Targeting Calcitonin Gene-related Peptide Research Articles

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

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

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

BackgroundMigraine 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.MethodsThe 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.ResultsDuring 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).ConclusionsOur 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 registrationThe study was registered in clinicaltrials.gov with code NCT04659226 and in the Novartis database with code CAMG334AIT05T.

Meningeal lymphatic CGRP signaling governs pain via cerebrospinal fluid efflux and neuroinflammation in migraine models.

Recently developed anti-migraine therapeutics targeting calcitonin gene-related peptide (CGRP) signaling are effective, though their sites of activity remain elusive. Notably, the lymphatic vasculature is responsive to CGRP signaling, but whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology is unknown. Mice with lymphatic vasculature deficient in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin (NTG)-mediated chronic migraine exhibit reduced pain and light avoidance compared to NTG-treated littermate controls. Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG revealed increased MLV-immune interactions compared to cells from untreated mice. Interestingly, the relative abundance of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM1)-interacting CD4+ T cells was increased in the deep cervical lymph nodes of NTG-treated control mice but not in NTG-treated CalcrliLEC mice. Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial (VE)-cadherin rearrangement and reduced functional permeability. Likewise, intra cisterna magna injection of CGRP caused rearrangement of VE-Cadherin, decreased MLV uptake of cerebrospinal fluid (CSF), and impaired CSF drainage in control mice, but not in CalcrliLEC mice. Collectively, these findings reveal a previously unrecognized role for lymphatics in chronic migraine, whereby CGRP signaling primes MLVs-immune interactions and reduces CSF efflux.

New Daily Persistent Headache.

This article describes the clinical features, etiology, differential diagnosis, management, and prognosis of new daily persistent headache. New daily persistent headache has attracted renewed attention as it may arise in the setting of a COVID-19 infection. Spontaneous intracranial hypotension, particularly from CSF-venous fistulas, remains an important secondary headache disorder to consider before diagnosing new daily persistent headache. Symptomatic treatment for new daily persistent headache may include acute and preventive therapies used for migraine and tension-type headache, such as triptans, oral preventive agents, onabotulinumtoxinA, and agents that target calcitonin gene-related peptide. New daily persistent headache is a daily headache syndrome that starts acutely and can only be diagnosed after 3 months have elapsed and other secondary and primary headache diagnoses have been excluded. The clinical manifestations largely resemble either chronic migraine or chronic tension-type headache. The underlying cause is unknown, but it is plausible that multiple etiologies exist and that it is not a single disease entity. The prognosis is variable but often poor, and the treatment approach is largely extrapolated from the management of chronic migraine and chronic tension-type headache.

Elevated plasma levels of calcitonin gene-related peptide in individuals with rosacea: A cross-sectional case-control study.

Understanding the role of calcitonin gene-related peptide (CGRP) in the pathogenesis of rosacea might provide new therapeutic avenues for individuals with this disease. To compare plasma levels of CGRP between individuals with rosacea and healthy controls. In this cross-sectional case-control study conducted in Copenhagen, Denmark, we collected blood samples from the antecubital vein from adults with rosacea and from healthy controls. We enrolled 123 individuals with rosacea and 68 healthy controls. After adjusting for age and sex, plasma levels of CGRP were significantly higher in individuals with rosacea (mean, 95% confidence interval: 140.21 pmol/L, 128.50-151.92 pmol/L), compared with controls (110.77 pmol/L, 99.91-120.14 pmol/L, p = 0.002). Plasma levels of CGRP were not affected by age, sex, BMI, concomitant migraine, rosacea sub- or phenotype, concomitant disease or current treatment. Participants were not age-, sex- and BMI-matched. Elevated plasma levels of CGRP in individuals with rosacea suggest a role of CGRP in the pathogenesis of rosacea. Targeting CGRP signalling might hold therapeutic promise in people affected by this disease. NCT03872050.

Real-world Impact of Fremanezumab on Migraine-Related Health Care Resource Utilization in Patients with Comorbidities, Acute Medication Overuse, and/or Unsatisfactory Prior Migraine Preventive Response.

Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, is indicated for preventive treatment of migraine in adults. Real-world evidence assessing the effect of fremanezumab on migraine-related medication use, health care resource utilization (HCRU), and costs in patient populations with comorbidities, acute medication overuse (AMO), and/or unsatisfactory prior migraine preventive response (UPMPR) is needed. Data for this US, retrospective claims analysis were obtained from the Merative® MarketScan® Commercial and supplemental databases. Eligible adults with migraine initiated fremanezumab between 1 September 2018 and 30 June 2019 (date of earliest fremanezumab claim is the index date), had≥ 12months of continuous enrollment prior to initiation (preindex period) and ≥ 6months of data following initiation (postindex period; variable follow-up after 6months), and had certain preindex migraine comorbidities (depression, anxiety, and cardiovascular disease), potential AMO, or UPMPR. Changes in migraine-related concomitant acute and preventive medication use, HCRU, and costs were assessed pre- versus postindex. In total, 3193 patients met the eligibility criteria. From pre- to postindex, mean (SD) per patient per month (PPPM) number of migraine-related acute medication and preventive medication claims (excluding fremanezumab), respectively, decreased from 0.97 (0.90) to 0.86 (0.87) (P < 0.001) and 0.94 (0.74) to 0.81 (0.75) (P < 0.001). Migraine-related outpatient and neurologist office visits, emergency department visits, and other outpatient services PPPM decreased pre- versus postindex (P < 0.001 for all), resulting in a reduction in mean (SD) total health care costs PPPM from US$541 (US$858) to US$490 (US$974) (P = 0.003). Patients showed high adherence and persistence rates, with mean (SD) proportion of days covered of 0.71 (0.29), medication possession ratio of 0.74 (0.31), and persistence duration of 160.3 (33.2) days 6months postindex. Patients with certain migraine comorbidities, potential AMO, and/or UPMPR in a real-world setting had reduced migraine-related medication use, HCRU, and costs following initiation of fremanezumab. Graphical abstract available for this article.

Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update.

To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene-related peptide (CGRP) for the prevention of migraine. All migraine preventive therapies previously considered to be first-line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine-specific therapies have been developed based on a broad foundation of pre-clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP-targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first-line approaches. Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo-controlled clinical trials, post hoc analyses and open-label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. The evidence for the efficacy, tolerability, and safety of CGRP-targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive "real-world" clinical experience. The data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies and that serious adverse events associated with CGRP-targeting therapies are rare. The CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.

Eptinezumab for the preventive treatment of episodic and chronic migraine: a narrative review.

Eptinezumab, a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), was recently approved in Europe for the prophylactic treatment of migraine in adults who have at least four migraine days a month. Eptinezumab is administered by intravenous infusion every 12 weeks. During recent months, a considerable amount of evidence from eptinezumab trials has been published. The aim of this review is to describe the existing evidence on the tolerability, safety and efficacy of eptinezumab in patients with migraine. Data from randomized (PROMISE-1, PROMISE-2, RELIEF and DELIVER) and open-label (PREVAIL) phase 3 clinical trials have demonstrated the favorable effect of eptinezumab in migraine symptoms from first day of treatment. These studies showed that eptinezumab results in an overall reduction in mean monthly migraine days (MMDs), increases in the ≥50% and ≥ 75% migraine responder rates (MRRs) and improvements in patient-reported outcome measures in both patients with episodic migraine (EM) and with chronic migraine (CM), including patients who failed previous preventive treatments. The RELIEF trial also showed that eptinezumab, within 2 h of administration, reduced headache pain, migraine-associated symptoms and acute medication use when administered during a migraine attack. Eptinezumab benefits manifested as early as day 1 after dosing and with the subsequent doses lasted up to at least 2 years. Treatment-emergent adverse events reported by ≥2% of patients included upper respiratory tract infection and fatigue. Current evidence demonstrates that eptinezumab has a potent, fast-acting, sustained migraine preventive effect in patients with EM and CM. Eptinezumab has also shown to be well tolerated, supporting its use in the treatment of patients with migraine and inclusion in the current migraine therapeutic options.

Monoclonal Antibody Targeting CGRP Relieves Cisplatin-Induced Neuropathic Pain by Attenuating Neuroinflammation.

Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1β, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1β, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.

Efficacy and Safety of Anti-calcitonin Gene-Related Peptide (CGRP) Monoclonal Antibodies in Preventing Migraines: A Systematic Review.

The neuropeptide calcitonin gene-related peptide (CGRP) is an essential pathophysiological treatment for migraines. A unique class of medications called CGRP monoclonal antibodies target CGRP and its receptor and have demonstrated promising benefits in the treatment and prevention of migraines. This study sought to identify and assess the quality of existing systematic reviews about the effectiveness of CGRP antibodies for preventing migraines, as well as systematically review and synthesize the evidence on these topics. This included the four Food and Drug Administration (FDA)-approved medications erenumab, galcanezumab, fremanezumab, and eptinezumab. The effectiveness and safety of these monoclonal antibodies in preventing migraines should also be examined in light of patient characteristics, and any gaps in the body of knowledge should be noted in order to suggest new lines of investigation. Data gathering included a thorough search of internet databases (PubMed, Cochrane Library, Web of Science, and Scopus) for relevant research released between 2018 and 2023. The findings imply that CGRP monoclonal antibodies are efficient and secure for preventing migraines and may be considered a first-line alternative for treating migraines and drug misuse. The results further imply that combination treatment with CGRP antibodies and onabotulinumtoxinA may enhance the prevention of migraine in adults. With suggestions for more studies to find and address these variables, the significance of genetic and epigenetic factors in the progression of pediatric patients' acute postoperative pain to chronic postsurgical pain is underlined. All four anti-CGRP monoclonal antibodies, erenumab, fremanezumab, galcanezumab, and eptinezumab, were shown to be safe and effective for the prevention of migraine when the research additionally looked at their individual effectiveness and safety. Additionally, the study discovered considerable variances in effectiveness amongst various groups. However, further investigation is required to establish the best time and dosage and the effect of patient characteristics on the effectiveness and safety of these medications.

Predictors of galcanezumab response in a real-world study of Korean patients with migraine

To assess factors associated with galcanezumab response in a real-world study of Korean patients with migraine. Predictors of the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP(-R) mAb) have been rarely investigated in Asians. We prospectively recruited and followed up patients with migraine who received monthly galcanezumab treatment in a single university hospital from June 2020 to October 2021. We defined the treatment response with ≥ 50% reduction in moderate/severe headache days in the 3rd month of treatment compared to baseline. Responders and non-responders were compared in terms of demographics, disease characteristics and severity, and previous response to migraine prophylactic treatments. Potential predictors of anti-CGRP(-R) mAb response were tested by using the univariable and multivariable logistic regression analyses. Among 104 patients (81.7% female; mean age 42.0 ± 13.02; 76.9% chronic migraine; and 45.5% medication overuse headache) included, 58 (55.7%) were responders. Non-responders had more chronic migraine, medication overuse headache, monthly headache days, days with acute medication, and daily headaches (i.e. chronic migraine persisting everyday without remission). The multivariable logistic analysis showed chronic migraine (OR 0.05 [95% CI 0.00–0.82], p = 0.036) and the number of previously failed preventive medication classes (OR 0.55 [95% CI 0.33–0.92], p = 0.024] were independently associated with treatment response. Chronic migraine and multiple failures from preventive medication are associated with poor galcanezumab response. Further studies are needed to investigate if earlier treatment before disease chronification or multiple failures may lead to a greater therapeutic gain from anti-CGRP(-R) mAb treatment.

Molecular Mechanisms of Migraine: Nitric Oxide Synthase and Neuropeptides.

Migraine is a common condition with disabling attacks that burdens people in the prime of their working lives. Despite years of research into migraine pathophysiology and therapeutics, much remains to be learned about the mechanisms at play in this complex neurovascular condition. Additionally, there remains a relative paucity of specific and targeted therapies available. Many sufferers remain underserved by currently available broad action preventive strategies, which are also complicated by poor tolerance and adverse effects. The development of preclinical migraine models in the laboratory, and the advances in human experimental migraine provocation, have led to the identification of key molecules likely involved in the molecular circuity of migraine, and have provided novel therapeutic targets. Importantly, the identification that vasoconstriction is neither necessary nor required for headache abortion has changed the landscape of migraine treatment and has broadened the therapy targets for patients with vascular risk factors or vascular disease. These targets include nitric oxide synthase (NOS) and several neuropeptides that are involved in migraine. The ability of NO donors and infusion of some of these peptides into humans to trigger typical migraine-like attacks has supported the development of targeted therapies against these molecules. Some of these, such as those targeting calcitonin gene-related peptide (CGRP), have already reached clinical practice and are displaying a positive outcome in migraineurs for the better by offering targeted efficacy without significant adverse effects. Others, such as those targeting pituitary adenylate cyclase activating polypeptide (PACAP), are showing promise and are likely to enter phase 3 clinical trials in the near future. Understanding these nitrergic and peptidergic mechanisms in migraine and their interactions is likely to lead to further therapeutic strategies for migraine in the future.

Rimegepant for migraine: acute efficacy beyond the USA

The safety and efficacy of rimegepant, a synthetic molecule that competes with calcitonin gene-related peptide (CGRP) for binding to its receptor, have been shown in two phase 3 studies on symptomatic treatment 1 Lipton RB Croop R Stock EG et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N Engl J Med. 2019; 381: 142-149 Crossref PubMed Scopus (177) Google Scholar , 2 Croop R Goadsby PJ Stock DA et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019; 394: 737-745 Summary Full Text Full Text PDF PubMed Scopus (172) Google Scholar and one on prophylactic treatment 3 Croop R Lipton RB Kudrow D et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021; 397: 51-60 Summary Full Text Full Text PDF PubMed Scopus (106) Google Scholar of migraine, all done in the USA. On the basis of these data, rimegepant was the first CGRP antagonist (gepant) to be approved by the US Food and Drug Administration and European Medicines Agency for both symptomatic and prophylactic treatment of migraine, giving it a unique and innovative role in the treatment of headaches. Rimegepant is available as a pill for oral administration as needed by people with migraine (ie, whenever they have a migraine attack 4 Mitsikostas DD Belesioti I Arvaniti C et al. Patients' preferences for headache acute and preventive treatment. J Headache Pain. 2017; 18: 102 Crossref PubMed Scopus (26) Google Scholar ), possibly without the risk of developing medication overuse headache, and without the need to take another medication for migraine prophylaxis. Until the development of the anti-CGRP treatments, all prophylactic anti-migraine medications had been repurposed from other diseases; these older treatments have little evidence of efficacy in migraine prophylaxis and have well known side-effects, which increases the likelihood that individuals have adverse events, reducing adherence and benefit. 5 Charles A Pozo-Rosich P Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019; 394: 1765-1774 Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar By contrast, CGRP-pathway-targeting drugs are mechanism-based, are migraine-specific, and have very good evidence of tolerability and safety. 6 Hepp Z Dodick DW Varon SF Gillard P Hansen RN Devine EB Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015; 35: 478-488 Crossref PubMed Scopus (254) Google Scholar Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trialAmong adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. Full-Text PDF

Peter Goadsby: knowledge of politics, politics of knowledge

If you work in headache and migraine, you don't need me to tell who Peter Goadsby is, but just in case, he is professor of neurology and director of the National Institute for Health Research's clinical research facility at King's College London, consultant neurologist at King's College Hospital and Great Ormond Street Hospital (both London, UK), and professor emeritus of neurology at the University of California (Los Angeles, CA, USA). I am sure you'll know that he challenged the received vascular mechanism of migraine to unravel one based on dysfunctional neuropeptide production in the trigeminal nerve. You will also know his work lies behind the advent of drugs targeting calcitonin gene-related peptide (CGRP) and its receptor—monoclonal antibodies for keeping migraine at bay, and gepants, which have given relief to many migraineurs. You might even know about his being co-recipient of the 2021 Brain Prize, and his election as a fellow to the Royal Society in May, 2022. But you won't be aware that he initially told me he was so focused on his work that he'd be pretty dull to write about. Well, that was hardly true: especially when he told me he once thought he'd become a politician—a politician with knowledge.

Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trial

No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant-an orally administered small molecule CGRP antagonist-with placebo in the acute treatment of migraine among adults in these countries. This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran-Mantel Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed. 1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4-13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6-20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events. Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. BioShin Limited. For the Chinese and Korean translations of the abstract see Supplementary Materials section.

Effectiveness of Fremanezumab for the Preventive Treatment of Migraine: Second Interim Analysis of the Observational PEARL Study (P12-12.002)

Effectiveness of Fremanezumab for the Preventive Treatment of Migraine: Second Interim Analysis of the Observational PEARL Study (P12-12.002)

Migraine: from pathophysiology to treatment

Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system areas and networks. A growing increase in the understanding of migraine pathophysiology in recent years has facilitated translation of that knowledge into novel treatments, which are currently becoming available to patients in many parts of the world and are substantially changing the clinical approach to the disease. In the first part of this review, we will provide an up to date overview of migraine pathophysiology by analyzing the anatomy and function of the main regions involved in the disease, focusing on how these give rise to the plethora of symptoms characterizing the attacks and overall disease. The second part of the paper will discuss the novel therapeutic agents that have emerged for the treatment of migraine, including molecules targeting calcitonin gene-related peptide (gepants and monoclonal antibodies), serotonin 5-HT1F receptor agonists (ditans) and non-invasive neuromodulation, as well as providing a brief overview of new evidence for classic migraine treatments.

Effect of switching to erenumab in non-responders to a CGRP ligand antibody treatment in migraine: A real-world cohort study.

Therapeutic options for migraine prevention in non-responders to monoclonal antibodies (mAbs) targeting Calcitonin Gene-Related Peptide (CGRP) and its receptor are often limited. Real-world data have shown that non-responders to the CGRP-receptor mAb erenumab may benefit from switching to a CGRP ligand mAb. However, it remains unclear whether, vice versa, erenumab is effective in non-responders to CGRP ligand mAbs. In this study, we aim to assess the efficacy of erenumab in patients who have previously failed a CGRP ligand mAb. This monocentric retrospective cohort study included patients with episodic or chronic migraine in whom a non-response (< 30% reduction of monthly headache days during month 3 of treatment compared to baseline) to the CGRP ligand mAbs galcanezumab or fremanezumab led to a switch to erenumab, and who had received at least 3 administrations of erenumab. Monthly headache days were retrieved from headache diaries to assess the ≥30% responder rates and the absolute reduction of monthly headache days at 3 and 6 months of treatment with erenumab in this cohort. From May 2019 to July 2022, we identified 20 patients who completed 3 months of treatment with erenumab after non-response to a CGRP ligand mAb. Fourteen patients continued treatment for ≥6 months. The ≥30% responder rate was 35% at 3 months, and 45% at 6 months of treatment with erenumab, respectively. Monthly headache days were reduced from 18.6 ± 5.9 during baseline by 4.1 ± 3.1 days during month 3, and by 7.0 ± 4.8 days during month 6 compared to the month before treatment with erenumab (p < 0.001, respectively). Responders and non-responders to erenumab did not differ with respect to demographic or headache characteristics. Switching to erenumab in non-responders to a CGRP ligand mAb might be beneficial in a subgroup of resistant patients, with increasing responder rates after 6 months of treatment. Larger prospective studies should aim to predict which subgroup of patients benefit from a switch.

Evaluating the efficacy of CGRP mAbs and gepants for the preventive treatment of migraine: A systematic review and network meta-analysis of phase 3 randomised controlled trials.

Several novel treatments targeting the calcitonin gene-related peptide pathway have been developed for migraine. We evaluated the efficacy of these medications, including atogepant, rimegepant, erenumab, eptinezumab, fremanezumab, and galcanezumab, for the prevention of migraine via network meta-analysis. Databases, including MEDLINE via PubMed, EMBASE, and Cochrane central, were systematically reviewed, and all eligible phase 3 randomised controlled trials were included. Nineteen studies (n = 14,584 participants) were included. Studies included episodic (n = 11) and chronic (n = 4) migraine or both (n = 4). All interventions, except for eptinzumab 30 mg, significantly reduced mean monthly migraine days compared to placebo. All medications had a higher ≥50% responder rate than placebo and results were statistically significant in those with the subcutaneous or intravenous route of administrations, but not with the oral one. All medications significantly reduced mean monthly headache days, although no data for this outcome was available for rimegepant, and mean monthly acute medication days, with no data for eptinezumab. The results show that medications targeting calcitonin gene-related peptide were effective in preventing migraine compared to placebo. Considering limitations of single studies, different populations such as episodic and chronic migraine, and the absence of head-to-head trials, all novel treatments decreased mean monthly migraine and headache days, and showed higher 50%, 75% and 100% responder rates than placebo.Trial registration: PROSPERO registration: CRD42022310579.

Randomized controlled studies evaluating Topiramate, Botulinum toxin type A, and mABs targeting CGRP in patients with chronic migraine and medication overuse headache: A systematic review and meta-analysis.

This systematic review focuses on chronic migraine patients with medication overuse headache using, respectively, topiramate, botulinum toxin type A, and human monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. A systematic search was conducted in the databases CENTRAL, MEDLINE, Embase and Web of Science until May 2022. We included randomized controlled trials reporting the outcomes of change in monthly headache/migraine days, ≥50% response rates and change in medication overuse status. Studies were excluded if response rates were not reported. Risk of bias assessment was performed using the Cochrane RoB2 tool. The quality of evidence for outcomes across included studies was evaluated according to the five factors outlined in Cochrane GRADE approach. The initial search resulted in 1599 records. Following screening, 10 studies met our inclusion criteria, while seven studies with sufficient data were included in the meta-analysis. Studies assessing Botulinum toxin type A included 1139 patients and showed a mean reduction in headache frequency by 1.92 days per month compared to placebo (-1.92; 95% CI -2.68 to -1.16). Studies assessing human monoclonal antibodies included 1982 patients, and showed significant positive effect compared to placebo for all measured outcomes. The overall odds ratio for the ≥50% response rate was 2.90 (95% CI, 2.23 to 3.78). No significant difference was observed in the frequency of adverse effect for both Botulinum toxin type A and low dose of human monoclonal antibodies compared to placebo. There is currently insufficient evidence to determine the impact of topiramate in chronic migraine patients with medication overuse headache. Botulinum toxin type A and human monoclonal antibodies targeting calcitonin gene-related peptide receptor were beneficial in reducing monthly migraine days and ≥50% response rate, but uncertainties remained for Botulinum toxin type A regarding response rate. The effect size for human monoclonal antibodies was greater with relatively lower drop-out rate. High-quality randomized trials are required to evaluate the effect of topiramate in chronic migraine patients with medication overuse headache.