Real-world persistence and costs among patients with chronic migraine treated with onabotulinumtoxinA or calcitonin gene-related peptide monoclonal antibodies.

BACKGROUND: Chronic migraine (CM) is a common neurologic disorder that imposes substantial burden on payers, patients, and society. Low rates of persistence to oral migraine preventive medications have been previously documented; however, less is known about persistence and costs associated with innovative nonoral migraine preventive medications. OBJECTIVE: To evaluate real-world persistence and costs among adults with CM treated with onabotulinumtoxinA (onabotA) or calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs). METHODS: This was a retrospective, longitudinal, observational study analyzing the IBM MarketScan Commercial and Medicare databases. The study sample included adults with CM initiating treatment with either onabotA or a CGRP mAb on or after January 1, 2018. Persistence and costs over 12 months after treatment initiation were evaluated using chi-square and Student's t-tests. Persistence to onabotA was compared with CGRP mAbs as a weighted average of the class and by individual CGRP mAbs. Mean pharmacy (acute and preventive), medical (inpatient, emergency department, and outpatient), and total costs are reported. Multivariate regression analyses were conducted to generate adjusted estimates of persistence and costs after controlling for potential confounders (age, sex, region, insurance type, number of baseline comorbidities, Charlson Comorbidity Index, and number of previously used oral migraine preventive medications). RESULTS: Of 66,303 individuals with onabotA or CGRP mAb claims, 2,697 with CM met the inclusion/exclusion criteria. In the total population, individuals were primarily female (85.5%), lived in the South (48.5%), and had a mean (SD) age of 44 (12) years, which was consistent across the onabotA and CGRP mAb cohorts. Common comorbid conditions included anxiety (23.9%), depression (18.2%), hypertension (16.5%), and sleep disorders (16.9%). After adjusting for potential confounding variables, persistence to onabotA during the 12-month follow-up period was 40.7% vs 27.8% for CGRP mAbs (odds ratio [OR] = 0.683; 95% CI = 0.604-0.768; P < 0.0001). Persistence to erenumab, fremanezumab, and galcanezumab was 25.5% (OR = 0.627; 95% CI = 0.541-0.722; P < 0.0001), 30.3% (OR = 0.746; 95% CI = 0.598-0.912; P = 0.0033), and 33.7% (OR = 0.828; 95% CI = 0.667-1.006; P = 0.058). All-cause ($18,292 vs $18,275; P = 0.9739) and migraine-related ($8,990 vs $9,341; P = 0.1374) costs were comparable between the onabotA and CGRP mAb groups. CONCLUSIONS: Among adults with CM receiving onabotA and CGRP mAbs, individuals initiating onabotA treatment had higher persistence compared with those receiving CGRP mAbs. Total all-cause and migraine-related costs over 12 months were comparable between those receiving onabotA and CGRP mAbs. DISCLOSURES: This study was sponsored by Allergan (prior to its acquisition by AbbVie), they contributed to the design and interpretation of data and the writing, reviewing, and approval of final version. Writing and editorial assistance was provided to the authors by Dennis Stancavish, MS, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and was funded by AbbVie. The opinions expressed in this article are those of the authors. The authors received no honorarium/fee or other form of financial support related to the development of this article. Dr Schwedt serves on the Board of Directors for the American Headache Society and the American Migraine Foundation. Within the prior 12 months he has received research support from Amgen, Henry Jackson Foundation, Mayo Clinic, National Institutes of Health, Patient-Centered Outcomes Research Institute, SPARK Neuro, and US Department of Defense. Within the past 12 months, he has received personal compensation for serving as a consultant or advisory board member for AbbVie, Allergan, Axsome, BioDelivery Science, Biohaven, Collegium, Eli Lilly, Ipsen, Linpharma, Lundbeck, and Satsuma. He holds stock options in Aural Analytics and Nocira. He has received royalties from UpToDate. Dr Lee and Ms Shah are employees of AbbVie and may hold AbbVie stock. Dr Gillard was an employee of AbbVie and may hold AbbVie stock. Dr Knievel has served as a consultant for AbbVie, Amgen, Eli Lilly, and Biohaven; conducted research for AbbVie, Amgen, and Eli Lilly; and is on speaker programs for AbbVie and Amgen. Dr McVige has served as a speaker and/or received research support from Allergan (now AbbVie Inc.), Alder, Amgen/Novartis, Avanir, Biohaven, Eli Lilly, Lundbeck, and Teva. Ms Wang and Ms Wu are employees of Genesis Research, which provides consulting services to AbbVie. Dr Blumenfeld, within the past 12 months, has served on advisory boards for Allergan, AbbVie, Aeon, Alder, Amgen, Axsome, BDSI, Biohaven, Impel, Lundbeck, Lilly, Novartis, Revance, Teva, Theranica, and Zosano; as a speaker for Allergan, AbbVie, Amgen, BDSI, Biohaven, Lundbeck, Lilly, and Teva; as a consultant for Allergan, AbbVie, Alder, Amgen, Biohaven, Lilly, Lundbeck, Novartis, Teva, and Theranica; and as a contributing author for Allergan, AbbVie, Amgen, Biohaven, Novartis, Lilly, and Teva. He has received grant support from AbbVie and Amgen. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvieclinicaltrials.com/hcp/data-sharing/.

Temporal analysis of remote electric neuromodulation for the prevention of migraine.

Aim: To evaluate the onset, magnitude and persistence of efficacy of remote electrical neuromodulation (REN) compared with placebo for the preventive treatment of migraine. Materials & methods: Analysis was conducted on data from a prospective, double-blind, placebo-controlled clinical trial, which assessed the efficacy of REN for the prevention of migraine. The number of monthly migraine days (MMD) per group was calculated in 2-week intervals and compared between the groups. Results: Differences between the active (N = 95) and placebo (N = 84) groups reached significance at 2 weeks: therapeutic gain 0.84 MMD; p = 0.036. 4 weeks gain 1.59 MMD; p = 0.025, 6 weeks gain 2.27 MMD; p < 0.001, 8 weeks gain 2.68 MMD; p < 0.001. Conclusion: REN provides rapid and consistent efficacy in preventive treatment of migraine.

Multimodal Migraine Management and the Pursuit of Migraine Freedom: A Narrative Review.

Migraine is a neurologic disease with a complex pathophysiology that can be controlled with current treatment options but not cured. Therefore, treatment expectations are highly variable. The concept of migraine freedom was recently introduced and can mean different things, with some, for example, expecting complete freedom from headache and associated symptoms and others accepting the occasional migraine attack if it does not impact functioning. Therefore, migraine management should be optimized so that patients can have the best opportunity to achieve their optimal treatment goals. With migraine freedom as a goal and, given the complex pathophysiology of migraine and the high incidence of comorbidities among individuals with migraine, treatment with a single modality may be insufficient, as it may not achieve migraine freedom in those with more frequent or disabling attacks. In this clinical perspective article, we have identified four key, partially overlapping principles of multimodal migraine treatment: (1) manage common comorbidities; (2) control modifiable risk factors for progression by addressing medication and caffeine overuse; (3) diagnose and treat secondary causes of headache, if present; and (4) individualize acute and preventive treatments to minimize pain, functional disability, and allodynia. There are many barriers to pursuing migraine freedom, and strategies to overcome them should be optimized. Migraine freedom should be an aspirational goal both at the individual attack level and for the disease overall. We believe that a comprehensive and multimodal approach that addresses all barriers people with migraine face could move patients closer to migraine freedom.

Injection technique of the upper face with onabotulinumtoxinA in chronic migraine.

BACKGROUND: The objective is to review the technique of onabotulinumtoxinA injection treatment in the glabellar and frontal regions using the PREEMPT (Phase III REsearch Evaluating Migraine Prophylaxis Therapy) paradigm, with review of the aesthetic issues related to the procedure. OnabotulinumtoxinA is an effective medication for the prevention of chronic migraine. The PREEMPT injection paradigm has been validated in randomized clinical trials and real-world settings. This treatment includes injections in the forehead and glabella area. In addition, for aesthetic uses, glabella onabotulinumtoxinA injections are done in similar muscles specifically the procerus, corrugator supercilii, and frontalis muscles. Often patients who have been injected with onabotulinumtoxinA for chronic migraine have concerns about their appearance and will ask if they can see an aesthetic injector to improve this. This is a difficult issue as onabotulinumtoxinA should be injected with an interval of 10-12 weeks to avoid development of antibodies against onabotulinumtoxinA, so all injections (migraine and aesthetic) should ideally be done close together; however, if an aesthetic injection is done on the same day as a PREEMPT injection, the effect of the PREEMPT injection will not yet be visible as it takes time for onabotulinumtoxinA effects to be seen. Thus, there is a risk of a potential overdose in a particular area if aesthetic injections are done without input from the PREEMPT injector. METHODS: This is a narrative review supported by photographic documentation showing the technique of onabotulinumtoxinA injection of the upper face, considering anatomical differences between patients, and combining the needs in neurology and aesthetic medicine fields. RESULTS: Practitioners treating chronic migraine often modify some of the principles of the PREEMPT paradigm. Many practitioners are unsure about injections in the glabellar and frontal areas. The authors present a technique for using the PREEMPT protocol and adapting this to the individual patient's anatomy to prevent an unsightly appearance or ptosis. In addition, sites are provided where an aesthetic injector could inject to improve the patient's appearance without overlapping with the PREEMPT injection sites. CONCLUSION: Adherence to the PREEMPT injection protocol provides an evidence-based approach to achieving clinical benefit for patients with chronic migraine. Aesthetic elements of the treatment of the glabella and forehead require additional attention. The authors provide practical considerations and recommendations regarding this.

Once-daily oral atogepant for the long-term preventive treatment of migraine: Findings from a multicenter, randomized, open-label, phase 3 trial.

OBJECTIVE: To assess long-term safety, tolerability, and efficacy of once-daily oral atogepant 60 mg in adults with migraine. BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of episodic migraine. METHODS: A 52-week, multicenter, randomized, open-label trial of adults (18-80 years) with migraine. Lead-in trial completers or newly enrolled participants with 4-14 migraine days/month were enrolled and randomized (5:2) to atogepant 60 mg once daily or oral standard care (SC) migraine preventive medication. The primary objective was to evaluate the safety and tolerability of atogepant; safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, and Columbia-Suicide Severity Rating Scale scores. Efficacy assessments (atogepant only) included change from baseline in mean monthly migraine days (MMDs) and the proportion of participants with reductions from baseline of ≥50%, ≥75%, and 100% in MMDs. RESULTS: The trial included 744 participants randomized to atogepant 60 mg (n = 546) or SC (n = 198). The atogepant safety population was 88.2% female (n = 479/543) with a mean (standard deviation) age of 42.5 (12.0) years. TEAEs occurred in 67.0% (n = 364/543) of participants treated with atogepant 60 mg. The most commonly reported TEAEs (≥5%) were upper respiratory tract infection (10.3%; 56/543), constipation (7.2%; 39/543), nausea (6.3%; 34/543), and urinary tract infection (5.2%; 28/543). Serious TEAEs were reported in 4.4% (24/543) for atogepant. Mean (standard error) change in MMDs for atogepant was -3.8 (0.1) for weeks 1-4 and -5.2 (0.2) at weeks 49-52. Similarly, the proportion of participants with ≥50%, ≥75%, and 100% reductions in MMDs increased from 60.4% (310/513), 37.2% (191/513), and 20.7% (106/513) at weeks 1-4 to 84.2% (282/335), 69.9% (234/335), and 48.4% (162/335), at weeks 49-52. CONCLUSION: Daily use of oral atogepant 60 mg for preventive treatment of migraine during this 1-year, open-label trial was safe, well tolerated, and efficacious.

Phase Ib, open-label, fixed-sequence, drug-drug interaction, safety, and tolerability study between atogepant and ubrogepant in participants with a history of migraine.

OBJECTIVE: To evaluate potential drug-drug interactions of ubrogepant and atogepant. BACKGROUND: Ubrogepant and atogepant, calcitonin gene-related peptide (CGRP) receptor antagonists, are recently approved drugs for acute and preventive treatment of migraine, respectively. For patients with migraine who are prescribed atogepant for the preventive treatment of migraine, health care providers could prescribe ubrogepant for the acute treatment of breakthrough migraine attacks. METHODS: A phase Ib, multi-center, open-label, fixed-sequence study was conducted in participants diagnosed with migraine for at least 1 year. To assess the primary objective of pharmacokinetic interactions in this phase I trial, the highest United States Food and Drug Administration-approved individual dose strengths of atogepant (60 mg once daily) and ubrogepant (100 mg) were utilized, with ubrogepant being administered on a fixed-dose schedule every 3 days, regardless of whether a participant was experiencing a migraine attack. Secondary endpoints included safety and tolerability. Clinical safety measurements were monitored throughout the study. RESULTS: Of the 31 participants enrolled, 26 completed the study. A single dose of ubrogepant had no statistically significant effect on atogepant pharmacokinetics. Co-administration of ubrogepant with atogepant resulted in a 19% increase (geometric mean ratio 118.80, 90% confidence interval [CI] 108.69-129.84) in the ubrogepant area under the plasma concentration-time curve and a 26% increase (geometric mean ratio 125.63, 90% CI 105.58-149.48) in the ubrogepant maximum plasma concentration. These statistically significant changes in ubrogepant exposure were not clinically meaningful, and no new safety concerns were identified for the combination. CONCLUSION: The combination use of atogepant and ubrogepant was safe and well tolerated in adult participants with a history of migraine enrolled in the study. Pharmacokinetic changes during co-administration were not clinically meaningful.

Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial.

OBJECTIVE: To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine. BACKGROUND: Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary. RESULTS: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval -3.9 to -1.5], p < 0.001). The significance was maintained when analyzing the episodic (-3.2 ± 3.4 vs. -1.0 ± 3.6, p = 0.003) and chronic (-4.7 ± 4.4 vs. -1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group. CONCLUSION: Applied every other day, REN is effective and safe for the prevention of migraine.

Effectiveness and Safety of Chronic Migraine Preventive Treatments: A Systematic Literature Review.

INTRODUCTION: Numerous medications are used for the preventive treatment of chronic migraine (CM), including oral treatments, onabotulinumtoxinA (onabotA; BOTOX), and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). Despite substantial clinical trial evidence, less is published about the real-world experience of these treatments based on data routinely collected from a variety of sources. This systematic review assessed real-world evidence on the effectiveness and safety of preventive treatments for CM in adults. METHODS: A systematic search of MEDLINE, Embase, and the Cochrane library with back-referencing and supplementary searches retrieved data published between January 2010 and February 2020. Publications were screened, extracted, and quality assessed. Data were narratively synthesized. Search criteria included preventive medications for CM. Evidence was available for topiramate, onabotulinumtoxinA, CGRP mAbs (erenumab, galcanezumab, and fremanezumab). OnabotulinumtoxinA was most commonly assessed (55 studies), followed by erenumab (six studies), multiple CGRP mAbs (one study), and topiramate (one study). Long-term data (> 1 year) were available for onabotulinumtoxinA only, with erenumab reported up 6 months, topiramate up to 3 months, and multiple CGRP mAbs up to 12 months. RESULTS: Substantial data demonstrated that onabotulinumtoxinA reduces the number/frequency of headaches, concomitant acute medication use, and impact of headaches on well-being and daily activity. More limited evidence showed benefits for the same parameters with erenumab. Single studies suggested topiramate and multiple CGRP mAbs decrease the number/frequency of headaches and impact of headaches. To date, onabotulinumtoxinA is the only preventive treatment for CM that has long-term safety data in real-world settings reporting treatment-related adverse events of up to 3 years. CONCLUSION: While substantial real-world evidence supports the long-term effectiveness and safety of onabotulinumtoxinA, real-world data on other preventive treatments of CM are currently limited to short term effectiveness due to their more recent approvals.

Post hoc analysis of clinical trial data and pharmacokinetic data to assess wearing-off of erenumab within monthly treatment cycle.

BACKGROUND: Treatment wearing-off has been reported for calcitonin gene-related peptide-pathway monoclonal antibodies, including erenumab, specifically in the last week of the monthly dosing cycle. OBJECTIVE: We sought to determine the consistency of erenumab effect throughout the monthly treatment cycle. METHODS: In this post hoc analysis of four pivotal double-blind, randomized controlled studies of erenumab in episodic and chronic migraine, we assessed wearing-off based on change in weekly migraine days at week 4 versus average over weeks 1-3 in each monthly dosing cycle. Analyses were conducted at each monthly dosing cycle in all patients, in responders (≥50% reduction in weekly migraine days), and in consistent responders (response in ≥2monthly cycles). RESULTS: There was no evidence of wearing-off in the full study populations of two global studies (N = 946 and N = 656) and two Japan studies (N = 475 and N = 261). In the full study population, mean change in weekly migraine days at week 4 compared with the average over week 1-3 ranged from 0.15 days improvement to 0.19 days worsening in the placebo group and 0.08 days improvement to 0.20 days worsening in the erenumab groups. A subgroup of responders experienced wearing-off, but the extent of wearing-off did not differ between erenumab and placebo groups. The mean change in weekly migraine days at week 4 compared with the average over weeks 1-3 ranged from 0.34 to 0.61 days worsening in the placebo group and 0.27 to 0.78 days worsening in the erenumab groups. Few patients had persistent wearing-off in ≥2 consecutive monthly treatment cycles. For erenumab-treated responders, serum erenumab concentrations were similar among patients experiencing wearing-off and those maintaining response. CONCLUSION: No systematic wearing-off with erenumab was identified. Further research is needed to determine if wearing-off reported for some patients in clinical practice reflects a true treatment response pattern or normal fluctuations in migraine frequency.

Effect of Atogepant for Preventive Migraine Treatment on Patient-Reported Outcomes in the Randomized, Double-blind, Phase 3 ADVANCE Trial.

BACKGROUND AND OBJECTIVES: The oral calcitonin gene-related peptide receptor antagonist atogepant is indicated for the preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes with atogepant in adults with migraine. METHODS: In this phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (ADVANCE), adults with 4-14 migraine days per month received atogepant (10, 30, or 60 mg) once daily or placebo. Secondary endpoints included changes from baseline in Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1 Role Function-Restrictive (RFR) domain at week 12 and mean monthly Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domains across the 12-week treatment period. Exploratory endpoints included change in MSQ Role Function-Preventive (RFP) and Emotional Function (EF) domains; AIM-D total scores; and change in Headache Impact Test (HIT)-6 scores. RESULTS: Of 910 participants randomized, 873 comprised the modified intent-to-treat population (atogepant: 10 mg [n = 214]; 30 mg [n = 223]; and 60 mg [n = 222]; placebo [n = 214]). All atogepant groups demonstrated significantly greater improvements vs placebo in MSQ RFR that exceeded minimum clinically meaningful between-group difference (3.2 points) at week 12 (least-square mean difference [LSMD] vs placebo: 10 mg [9.9]; 30 mg [10.1]; 60 mg [10.8]; all p < 0.0001). LSMDs in monthly AIM-D PDA and PI scores across the 12-week treatment period improved significantly for the atogepant 30 (PDA: -2.54; p = 0.0003; PI: -1.99; and p = 0.0011) and 60 mg groups (PDA: -3.32; p < 0.0001; PI: -2.46; p < 0.0001), but not for the 10 mg group (PDA: -1.19; p = 0.086; PI: -1.08; p = 0.074). In exploratory analyses, atogepant 30 and 60 mg were associated with nominal improvements in MSQ RFP and EF domains, other AIM-D outcomes, and HIT-6 scores at the earliest time point (week 4) and throughout the 12-week treatment period. Results varied for atogepant 10 mg. DISCUSSION: Atogepant 30 and 60 mg produced significant improvements in key patient-reported outcomes including MSQ-RFR scores and both AIM-D domains. Nominal improvements also occurred for other MSQ domains and HIT-6, reinforcing the beneficial effects of atogepant as a new treatment for migraine prevention. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03777059. Submitted: December 13, 2018; First patient enrolled: December 14, 2018. CLINICALTRIALS: gov/ct2/show/NCT03777059. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that daily atogepant is associated with improvements in health-related quality-of-life measures in patients with 4-14 migraine days per month.

Rates of Response to Atogepant for Migraine Prophylaxis Among Adults: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Some patients with migraine, particularly those in primary care, require effective, well-tolerated, migraine-specific oral preventive treatments. Objective: To examine the efficacy of atogepant, an oral, small-molecule, calcitonin gene-related peptide receptor antagonist, using 4 levels of mean monthly migraine-day (MMD) responder rates. Design, Setting, and Participants: This secondary analysis of a phase 3, double-blind, placebo-controlled randomized clinical trial evaluated the efficacy and safety of atogepant for the preventive treatment of migraine from December 14, 2018, to June 19, 2020, in adults with 4 to 14 migraine-days per month at 128 sites in the US. Interventions: Patients were administered 10 mg of atogepant (n = 222), 30 mg of atogepant (n = 230), 60 mg of atogepant (n = 235), or placebo (n = 223) once daily in a 1:1:1:1 ratio for 12 weeks. Main Outcomes and Measures: These analyses evaluated treatment responder rates, defined as participants achieving 50% or greater (α-controlled, secondary end point) and 25% or greater, 75% or greater, and 100% (prespecified additional end points) reductions in mean MMDs during the 12-week blinded treatment period. Results: Of 902 participants (mean [SD] age, 41.6 [12.3] years; 801 [88.8%] female; 752 [83.4%] White; 825 [91.5%] non-Hispanic), 873 were included in the modified intention-to-treat population (placebo, 214; 10 mg of atogepant, 214; 30 mg of atogepant, 223; and 60 mg of atogepant, 222). For the secondary end point, a 50% or greater reduction in the 12-week mean of MMDs was achieved by 119 of 214 participants (55.6%) treated with 10 mg of atogepant (odds ratio, 3.1; 95% CI, 2.1-4.6), 131 of 223 participants (58.7%) treated with 30 mg atogepant (odds ratio, 3.5; 95% CI, 2.4-5.3), 135 of 222 participants (60.8%) treated with 60 mg of atogepant (odds ratio, 3.8; 95% CI, 2.6-5.7), and 62 of 214 participants (29.0%) given placebo (P < .001). The numbers of participants who reported a 25% or greater reduction in the 12-week mean of MMDs were 157 of 214 (73.4%) for 10 mg of atogepant, 172 of 223 (77.1%) for 30 mg of atogepant, and 180 of 222 (81.1%) for 60 mg of atogepant vs 126 of 214 (58.9%) for placebo (P < .002). The numbers of participants who reported a 75% or greater reduction in mean MMDs were 65 of 214 (30.4%) for 10 mg of atogepant, 66 of 223 (29.6%) for 30 mg of atogepant, and 84 of 222 (37.8%) for 60 mg of atogepant compared with 23 of 214 (10.7%) for placebo (P < .001). The numbers of participants reporting 100% reduction in mean MMDs were 17 of 214 (7.9%) for 10 mg of atogepant (P = .004), 11 of 223 (4.9%) for 30 mg of atogepant (P = .02), and 17 of 222 (7.7%) for 60 mg of atogepant (P = .003) compared with 2 of 214 (0.9%) for placebo. Conclusions and Relevance: At all doses, atogepant was effective during the 12-week double-blind treatment period beginning in the first 4 weeks, as evidenced by significant reductions in mean MMDs at every responder threshold level. Higher atogepant doses appeared to produce the greatest responder rates, which can guide clinicians in individualizing starting doses. Trial Registration: ClinicalTrials.gov Identifier: NCT03777059.

Adjunctive treatment of chronic migraine using an oral dental device: overview and results of a randomized placebo-controlled crossover study.

OBJECTIVE: To assess the nocioceptive input of habitual nocturnal jaw clenching that acts as a contributing factor in migraine pathogenesis. BACKGROUND: Habitual nocturnal jaw clenching has been implicated as a trigger, particularly in those whose headaches are present upon waking or shortly thereafter. Nocturnal EMG studies of patients diagnosed with migraine show nearly twice the temporalis clenching EMG levels and double the bite force as matched asymptomatic controls, leading to the speculation that parafunctional clenching activity may have some role in headache pathogenesis. The NTI (Nociceptive Trigeminal Inhibition) oral device is a dental splint designed to reduce nocturnal jaw clenching intensity and is FDA approved for the prevention of medically diagnosed migraine pain based on open label studies. There are no prior placebo-controlled trials to assess the migraine prevention efficacy of the NTI splint. This is the first placebo-controlled cross-over study to assess the efficacy of the NTI splint in patients with Chronic Migraine. METHOD: A placebo controlled, single-blinded cross-over study was done with IRB oversight assessing the efficacy of the NTI splint compared to placebo using the change in the HIT-6 score as the outcome measure. RESULTS: 68% of refractory chronic migraine sufferers using the NTI as measured by sequential HIT 6 scores had at least a one-category improvement (severe to substantial, or substantial to some, or some to none) compared to 12% when using a placebo device. 36% of subjects using the NTI device reported a two-category improvement in their HIT-6 score, compared to 0% when using placebo. CONCLUSION: The improvement in HIT-6 scores produced by the NTI device, suggests that patients with Chronic Migraine may have intense nocturnal jaw clenching as a contributing factor to their headache related disability. An NTI device is one method of assessing whether jaw-clenching is a contributing factor to ongoing migraine. TRIAL REGISTRATION: Current Controlled Trials NCT04871581. 04/05/2021. Retrospectively registered.

Erenumab dosage for migraine prevention: An evidence-based narrative review with recommendations.

BACKGROUND: Therapeutic monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor or its ligand have changed the landscape of treatment options for migraine. Erenumab is the first and only fully human monoclonal antibody designed to target and block the CGRP receptor. It is approved by the Food and Drug Administration for preventive treatment of migraine in adults. The recommended dose of erenumab is 70 mg monthly, with guidance that some patients may benefit from the 140 mg monthly dose. There is a need for information to guide clinical practice on the comparative efficacy and safety of these two dosing options. OBJECTIVE: To evaluate therapeutic and tolerability differences between erenumab 70 and 140 mg based on evidence from published literature. METHODS: This narrative review evaluates therapeutic and tolerability differences between erenumab 70 and 140 mg based on a literature search using PubMed interface, Embase and Ovid MEDLINE(R) databases. The key search terms included migraine, AMG 334, AMG334, erenumab, erenumab-aooe, and Aimovig. The search was limited to English language articles or conference abstracts published up to May 2021. RESULTS: From the literature search, we retrieved 23 relevant articles/conference abstracts (19 articles [5 randomized, double-blind studies] and 4 conference abstracts) for inclusion in this narrative review. Although the recommended starting dosage of erenumab is 70 mg, this narrative review of the literature indicates that some patients may benefit from a dosage of 140 mg erenumab once monthly-especially those with difficult-to-treat disease and prior treatment failures. The evidence indicates that erenumab at 140 mg has a numerically better efficacy than 70 mg across a broad spectrum of migraine outcomes, including preventing progression to chronic migraine. CONCLUSION: Cumulative data from the literature support a therapeutic gain with an increase from erenumab 70 to 140 mg and a rationale for initiating 140 mg in selected patients.

Does "wearing off" of efficacy occur in galcanezumab-treated patients at the end of the monthly treatment cycle? Post hoc analyses of four phase III randomized trials.

OBJECTIVE: The purpose of this study was to propose a definition of "wearing off" at the individual patient-level and determine the percentage of patients with migraine who experience "wearing off" of efficacy of galcanezumab at the end of a treatment cycle using this predefined threshold. BACKGROUND: Anecdotal reports suggest that some patients may experience "wearing off" of efficacy during the last week of their calcitonin gene-related peptide monoclonal antibody treatment cycle. A previous post hoc analysis of galcanezumab demonstrated consistent efficacy at each week throughout all monthly dosing intervals at the population-level, but "wearing off" has not been assessed at the individual patient-level. METHODS: Post hoc analyses of clinical trial data from four galcanezumab phase III, randomized, placebo-controlled studies in a total of 2680 patients with high-frequency episodic migraine (EVOLVE-1, EVOLVE-2, and CONQUER studies) or chronic migraine (CM; REGAIN and CONQUER studies) were conducted. "Wearing off" was defined as an increase of greater than or equal to 2 weekly migraine headache days in the last week of the treatment cycle compared to the second week for at least 2 months. The analyses were conducted (1) in all patients and (2) in patients with a clinically meaningful response to treatment. RESULTS: The percentage of patients meeting the threshold of "wearing off" was not statistically significantly different among the placebo, galcanezumab 120 mg, and galcanezumab 240 mg treatment groups, both in the total population and in patients with a clinically meaningful response (all ≤9.0%). Although the frequency of "wearing off" in patients with CM and prior preventive failures was numerically greater in the galcanezumab groups (8/89 or 9.0%) compared to placebo (3/95 or 3.2%), these differences were not statistically significant. CONCLUSIONS: Consistent with previous analyses at the population-level that showed no evidence of decreased efficacy at the end of a treatment cycle, rates of individual patients meeting the threshold of "wearing off" in this analysis were low and similar among placebo, galcanezumab 120 mg, and galcanezumab 240 mg treatment groups.

Ubrogepant Is Safe and Efficacious in Participants Taking Concomitant Preventive Medication for Migraine: A Pooled Analysis of Phase 3 Trials.

INTRODUCTION: Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine that can be used to treat breakthrough attacks in individuals taking preventive treatment for migraine. We evaluated the impact of preventive medication use on the efficacy and safety of ubrogepant for the acute treatment of migraine. METHODS: This was an analysis of pooled efficacy data from the ACHIEVE I and ACHIEVE II phase 3 trials, in which efficacy of ubrogepant was assessed at 2 h after taking study medication for pain freedom, absence of most bothersome symptom (MBS), and pain relief. In addition, a long-term safety (LTS) extension trial was completed where safety was assessed on the basis of incidence and severity of treatment-emergent adverse events (TEAEs). Outcomes were compared between participants with or without prior (within 6 months) preventive medication use (anticonvulsants, beta blockers, antidepressants, or onabotulinumtoxinA). For efficacy analyses, data were pooled across ACHIEVE trials for the 50 mg and placebo groups; for safety analyses, data for all dose groups (50 mg and 100 mg) in the LTS trial were pooled. RESULTS: Preventive treatments were used by 417 of 2247 (18.6%) participants analyzed in the ACHIEVE trials and by 143 of 813 (17.5%) participants in the LTS trial. Responder rates for all outcomes were similar between participants with or without preventive treatment within each dose group (p > 0.05). No significant differences were noted across the different preventive medications. Rates and types of TEAEs were similar between participants with or without preventive treatment. No serious treatment-related adverse events were reported. CONCLUSION: Efficacy and safety of ubrogepant for the acute treatment of migraine were similar between participants with or without prior or current use of concomitant preventive medication. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02828020 (ACHIEVE I), NCT02867709 (ACHIEVE II), and NCT02873221 (long-term safety trial).

Real-World Evidence for Control of Chronic Migraine Patients Receiving CGRP Monoclonal Antibody Therapy Added to OnabotulinumtoxinA: A Retrospective Chart Review.

INTRODUCTION: Combination use of onabotulinumtoxinA and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) has the potential to be more effective than either therapy alone for migraine prevention. METHODS: This retrospective, longitudinal chart review included adults with chronic migraine treated at one clinical site with ≥ 2 consecutive cycles of onabotulinumtoxinA and ≥ 1 month of subsequent combination treatment with CGRP mAbs. Charts at time of mAb prescription (baseline) and up to four visits ~ 3, 6, 9, and 12 months post-baseline were reviewed for safety, tolerability, and outcome measures (monthly headache days [MHDs], headache intensity, and migraine-related disability [MIDAS]). RESULTS: Of 300 charts reviewed, 257 patients met eligibility criteria (mean age: 50 years; 82% women). Average headache frequency was 21.5 MHDs before initiation of onabotulinumtoxinA and 12.1 MHDs before adding CGRP mAb therapy. Prescribed mAbs were erenumab (78%), fremanezumab (6%), and galcanezumab (16%). Over the entire study, patients discontinued CGRP mAb more frequently than onabotulinumtoxinA (23 vs. 3%). Adverse events occurred in 28% of patients, most commonly constipation (9%). Compared with onabotulinumtoxinA alone (baseline), MHDs decreased significantly at all visits (mean decrease: 3.5-4.0 MHDs over ~ 6-12 months of combination treatment); 45.1% of patients had clinically meaningful improvement in migraine-related disability (≥ 5-point reduction in MIDAS score) after ~ 6 months. CONCLUSIONS: In this real-world study, combination treatment with onabotulinumtoxinA and CGRP mAbs was well tolerated, with no new safety signals identified, and was associated with additional clinically meaningful benefits. More real-world and controlled trials should be considered to further assess safety and potential benefits of combination treatment. Video abstract: Real-world data suggests that CGRP inhibitors improve onabotulinumtoxinA efficacy for chronic migraine (MP4 20,067 kb).

Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II.

OBJECTIVE: To examine the safety and efficacy of ubrogepant for acute treatment of migraine across cardiovascular (CV) disease risk categories. METHODS: ACHIEVE I and II were multicenter, double-blind, single-attack, phase 3 trials in adults with migraine, with or without aura. Participants were randomized 1:1:1 to placebo or ubrogepant (50 or 100 mg in ACHIEVE I; 25 or 50 mg in ACHIEVE II), to treat one migraine attack of moderate or severe headache pain intensity. This post-hoc analysis pooled data from ubrogepant 50 mg and placebo groups from the ACHIEVE trials to examine the safety and efficacy of ubrogepant by baseline cardiovascular disease risk factors. Using a cardiovascular risk assessment algorithm, participants were categorized as having no cardiovascular risk, low cardiovascular risk or moderate-high cardiovascular risk at baseline. Treatment-emergent adverse events were documented 48 h and 30 days after taking the trial medication. Co-primary efficacy outcomes were 2-h pain freedom and 2-h absence of most bothersome migraine-associated symptom. RESULTS: Overall, 3358 participants were randomized in the ACHIEVE trials (n = 2901 safety population; n = 2682 modified intent-to-treat population). In the safety population, 11% of participants were categorized as moderate-high (n = 311), 32% low (n = 920), and 58% no cardiovascular risk factors (n = 1670). The proportion of ubrogepant participants reporting a treatment-emergent adverse event was comparable across risk categories and similar to placebo. The treatment effects of ubrogepant versus placebo were consistent across cardiovascular risk categories for all efficacy outcomes. CONCLUSION: The safety and efficacy of ubrogepant for the acute treatment of a single migraine attack did not differ by the presence of major cardiovascular risk factors. No evidence of increased treatment-emergent adverse events or cardiac system organ class adverse events with ≥2 major cardiovascular risk factors and no safety concerns were identified.Trial Registration: ACHIEVE I ClinicalTrials.gov number, NCT02828020; ACHIEVE II ClinicalTrials.gov number, NCT02867709.

Pharmacokinetics and safety of ubrogepant when coadministered with calcitonin gene-related peptide-targeted monoclonal antibody migraine preventives in participants with migraine: A randomized phase 1b drug-drug interaction study.

OBJECTIVE: To evaluate the impact of two calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant. BACKGROUND: People taking CGRP-targeted mAbs for migraine prevention sometimes take ubrogepant, an oral small-molecule CGRP receptor antagonist, for acute treatment of breakthrough migraine attacks. DESIGN: In this two-arm, multicenter, open-label, phase 1b trial, adults with migraine were randomized to arm 1 (ubrogepant ± erenumab) or arm 2 (ubrogepant ± galcanezumab). The PK profile of ubrogepant was characterized for administration before and 4 days after CGRP-targeted mAb injection. Participants received single-dose ubrogepant 100 mg on day 1, subcutaneous erenumab 140 mg (arm 1) or galcanezumab 240 mg (arm 2) on day 8, and ubrogepant 100 mg once daily on days 12-15. In each study arm, serial blood samples were drawn on days 1 and 12 for measurement of plasma ubrogepant concentrations. The primary outcomes were area under the plasma ubrogepant concentration-time curve (AUC) from time 0 to t post-dose (AUC0- t ) and from time 0 to infinity (AUC0-inf ), and maximum plasma concentration (Cmax ) of ubrogepant when ubrogepant was administered before or after a single dose of erenumab or galcanezumab. Vital signs and laboratory parameters were monitored. RESULTS: Forty participants enrolled (20 per arm; mean [standard deviation] ages, 32.2 [8.9] and 38.4 [8.8] years; 50% [10/20] and 60% [12/20] female in arms 1 and 2, respectively). There were no significant differences in ubrogepant Cmax after versus before erenumab administration (geometric least-squares mean [LSM] ratio, 1.04 [90% CI, 0.93-1.16]), and no significant differences in AUC0- t (1.06 [0.96-1.16]) or AUC0-inf (1.05 [0.96-1.15]). Similarly, ubrogepant Cmax (1.00 [90% CI, 0.82-1.20]), AUC0- t (1.05 [0.90-1.23]), and AUC0-inf (1.05 [0.90-1.22]) geometric LSM ratios were statistically equivalent after galcanezumab versus ubrogepant alone. Treatment-emergent adverse events (TEAEs) were similar to those reported with each treatment alone. No serious TEAEs, TEAEs leading to discontinuation, or clinically relevant changes in laboratory parameters or vital signs were reported. CONCLUSIONS: The PK profile of ubrogepant was not significantly changed and no safety concerns were identified when ubrogepant was coadministered with erenumab or galcanezumab.

Efficacy of ubrogepant based on prior exposure and response to triptans: A post hoc analysis.

OBJECTIVE: To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans. BACKGROUND: Although triptans have improved migraine treatment, their efficacy and tolerability may limit their utility in some individuals. Ubrogepant is a small-molecule, oral calcitonin gene-related peptide receptor antagonist approved by the Food and Drug Administration for acute treatment of migraine in adults. METHODS: This post hoc analysis of pooled data from the pivotal trials ACHIEVE I and II, identically designed, randomized, double-blind, phase 3, single-attack trials of ubrogepant in adults with a history of migraine with/without aura, examined the efficacy and tolerability of ubrogepant 50 mg versus placebo based on participants' historical experience with triptans: triptan responder, triptan-insufficient responder, and triptan naïve. Co-primary efficacy endpoints were pain freedom and absence of most bothersome migraine-associated symptom (MBS) 2 h post initial dose. Adverse events (AEs) within historical triptan experience subgroups were evaluated. RESULTS: In the pooled analysis population (n = 1799), 682 (placebo, n = 350; ubrogepant 50 mg, n = 332), 451 (placebo, n = 223; ubrogepant, n = 228), and 666 (placebo, n = 339; ubrogepant, n = 327) participants were triptan responders, triptan-insufficient responders, and triptan-naïve, respectively. Response rates on co-primary efficacy endpoints were higher for ubrogepant versus placebo across all groups. Treatment-by-subgroup interaction p values based on odds ratios for pain freedom (p = 0.290) and absence of MBS (p = 0.705) indicated no significant impact of historical triptan experience on ubrogepant efficacy. AE incidence for ubrogepant did not differ appreciably across historical triptan experience subgroups. CONCLUSIONS: Ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan-insufficient responders, and triptan-naïve based on their historical experience with triptans.