Targeting Calcitonin Gene-related Peptide Research Articles

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.

Nutrition and Calcitonin Gene Related Peptide (CGRP) in Migraine.

Targeting calcitonin gene-related peptide (CGRP) and its receptor by antibodies and antagonists was a breakthrough in migraine prevention and treatment. However, not all migraine patients respond to CGRP-based therapy and a fraction of those who respond complain of aliments mainly in the gastrointestinal tract. In addition, CGRP and migraine are associated with obesity and metabolic diseases, including diabetes. Therefore, CGRP may play an important role in the functioning of the gut-brain-microflora axis. CGRP secretion may be modulated by dietary compounds associated with the disruption of calcium signaling and upregulation of mitogen-activated kinase phosphatases 1 and 3. CGRP may display anorexigenic properties through induction of anorexigenic neuropeptides, such as cholecystokinin and/or inhibit orexigenic neuropeptides, such as neuropeptide Y and melanin-concentrating hormone CH, resulting in the suppression of food intake, functionally coupled to the activation of the hypothalamic 3',5'-cyclic adenosine monophosphate. The anorexigenic action of CGRP observed in animal studies may reflect its general potential to control appetite/satiety or general food intake. Therefore, dietary nutrients may modulate CGRP, and CGRP may modulate their intake. Therefore, anti-CGRP therapy should consider this mutual dependence to increase the efficacy of the therapy and reduce its unwanted side effects. This narrative review presents information on molecular aspects of the interaction between dietary nutrients and CGRP and their reported and prospective use to improve anti-CGRP therapy in migraine.

Trigeminal neuralgia and the merit of small clinical trials

Trigeminal neuralgia is a severe chronic neuropathic pain condition characterised by paroxysmal pain in a region of the face corresponding to one or more divisions of the trigeminal nerve. 1 Cruccu G Di Stefano G Truini A Trigeminal neuralgia. N Engl J Med. 2020; 383: 754-762 Crossref PubMed Scopus (90) Google Scholar Available treatments are not always effective and can be associated with intolerable side-effects. 2 Bendtsen L Zakrzewska JM Abbott J et al. European Academy of Neurology guideline on trigeminal neuralgia. Eur J Neurol. 2019; 26: 831-849 Crossref PubMed Scopus (171) Google Scholar In trigeminal neuralgia, and in neuropathic pain in general, available drugs have all been identified through empirical clinical observations, whereas investigational drugs identified through bottom-up translational approaches have not been efficacious in clinical trials. 3 Finnerup NB Attal N Haroutounian S et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015; 14: 162-173 Summary Full Text Full Text PDF PubMed Scopus (2042) Google Scholar This situation contrasts with migraine, for which several new drugs have been identified through translational approaches and approved for clinical use, from the triptans in the 1990s to more recent approvals of selective serotonin receptor agonists and drugs targeting calcitonin gene-related peptide (CGRP). Safety and efficacy of erenumab in patients with trigeminal neuralgia in Denmark: a double-blind, randomised, placebo-controlled, proof-of-concept studyErenumab did not reduce pain intensity compared with placebo in patients with trigeminal neuralgia and CGRP probably does not have an important role in paroxysmal pain. Well tolerated, effective treatments in trigeminal neuralgia are still needed. Full-Text PDF

New Oral Drugs for Migraine.

Migraine is a common and disabling neurological disorder, with several manifestations, of which pain is just one. Despite its worldwide prevalence, there remains a paucity of targeted and effective treatments for the condition, leaving many of those affected underserved by available treatments. Work over the last 30+ years has recently led to the emergence of the first targeted acute and preventive treatments in our practice since the triptan era in the early 1990s, which are changing the landscape of migraine treatment. These include the monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. Evolving work on novel therapeutic targets, as well as continuing to exploit drugs used in other disorders that may also have a therapeutic effect in migraine, is likely to lead to more and more treatments being able to be offered to migraineurs. Future work involves the development of agents that lack vasoconstrictive effects, such as lasmiditan, do not contribute to medication overuse, such as the gepants, and do not interact with other drugs that may be used for the disorder, as well as agents that can act both acutely and preventively, thereby utilising the quantum between acute and preventive drug effects which has been demonstrated with different migraine drugs before. Here we discuss the evolution of oral migraine treatments over the last 5 years, including those that have gained regulatory approval and reached clinical practice, those in development and potential other targets for the future.

CGRP-Targeted Therapy for Episodic and Chronic Cluster Headache.

Chronic cluster headache (CH) substantially affects patients' quality of life, and treatment remains challenging. The current article reviewed controlled studies for new treatment options targeting calcitonin gene-related peptide (CGRP) or its receptors in CH and discussed the current gaps and future directions for the treatment of chronic CH. Two anti-CGRP monoclonal antibodies (i.e., galcanezumab and fremanezumab) completed randomized-control trials for efficacy for the preventive treatment of episodic and chronic CH. Galcanezumab was effective for preventing episodic CH but not chronic CH. Fremanezumab was ineffective in preventing episodic and chronic CH. Studies for other anti-CGRP monoclonal antibodies and CGRP antagonists are still pending for results. There are no randomized controlled trials for CGRP-targeted therapies that showed efficacy for chronic CH prevention. The different responses to galcanezumab between episodic and chronic CH may be due to the study design, i.e., the allowance of concomitant preventive therapies in the chronic CH study but not in the episodic CH study. Another reason for the discrepancies is the different roles and sensitivity of CGRP in chronic CH.

Use of Non-pharmacological Therapies in Individuals With Migraine Eligible for Treatment With Monoclonal Antibodies Targeting Calcitonin Gene-Related Peptide (CGRP)-Signaling: A Single-Center Cross-Sectional Observational Study.

IntroductionAccessibility of treatment with monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) signaling pathway is impeded by regulatory restrictions. Affected individuals may seek out other services including non-pharmacological therapies. Thus, we found it timely to ascertain the use of non-pharmacological therapies in individuals with treatment-resistant migraine eligible for and naïve to treatment with CGRP-signaling targeting monoclonal antibodies.MethodsWe conducted a single-center cross-sectional observational study of patients eligible for and naïve to treatment with monoclonal antibodies targeting CGRP or its receptor. We recorded demographical information (gender, age, educational level, employment status, and income), disease burden (frequency of headache days and migraine days), previous use of preventive pharmacological medications for migraine, and use of non-pharmacological therapies over the past 3 months including frequency of interventions, costs, and patient-reported assessment of efficacy on a 6-point scale (0: no efficacy, 5: best possible efficacy).ResultsWe included 122 patients between 17 June 2019 and 6 January 2020; 101 (83%) were women and the mean age was 45.2 ± 13.3 years. One-third (n = 41 [34%]) had used non-pharmacological therapy within the past 3 months. Among these participants, the median frequency of different interventions was 1 (IQR: 1–2), the median number of monthly visits was 2.3 (IQR: 1.3–4), mean and median monthly costs were 1,086 ± 1471, and 600 (IQR: 0–1200) DKK (1 EUR = ~7.5 DKK), respectively, and median patient-reported assessment of the efficacy of interventions was 2 (IQR: 0–3).ConclusionEven in a high-income country with freely accessible headache services and universal healthcare coverage, there was a non-negligible direct cost in parallel with low satisfaction for non-pharmacological therapies among patients at a tertiary headache center.

Eficácia e Segurança do Fremanezumab na Enxaqueca: Experiência de Vida Real de um Centro Neurológico Privado

Introduction: Migraine is the first cause of disability under 50 years of age. In the last decade there were significant advances in the comprehension of this disorder that led to the development of specific treatments, such as those targeting calcitonin gene-related peptide (CGRP) or its receptor including monoclonal antibodies. Here, we present real life results of a cohort of migraine patients treated with fremanezumab. Material and Methods: We analysed data, collected prospectively for 18 months, of consecutive patients with migraine treated with fremanezumab in a Lisbon center. Patients had a baseline evaluation and monthly visits. Data included monthly headache days, a composite headache measure (days x pain intensity), acute treatment intake and adverse events. Patients also fulfilled quality of life and migraine impact scales at 1st, 3rd, 6th, 9th and 12th months of treatment and were evaluated after treatment withdrawal. Efficacy was defined as a reduction ≥ 30% or ≥ 50% of the number of monthly headache days (in chronic and episodic migraine, respectively) compared to baseline. Results: We included 29 patients (47.8 years of age, 25 female) with chronic (n=20) or high frequency episodic (n=9), migraine previously resistant to an average of 3.3 oral preventives/botulinum toxin, 20 with medication overuse. Efficacy increased from 62% in the 1st month to 76.9% on the 3rd and there was a significant reduction of migraine headache days, acute medication intake, index and HIT-6 scores and improved quality of life in all assessment periods compared to baseline. The most common adverse events were constipation (27.6%) and pain on the injection site (20.7%) leading to interruption of treatment in one patient. There was no increase in the number of headache days or acute medication intake five months after treatment interruption. Conclusion: These results corroborate data from clinical trials about the efficacy and safety of fremanezumab, showing an improvement of different migraine measures and impact, even in patients with resistant migraine and medication overuse. In general, adverse events were well tolerated not leading to treatment withdrawal.

EE433 A US Claims Database Analysis of the Impact of Fremanezumab on Migraine-Related Health Care Utilization and Costs in Patients with Common Comorbidities, Acute Medication Overuse, or Difficult-to-Treat Migraine

Patients with common comorbidities, acute medication overuse (AMO), or difficult-to-treat migraine (DTTM) may have high healthcare resource utilization (HCRU) and costs. There are limited real-world data on use of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) targeting calcitonin gene-related peptide (CGRP), in these patients. This retrospective claims database study evaluated migraine-related HCRU and costs for patients with comorbidities, AMO, or DTTM initiating fremanezumab treatment.

EE19 A Retrospective US Claims Database Analysis of the Impact of Fremanezumab on Migraine-Related Health Care Utilization and Costs in Patients with Potential Acute Medication Overuse

Real-world data are limited on use of fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that targets calcitonin gene-related peptide (CGRP), in migraine patients with acute medication overuse (AMO). This retrospective US claims database analysis evaluated migraine-related healthcare resource utilization (HCRU) and costs for patients with potential AMO initiating fremanezumab treatment.

EE226 A US Claims Database Analysis of the Impact of Fremanezumab on Migraine-Related Health Care Utilization and Costs in Patients with Common Comorbidities, Acute Medication Overuse, or Difficult-to-Treat Migraine Following Prior Erenumab Use

There are limited real-world data on fremanezumab, a fully-humanized monoclonal antibody (mAb; IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), in patients with prior exposure to other CGRP pathway-targeted mAbs such as erenumab. A US retrospective claims database study evaluated migraine-related healthcare resource utilization (HCRU) and costs for patients initiating fremanezumab treatment with common comorbidities, acute medication overuse (AMO), or difficult-to-treat migraine (DTTM) and prior erenumab exposure.

CO114 Real-World Reductions in Acute Medication Use for Patients with Migraine Initiating Fremanezumab: A 12-Month Retrospective US Claims Analysis

Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for preventive treatment of migraine in adults. A prior database study found claims for acute medication were reduced 6 months post-initiation of fremanezumab versus 6 months pre-initiation. Twelve-month post-initiation data are now available. Changes in acute medication use in the 12 months prior to fremanezumab initiation and during a 12-month follow-up period were retrospectively analyzed.

EE57 Real-World Reductions in Migraine-Related Health Care Resource Utilization and Costs for Patients Initiating Fremanezumab: A 12-Month Retrospective US Claims Analysis

Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for preventive treatment of migraine in adults. This retrospective analysis assessed baseline patient characteristics and migraine-related health care resource utilization (HCRU) and costs in US patients with migraine 12 months before and 12 months after initiating fremanezumab treatment.

Recent advances in targeting calcitonin gene-related peptide for the treatment of menstrual migraine: A narrative review.

Menstrual migraine (MM) has a longer duration and higher drug resistance than non-perimenstrual migraine. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in the peripheral and central nervous systems throughout the trigeminovascular system. The CGRP/CGRP receptor axis plays an important role in sensory physiology and pharmacology. CGRP receptor antagonists and anti-CGRP monoclonal antibodies (mAbs) have shown consistent efficacy and tolerability in the prevention of chronic or episodic migraine and are now approved for clinical use. However, few studies have reported the use of these drugs in MM, and no specific treatment for MM has been approved. This review aimed to shed light on the recent advances in targeting calcitonin gene-related peptides for the treatment of menstrual migraines in PubMed. In this review, we first discuss the axis of the CGRP/CGRP receptor. We then discuss the role of CGRP receptor antagonists and anti-CGRP mAbs in MM treatment. Finally, we discuss the role of the combination of anti-CGRP mAbs and CGRP receptor antagonists in migraine treatment and the drugs that inhibit CGRP release. Altogether, the anti-CGRP mAbs or CGRP receptor antagonists showed good efficacy and safety in the treatment of MM.

Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): a multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial

The monoclonal antibody eptinezumab, which targets calcitonin gene-related peptide, has shown migraine preventive effects starting the day following infusion and acceptable safety and tolerability in phase 3 trials, but benefits in the subpopulations of patients with previous preventive treatment failures were not examined. We aimed to investigate the safety and efficacy of eptinezumab for migraine prevention in adults with migraine and two-to-four previous preventive treatment failures. DELIVER was a multicentre, multi-arm, phase 3b trial comprising a 24-week double-blind, placebo-controlled period and a 48-week dose-blinded extension. We recruited adults with episodic or chronic migraine with at least 4 monthly migraine days (as per International Headache Society guidelines) and documented evidence of two-to-four previous preventive treatment failures within the past 10 years, from 96 study locations across Europe (n=93) and the USA (n=3). Patients were randomly assigned (1:1:1) via a centralised randomisation system, stratified by baseline monthly headache days and country, to eptinezumab 100 mg, eptinezumab 300 mg, or placebo. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (captured using a daily electronic diary) in weeks 1-12, assessed in the full analysis set. All participants and study personnel were masked to study drug assignments. The dose-blinded extension period is ongoing. The trial is registered with ClinicalTrials.gov, NCT04418765, and EudraCT, 2019-004497-25. Between June 1, 2020, and Oct 7, 2021, 891 individuals were randomly assigned and received at least one dose of study drug (safety population; eptinezumab 100 mg n=299 [34%], eptinezumab 300 mg n=294 [33%], placebo n=298 [33%]). 865 patients completed the placebo-controlled period. The change from baseline to weeks 1-12 in mean monthly migraine days was -4·8 (SE 0·37) with eptinezumab 100 mg, -5·3 (0·37) with eptinezumab 300 mg, and -2·1 (0·38) with placebo. The difference from placebo in change in mean monthly migraine days from baseline was significant with eptinezumab 100 mg (-2·7 [95% CI -3·4 to -2·0]; p<0·0001) and eptinezumab 300 mg (-3·2 [-3·9 to -2·5]; p<0·0001). Treatment-emergent adverse events occurred in 127 (42%) of 299 patients in the eptinezumab 100 mg group, in 120 (41%) of 294 in the eptinezumab 300 mg group, and in 119 (40%) of 298 in the placebo group. The most common treatment-emergent adverse event was COVID-19 (20 [7%] of 299 patients in the eptinezumab 100 mg group, 17 [6%] of 294 in the eptinezumab 300 mg group, and 16 [5%] of 298 in the placebo group). Serious adverse events were uncommon (five [2%] of 299 in the eptinezumab 100 mg group, seven [2%] of 294 in the eptinezumab 300 mg group, four [1%] of 298 in the placebo group) and included anaphylactic reaction (eptinezumab 300 mg n=2) and COVID-19 (eptinezumab 100 mg n=1 and eptinezumab 300 mg n=1). In adults with migraine and two-to-four previous preventive treatment failures, eptinezumab provided significant migraine preventive effects compared with placebo, with acceptable safety and tolerability, indicating that eptinezumab might be an effective treatment option for this patient population. The dose-blinded extension period will provide additional long-term safety data in patients with migraine and previous preventive treatment failures. H Lundbeck.