significant effects, including the following outcome indicators: (1) number of patients with ≥50% reduction from baseline in mean monthly migraine days (RR = 1.50, 95% CI [1.39,1.62], p < .00001); (2) number of patients with pain free at 2 h postdose (RR = 1.98, 95% CI [1.77, 2.20], p < .00001), and (3) number of patients with 2–24 h sustained pain free postdose (RR = 2.18, 95% CI [1.93, 2.46], p < .00001). However, the number of patients with any adverse events was significantly high in the antagonists group, relative to the control group (RR = 1.08, 95% CI [1.04, 1.12], p < .0001).ConclusionsCGRP antagonists are significantly effective for migraine treatment; however, they are associated with various adverse events. Due to limitations with regards to quantity and quality of the included studies, the above conclusions should be verified by more high quality studies.

New therapeutic agents marketed in 2020: Part 1

BackgroundAtogepant is an oral, small-molecule, calcitonin gene–related peptide receptor antagonist for the preventive treatment of migraine.MethodsIn the double-blind, phase 3 ADVANCE trial, participants with 4–14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time course of efficacy of atogepant for the preventive treatment of migraine. Analyses included change from baseline in mean monthly migraine days during each of the three 4-week treatment periods, change in weekly migraine days during weeks 1–4, and proportion of participants with a migraine on each day during the first week.ResultsWe analyzed 873 participants (n = 214 atogepant 10 mg, n = 223 atogepant 30 mg, n = 222 atogepant 60 mg, n = 214 placebo). For weeks 1–4, mean change from baseline in mean monthly migraine days ranged from −3.1 to −3.9 across atogepant doses vs −1.6 for placebo (p < 0.0001). For weeks 5–8 and 9–12, reductions in mean monthly migraine days ranged from −3.7 to −4.2 for atogepant vs −2.9 for placebo (p ≤ 0.012) and −4.2 to −4.4 for atogepant vs −3.0 for placebo (p < 0.0002), respectively. Mean change from baseline in weekly migraine days in week 1 ranged from −0.77 to −1.03 for atogepant vs −0.29 with placebo (p < 0.0001). Percentages of participants reporting a migraine on post-dose day 1 ranged from 10.8% to 14.1% for atogepant vs 25.2% with placebo (p ≤ 0.0071).ConclusionAtogepant demonstrated treatment benefits as early as the first full day after treatment initiation, and sustained efficacy across each 4-week interval during the 12-week treatment period.Clinical trial registration: ClinicalTrials.gov identifier: NCT03777059

Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial.

Migraine remains one of the most prevalent and disabling neurological disorders that often affects a person during their most productive years. Migraine afflicts approximately 11% of the adult population globally, causes substantial disability, which translates into lost productivity both at home and at work. Clearly there remains a need for new approaches to treat migraine and calcitonin gene-related peptide (CGRP) receptor antagonists have the potential to be a major advance in antimigraine therapy. CGRP was first proposed to play a role in migraine pathophysiology a little over 20 years ago and today there is considerable evidence that CGRP plays a key role in the pathogenesis of migraine. CGRP is a 37 amino acid vasoactive neuropeptide largely expressed in sensory neurons. It was observed that plasma levels of CGRP were elevated during the headache phase of migraine and the levels were normalized concomitantly with pain relief. This observation, along with other evidence, suggested that CGRP receptor antagonists might represent a novel approach to migraine treatment. The advent of small molecule CGRP receptor antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and effectiveness in treating migraine. This review will highlight the biology of CGRP as it pertains to migraine; discuss the CGRP receptor; spotlight the development of CGRP receptor antagonists; and examine site of action.

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. 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. 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.

Importance of the field: Calcitonin gene-related peptide (CGRP) receptor antagonists have recently come to attention with the development of olcegepant and telcagepant for the treatment of migraine. The availability of high-affinity, non-peptide antagonists opens the way for trials of these compounds in other conditions where CGRP antagonism might be useful, such as septic shock and inhibition of angiogenesis.Areas covered in this review: This review summarises knowledge about the structure and signalling properties of the CGRP receptor. The clinical ramifications of targeting the CGRP receptor, the profiles of existing antagonists and the requirements for screening new compounds will be discussed.What the reader will gain: Readers will gain an overview of how current non-peptide antagonists seem to bind similar epitopes contributed by both calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), the main CGRP receptor subunits. We will discuss how current antagonists have low bioavailability, limiting their use. For selectivity at CGRP receptors, it will be necessary to target parts of the receptor influenced by both RAMP1 and CLR.Take home message: For the design of radically new antagonists, more structural information on the receptor is needed. Current screens are largely based on measuring CGRP-mediated changes in cAMP. CGRP receptors can influence other signalling pathways and pathway-selective allosteric antagonists may be useful, but more information is needed about the mechanism of action of CGRP to assess the value of this.

Migraine is a disabling disorder that affects individuals of all ages. To date, there are multiple limitations to using guidelines-recommended treatments and preventive therapies. The goal of this review was to provide a comprehensive clinical review of the safety, efficacy and prescribing information of the emerging calcitonin gene-related peptide (CGRP) antagonists. Agents in this new pharmacologic class were approved by the US Food and Drug Administration (FDA) for the treatment of acute migraine attack pain and the management of episodic and chronic migraine. A total of 12 randomized, placebo-controlled clinical trials were identified and included in the review utilizing databases such as clinicaltrial.gov, PubMed and EMBASE. The trials collectively evaluated six CGRP antagonists starting from the orally administered CGRPs such as rimegepant and ubrogepant, to the quarterly IV administered CGRP such as eptinezumab, and the monthly/quarterly subcutaneously administered agents such as erenumab, fremanezumab and galcanezumab. All agents displayed significant efficacy compared with placebo, measured by reduction in mean monthly migraine days (MMD). In addition, CGRP antagonists displayed a great tolerability profile with few adverse effects. These medications were neither associated with any cardiovascular-related adverse effects, nor do they currently have specific contraindications to pre-existing cardiovascular conditions. This can present a safe alternative to a wide range of patients who cannot be appropriately treated with first-line treatments such as triptans. No treatment-related death was reported in any of the clinical trials outlined and discussed. Calcitonin gene-related peptide antagonists are safe and efficacious medications both in treating acute migraine headache pain and the management of episodic and chronic migraine. Head-to-head comparative studies with current guideline-recommended treatments are needed. However, CGRP antagonists are promising agents that present an alternative solution for patients living with migraine.

BackgroundAtogepant is a CGRP receptor antagonist used in prevention of migraine. This study assesses the safety and efficacy of this drug in management of migraine headaches.MethodsPubMed, Scopus, Web of Science, and Cochrane CENTRAL were searched until March 24, 2025. Outcomes assessed included monthly migraine and headache day change from baseline at 12 weeks, ≥ 50% reduction in monthly migraine days (MMD), acute medication use days at 12 weeks, treatment-emergent adverse events (TEAE), score on Role Function-Restrictive domain of MSQ at 12 weeks, score on daily activity performance and physical impairment domains of AIM-D at 12 weeks. Subgroup analysis was performed based on different doses of atogepant.ResultsSix RCTs comprising of 4052 patients were included. Atogepant showed significant improvement in patients with migraine in terms of MMD over 12 weeks at all doses, 10 mg, 30 mg, and 60 mg. Moreover, it also reduced monthly headache days, had 50% reduction in MMD, and reduced days requiring acute medication use. Atogepant was shown to increase the risk of TEAE, particularly gastrointestinal (GI) side effect including constipation and nausea, however, occurrence of other side effects with atogepant use was insignificant.ConclusionAtogepant is a highly effective CGRP antagonist for migraine prevention, however, it is associated with increased incidence of GI side effects. Further studies are needed to comprehensively investigate the relationship between atogepant dosage and migraine improvement and safety profile.Supplementary informationThe online version contains supplementary material available at 10.1186/s12883-025-04394-z.

Calcitonin gene-related peptide (CGRP) receptor antagonists have been suggested as novel treatments for acute migraine. This study aimed to use meta-analysis to compare the safety and tolerability of five existing oral CGRP receptor antagonists (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant) with that of a placebo or triptans against acute migraine. Five prominent databases were searched to identify randomized controlled trials on this topic. The primary safety outcomes of interest were any adverse events (AEs) and treatment-related adverse events (TRAEs), and secondary outcomes were individual events, namely diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting. Fifteen studies met the eligibility criteria and were examined in detail. Although, compared to placebo, oral CGRP receptor antagonists significantly increased the incidence of any AEs (risk ratio [RR] = 1.15; 95% confidence interval [CI] = 1.07-1.23), there was no difference in the incidence of TRAEs (RR = 1.18; 95% CI = 1.00-1.38). Moreover, CGRP receptor antagonists were safer than triptans with respect to primary safety outcomes, such as any AEs (RR = 0.78; 95% CI = 0.63-0.98) and TRAEs (RR = 0.68; 95% CI = 0.58-0.79). Despite oral CGRP receptor antagonists posing a significantly higher risk of AEs when compared to placebo, CGRP receptor antagonists have a favorable safety profile compared to triptans. Our findings inform strategies to enhance safety and tolerability in the treatment of acute migraine.