Characterizing the binding of TC-5619 and encenicline on the alpha7 nicotinic acetylcholine receptor using PET imaging in the pig.

The alpha7 nicotinic acetylcholine receptor (α7-nAChR) has has long been considered a promising therapeutic target for addressing cognitive impairments associated with a spectrum of neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, despite this potential, clinical trials employing α7-nAChR (partial) agonists such as TC-5619 and encenicline (EVP-6124) have fallen short in demonstrating sufficient efficacy. We here investigate the target engagement of TC-5619 and encenicline in the pig brain by use of the α7-nAChR radioligand 11C-NS14492 to characterize binding both with in vitro autoradiography and in vivo occupancy using positron emission tomography (PET). In vitro autoradiography demonstrates significant concentration-dependent binding of 11C-NS14492, and both TC-5619 and encenicline can block this binding. Of particular significance, our in vivo investigations demonstrate that TC-5619 achieves substantial α7-nAChR occupancy, effectively blocking approximately 40% of α7-nAChR binding, whereas encenicline exhibits more limited α7-nAChR occupancy. This study underscores the importance of preclinical PET imaging and target engagement analysis in informing clinical trial strategies, including dosing decisions.

Responder rates with eptinezumab over 24 weeks in patients with prior preventive migraine treatment failures: post hoc analysis of the DELIVER randomized clinical trial.

BACKGROUND AND PURPOSE: Eptinezumab reduced monthly migraine days more than placebo in the DELIVER study, a clinical trial with patients with difficult-to-treat migraine and prior preventive treatment failures. This post hoc analysis assesses the sustained response to eptinezumab at the population and patient level and evaluates the potential for response in initial non-responders. METHODS: Adults with chronic or episodic migraine and two to four prior preventive treatment failures were randomized to eptinezumab 100 mg, 300 mg or placebo every 12 weeks. Primary outcomes in this post hoc analysis are the proportion of patients with ≥30%, ≥50% or ≥75% reduction in monthly migraine days (i.e., migraine responder rates [MRRs]) during weeks 1-12 and weeks 13-24 and across 4-week intervals. Secondary outcomes are maintenance and shifts in MRRs from weeks 1-12 to weeks 13-24. RESULTS: Between weeks 1-12 and 13-24, ≥30% MRRs increased from 65.9% to 70.4% (100 mg) and from 71.0% to 74.5% (300 mg), versus 36.9% to 43.1% (placebo). The ≥50% and ≥75% MRRs were sustained or increased over the 24-week period. The largest increase in ≥30% MRRs occurred after the second infusion with eptinezumab. The percentage of initial non-responders (<30% MRRs during weeks 1-12) who experienced response (≥30% MRRs during weeks 13-24) to the second dose was 34.7% (100 mg) and 30.4% (300 mg) with eptinezumab versus 21.1% with placebo. CONCLUSION: Across MRR thresholds, most patients who responded to eptinezumab during weeks 1-12 maintained or improved response during weeks 13-24. More than one-third of initial non-responders became responders after their second infusion.

Efficacy and safety of eptinezumab in patients with chronic migraine and medication-overuse headache: a randomized, double-blind, placebo-controlled study.

BACKGROUND: For some people with migraine, despite taking greater amounts of acute headache medication (AHM), they develop an increase in monthly headache days. This cycle of increasing headache days, and in turn AHM use, can lead to a secondary headache disorder called medication-overuse headache (MOH). Preventive medications can prevent migraine from occurring and reduce reliance on AHMs, thereby preventing the cycle of MOH. This study was performed to evaluate the efficacy and safety of eptinezumab to prevent migraine/headache in a mainly Asian patient population with a dual diagnosis of chronic migraine and MOH. METHODS: SUNLIGHT was a phase 3, multicenter, double-blind, parallel-group, placebo-controlled trial. Patients aged 18-75 years with ≥ 8 migraine days/month and a diagnosis of MOH were randomly allocated (1:1) to one of two treatment groups: eptinezumab 100 mg or placebo. Monthly migraine days (MMDs) were captured using a daily electronic diary; the change from baseline in the number of MMDs over Weeks 1-12 was the primary efficacy endpoint. RESULTS: Patients were randomized to eptinezumab 100 mg (n = 93) or placebo (n = 100). Over Weeks 1-12, eptinezumab reduced mean MMDs more than placebo (difference between treatments was -1.2; p = 0.1484). Differences between treatment groups with p-values below 0.05 favoring eptinezumab were observed in 3 out of the 6 key secondary endpoints. CONCLUSION: All endpoints numerically favored eptinezumab treatment when compared to placebo; however, this study did not meet its primary endpoint and is therefore negative. No new safety signals were identified in this study, like previous reports that confirmed the safety and tolerability of eptinezumab treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04772742 (26/02/2021).

Long-term effectiveness of eptinezumab in patients with migraine and prior preventive treatment failures: extension of a randomized controlled trial.

BACKGROUND: Eptinezumab demonstrated efficacy in adults with migraine and prior preventive treatment failures in the placebo-controlled phase of the DELIVER clinical trial; its long-term effectiveness in this population has not yet been reported. The objective of this study was to evaluate the long-term effectiveness of eptinezumab in a migraine patient population during the 48-week extension phase of DELIVER. METHODS: DELIVER was conducted June 1, 2020 to September 15, 2022. 865 adults with migraine, with documented evidence of 2-4 prior preventive migraine treatment failures and with completion of the 24-week placebo-controlled period of DELIVER received eptinezumab (100 or 300 mg) during the dose-blinded extension, either continuing their randomized dose or, if originally receiving placebo, were randomized 1:1 to an eptinezumab dose (100 or 300 mg). A mixed model for repeated measures was used to evaluate changes from baseline in the number of monthly migraine days (MMDs). RESULTS: Of 865 patients entering the extension (eptinezumab 100 mg, n = 433; 300 mg, n = 432), 782 (90.4%) completed and 11 (1.3%) discontinued due to an adverse event. Eptinezumab was associated with early and sustained reductions in migraine frequency. Mean MMDs at baseline were approximately 14 days across groups. Mean (standard error) change from baseline in MMDs over the final dosing interval (weeks 61-72) was -6.4 (0.50) with placebo/eptinezumab 100 mg, -7.3 (0.49) with placebo/eptinezumab 300 mg, -7.1 (0.39) with eptinezumab 100 mg, and -7.0 (0.39) with eptinezumab 300 mg. During weeks 61-72, 63-70% of patients demonstrated ≥ 50% reduction in MMDs, and 36-45% demonstrated ≥ 75% reduction. Headache severity and acute medication use reductions, and patient-reported improvements in most bothersome symptom, disease status, quality of life, and work productivity, were observed. Adverse events were generally mild, transient, and similar in frequency/type to previous eptinezumab trials. CONCLUSIONS: The long-term effectiveness and safety/tolerability of eptinezumab in patients with migraine and 2-4 prior preventive treatment failures was demonstrated by high completion rates and migraine-preventive benefits sustained for up to 18 months, implying that eptinezumab is a viable long-term treatment option for patients still seeking successful migraine treatments. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765; URL: https://www. CLINICALTRIALS: gov/ct2/show/NCT04418765 ); EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25 ).

Pharmacokinetics and Safety of Eptinezumab in Healthy Chinese Participants: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: Most evidence suggests that the pharmacokinetics of monoclonal antibodies (mAbs) are not meaningfully altered by patient characteristics, including racial/ethnic differences. Nevertheless, the pharmacokinetic profile of eptinezumab has not been evaluated in a Chinese population. This study was designed to confirm the hypothesis that the pharmacokinetic profile of the anti-calcitonin gene-related peptide mAb, eptinezumab, is similar in healthy Chinese individuals to that of healthy non-Asian individuals and non-Asian patients with migraine. METHODS: Over a study period of 12 weeks, healthy adult Chinese participants (N = 20) were randomized (1:1) to receive a single intravenous dose of eptinezumab 100 mg (n = 10) or 300 mg (n = 10) in a prospective, single-site, open-label parallel-group trial. Blood samples for the evaluation of plasma eptinezumab concentrations were obtained over 84 days, and standard pharmacokinetic parameters were derived. RESULTS: Mean maximum plasma concentrations (Cmax) of eptinezumab occurred 1.0-1.5 h post start of infusion, were similar between the 100 mg and 300 mg dose groups, and slowly declined in a biphasic manner. Cmax and area under the drug concentration-time curve (AUC) increased in a dose-proportional manner. Volume of distribution and clearance were similar between the 100 mg and 300 mg dose groups, and half-life was 22.5-28.1 days. Eptinezumab was generally well tolerated with no new safety signals identified. Only one participant, randomized to the 100 mg dose group, was positive for eptinezumab anti-drug antibodies, but negative for neutralizing antibodies, with no impact on pharmacokinetics. CONCLUSION: The pharmacokinetic profile of eptinezumab in healthy Chinese individuals was generally similar to that reported for non-Asian populations with migraine, and eptinezumab was generally well tolerated. Evaluation of immunogenicity showed no evidence of an impact of anti-drug antibodies or neutralizing antibodies on safety profiles. This supports the globally approved doses of 100 mg and 300 mg as being appropriate for Chinese patients with episodic migraine or chronic migraine.

Efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures: subgroup analysis of the randomized, placebo-controlled DELIVER study.

BACKGROUND: Migraine is a disabling neurological disease adversely affecting many aspects of life. Most patients are still required to have failed several older oral preventive therapies before being reimbursed for a preventive, migraine-specific anti-calcitonin gene-related peptide treatment. In the 24-week placebo-controlled portion of DELIVER, eptinezumab was shown to reduce migraine frequency and resulted in higher migraine responder rates compared with placebo in patients with two to four previous preventive treatment failures. This subgroup analysis assessed if demographic or clinical characteristics were associated with differences in preventive benefits. METHODS: Migraine frequency reductions and responder rates (i.e., the proportion of patients reaching a ≥50% and ≥75% reduction in monthly migraine days relative to baseline) were determined in the total population and predefined subgroups by sex, age, migraine frequency (chronic migraine, episodic migraine, high-frequency episodic migraine, low-frequency episodic migraine), medication overuse, medication-overuse headache, and previous preventive treatment failures (2, >2). The primary endpoint was change from baseline in monthly migraine days over weeks 1-12. RESULTS: Eptinezumab 100 and 300 mg reduced monthly migraine days more than placebo over weeks 1-12 (-4.8 and -5.3 vs -2.1, respectively; p < 0.0001). In most subgroups, eptinezumab-treated patients demonstrated larger monthly migraine days reductions from baseline over weeks 1-12 than patients receiving placebo, with reductions maintained or increased over weeks 13-24. For ≥50% and ≥75% migraine responder rates, the odds ratios versus placebo all numerically favored eptinezumab. CONCLUSION: Eptinezumab had larger monthly migraine days reductions and higher responder rates than placebo across clinically relevant subgroups showing that, across different demographic populations and clinical characteristics, eptinezumab is effective in patients with migraine and prior preventive treatment failures.Trial Registration: ClinicalTrials.gov (Identifier: NCT04418765).

Eptinezumab improved patient-reported outcomes and quality of life in patients with migraine and prior preventive treatment failures.

BACKGROUND AND PURPOSE: In the phase 3b, randomized, double-blind, placebo-controlled DELIVER clinical trial, eptinezumab reduced migraine frequency and headache in adults with two to four prior preventive treatment failures. Here, the effect of eptinezumab on coinciding patient-reported outcomes is reported. METHODS: Adults were randomized to receive eptinezumab 100, 300 mg or placebo intravenously at weeks 12 and 24. The EQ-5D-5L, measuring overall patient health, and the six-item Headache Impact Test were completed every 4 weeks. The Patient Global Impression of Change was completed at weeks 4, 12 and 24. Patient-identified most bothersome symptom and the Migraine-Specific Quality of Life Questionnaire were administered at weeks 12 and 24. RESULTS: Eptinezumab improved patient-reported outcomes more than placebo, starting at week 4 and at all subsequent time points. By week 12, patients' overall health (EQ-5D-5L visual analog scale score) improved with eptinezumab treatment (difference from placebo in change from baseline: 100 mg, 5.1, 95% confidence interval [CI] 2.2, 8.1, p < 0.001; 300 mg, 7.5, 95% CI 4.5, 10.4, p < 0.0001). At week 12, eptinezumab improved headache-related quality of life (difference from placebo in change from baseline in Headache Impact Test total score: 100 mg, -3.8, 95% CI -5.0, -2.5, p < 0.0001; 300 mg, -5.4, 95% CI -6.7, -4.2, p < 0.0001), including each Migraine-Specific Quality of Life Questionnaire domain (p ≤ 0.0001, all comparisons). Over twice as many patients receiving eptinezumab than placebo reported much or very much improvement on the Patient Global Impression of Change and patient-identified most bothersome symptom. CONCLUSION: Patients with two to four prior preventive treatment failures receiving eptinezumab versus placebo reported greater improvements in well-being, quality of life and most bothersome symptoms compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04418765; EudraCT identifier: 2019-004497-25.

Effects of eptinezumab on self-reported work productivity in adults with migraine and prior preventive treatment failure in the randomized, double-blind, placebo-controlled DELIVER study.

BACKGROUND: The multinational phase 3b DELIVER trial was designed to evaluate the efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures across 17 countries. In the placebo-controlled portion, eptinezumab relative to placebo demonstrated greater reductions in migraine and headache frequency, migraine and headache severity, and acute medication use. The objective of this report is to describe the effects of eptinezumab on self-reported work productivity in the placebo-controlled portion of DELIVER. METHODS: Adults 18-75 years of age with migraine and documented evidence of 2 to 4 prior preventive treatment failures in the past 10 years were randomized to receive eptinezumab 100 mg, 300 mg, or placebo intravenously (IV) every 12 weeks. The Work Productivity and Activity Impairment questionnaire specific to migraine (WPAI:M), which comprises 6 items (4 of which are completed by currently employed patients only), was administered every 4 weeks. Changes from baseline in subscores (absenteeism, presenteeism, work productivity loss, and activity impairment) were calculated based on item responses. A mixed model for repeated measures was used to analyze changes from baseline in WPAI:M subscores. RESULTS: A total of 890 adults (mean age, 43.8 years) were included in the full analysis set (eptinezumab 100 mg, n = 299; eptinezumab 300 mg, n = 293; placebo, n = 298). Mean WPAI:M subscores at baseline indicated a negative impact of migraine attacks on work productivity and ability to complete normal daily activities. Eptinezumab improved WPAI:M subscores more than placebo at all assessment points throughout the study. Mean changes from baseline in self-reported work productivity loss were -19.5, -24.0, and -9.7 at Week 12; and -22.6, -20.2, and -7.2 at Week 24 (all P < 0.001 vs placebo) for eptinezumab 100 mg, eptinezumab 300 mg, and placebo, respectively. Mean changes from baseline in activity impairment were -21.3, -23.8, and -11.2 at Week 12; and -24.7, -22.6, and -10.1 at Week 24 (all P < 0.0001 vs placebo). Similarly, mean improvements in absenteeism and presenteeism were greater in the eptinezumab groups than in the groups receiving placebo at all timepoints (P < 0.05). CONCLUSION: In adults with migraine and prior preventive treatment failure, eptinezumab 100 mg and 300 mg IV every 12 weeks improved absenteeism, presenteeism, work productivity loss, and activity impairment more than placebo. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765 ); EudraCT (Identifier: 2019-004497-25) ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004497-25/PL ). Eptinezumab improves self-reported work productivity in patients with migraine and prior preventive treatment failures.

Shift in diagnostic classification of migraine after initiation of preventive treatment with eptinezumab: post hoc analysis of the PROMISE studies.

BACKGROUND: Monthly headache frequency directly correlates with personal/societal burden and impacts severity and preventive treatment decisions. This post hoc analysis identified shifts from higher to lower frequency headache categories over 6 months in patients with migraine participating in the PROMISE clinical trials receiving two eptinezumab doses. METHODS: Headache frequency at baseline and over study months 1-6 was categorized into 4 groups: chronic migraine (CM; ≥ 15 monthly headache days [MHDs]), high-frequency episodic migraine (HFEM; 10-14 MHDs), low-frequency episodic migraine (LFEM; 4-9 MHDs), and ≤ 3 MHDs. Outcomes included the percentage of patients within each MHD category, the percentage of patients improving by ≥ 1 MHD category, and the number of months with reduction of ≥ 1 MHD category. Data from patients who received approved eptinezumab doses (100 mg or 300 mg) or placebo were included. RESULTS: Mean headache frequency at baseline in PROMISE-1 was 10 MHDs; most patients were classified as having HFEM (48.6%) or LFEM (43.9%). At Month 1, 62/221 (28.1%), 75/222 (33.8%), and 45/222 (20.3%) patients who received eptinezumab 100 mg, 300 mg, and placebo had ≤ 3 MHDs, with 97/221 (43.9%), 108/222 (48.6%), and 84/222 (37.8%), respectively, falling below the diagnostic EM threshold at Month 6. More than one-third (79/221 [35.7%], 83/222 [37.4%], and 68/222 [30.6%] of patients in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively), had 6 months of reduction of ≥ 1 frequency category. At baseline in PROMISE-2, mean headache frequency was 20.5 MHDs. All patients (100%) in the eptinezumab 100 mg and placebo groups had CM, as did 99.4% of patients receiving eptinezumab 300 mg. At Month 1, 209/356 (58.7%), 216/350 (61.7%), and 167/366 (45.6%) patients treated with eptinezumab 100 mg, 300 mg, and placebo had ≤ 14 MHDs, with 240/356 (67.4%), 249/350 (71.1%), and 221/366 (60.4%), respectively, falling below CM threshold at Month 6. Additionally, 153/356 (43.0%), 169/350 (48.3%), and 116/366 (31.7%) patients in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively, had 6 months of reduction of ≥ 1 frequency category. CONCLUSION: In the PROMISE studies, episodic and chronic migraine patients treated with eptinezumab were more likely to reduce their headache frequency versus placebo, which directly and in a sustained way improved their diagnostic category classification. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02559895, NCT02974153.

Real-world effectiveness of vortioxetine in outpatients with major depressive disorder: functioning and dose effects.

BACKGROUND: Functional recovery is an important treatment goal in major depressive disorder (MDD). This study assessed the real-world effectiveness of vortioxetine in patients with MDD, with particular focus on functioning; dose-response was also assessed. METHODS: This was a non-interventional, prospective, multicenter study conducted in Greece. Adult outpatients with MDD (n = 336) initiating vortioxetine (5-20 mg/day flexible dosing) as treatment for a current major depressive episode were followed for 3 months. Analyses were stratified according to vortioxetine dosage at 3 months: 5-10 mg/day versus 15-20 mg/day. Functioning was assessed using the Sheehan Disability Scale (SDS). RESULTS: Mean ± standard error SDS total score decreased (improved) from 18.7 ± 0.3 at baseline to 12.9 ± 0.3 after 1 month of vortioxetine treatment and 7.8 ± 0.4 after 3 months (p < 0.001 vs. baseline for all comparisons). Functional recovery (SDS score ≤ 6) was achieved in 14.6% of patients after 1 month of treatment and 48.4% of patients after 3 months. Improvement from baseline in SDS total and domain scores at 3 months was more pronounced in patients receiving vortioxetine 15-20 mg/day than in those receiving vortioxetine 5-10 mg/day. The mean ± standard error change in SDS total score from baseline was 9.2 ± 0.8 in the 5-10 mg/day group and 12.1 ± 0.4 in the 15-20 mg/day group (p < 0.001). Limitations of this study include its non-interventional study design and lack of a control group or active comparator. CONCLUSIONS: Statistically significant and clinically relevant improvements in functioning were seen in patients with MDD treated with vortioxetine in a real-world setting. Higher doses of vortioxetine were associated with significantly greater improvements in functioning.

Long-term reductions in disease impact in patients with chronic migraine following preventive treatment with eptinezumab.

BACKGROUND: Eptinezumab is an anti-calcitonin gene-related peptide humanized monoclonal antibody approved for the preventive treatment of migraine in adults. The PREVAIL study demonstrated a favorable safety profile with sustained reductions in overall migraine-related burden in patients with chronic migraine (CM). This post hoc analysis aimed to examine item-level changes in the Migraine Disability Assessment (MIDAS) questionnaire over 2 years in participants with CM on eptinezumab treatment. METHODS: PREVAIL was an open-label, phase 3 trial that included 96 weeks of treatment where 128 adults received intravenous eptinezumab administered over 30 min every 12 weeks (wks) for up to 8 doses of 300 mg. MIDAS was administered at baseline, Wk12, and every 12wks thereafter. Two supplementary MIDAS items not included in the total score calculation assessed number of headache days in the past 3 months (MIDAS headache) and average headache pain severity (from 0 [none] to 10 [worst]). MIDAS total scores were summed from 5 items, each quantifying the number of days in the past 3 months with migraine-related disability. Items 1, 3, and 5 assessed absenteeism, namely how many days the patient missed work/school (Q1), household work (Q3), or family/social/leisure activities (Q5). Items 2 and 4 were measures of presenteeism, namely how many days the patient had reduced productivity in work/school (Q2) or household work (Q4). RESULTS: Mean MIDAS headache days decreased from 47.4 (baseline) to 17.1 (Wk12) and 16.3 (Wk104). The average headache pain severity score (0‒10) decreased from a mean of 7.3 (baseline) to 5.5 (Wk12) to 4.5 (Wk104). Mean MIDAS scores measuring absenteeism (Q1, 3, 5) changed from 9.7 days at baseline to 3.2 days (Wk12) and to 3.9 days (Wk104). Mean MIDAS scores measuring presenteeism (Q2, 4) at Wk12 decreased from 14.2 days at baseline to 5.2 days (Wk12, 104). Patients categorized with very severe MIDAS disability had a mean total MIDAS score of 84.8, with an average reduction of 56.7 days (Wk12), which was maintained at 32 days at Wk104. CONCLUSIONS: Long-term treatment with eptinezumab in patients with CM suggested sustained reductions in MIDAS-quantified disability, consistent with the sustained reductions in headache frequency and pain severity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02985398 .

Optimization of acute medication use following eptinezumab initiation during a migraine attack: post hoc analysis of the RELIEF study.

BACKGROUND: The benefits of preventive treatment on the effectiveness of migraine management have rarely been examined. This post hoc analysis investigated the impact of eptinezumab on the optimization of acute medication effectiveness using the 4-item Migraine Treatment Optimization Questionnaire (mTOQ-4) to measure acute medication optimization over 4 weeks post-infusion. METHODS: RELIEF was a 12-week, phase 3, multicenter, parallel-group, double-blind, placebo-controlled clinical trial conducted in patients aged 18-75 years with a ≥ 1-year history of migraine and 4-15 migraine days per month in the 3 months prior to screening. Patients were randomized 1:1 to a 30-min infusion of eptinezumab 100 mg or placebo within 1-6 h of a qualifying migraine attack. The mTOQ-6 and 6-item Headache Impact Test (HIT-6) were administered at screening visit and week 4. From the mTOQ-6, we calculated the mTOQ-4 using the following items: "2-h pain free," "24-h relief," "able to plan," and "feeling in control" to measure acute medication optimization. RESULTS: A total of 238 patients received eptinezumab 100 mg and 226 provided week 4 data; 242 received placebo and 232 provided week 4 data. In the eptinezumab arm, the proportion of patients with moderate/maximal optimization increased from 31.4% at baseline to 58.0% (26.6 percentage point increase) at week 4. The corresponding proportions in the placebo group were 40.5% to 50.4% (9.9 percentage point increase). Eptinezumab treatment was associated with numerically larger improvements in HIT-6 at week 4. Relative improvements with eptinezumab vs. placebo from baseline to week 4 in HIT-6 were greater in those with poor treatment optimization at baseline. CONCLUSIONS: In comparison with placebo, treatment with eptinezumab was associated with improvements in acute medication optimization as measured by mTOQ and reductions in headache impact, as measured by HIT-6. These benefits were greater in those with poor acute treatment optimization prior to preventive treatment with eptinezumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04152083 .

Rapid resolution of migraine symptoms after initiating the preventive treatment eptinezumab during a migraine attack: results from the randomized RELIEF trial.

BACKGROUND: Eptinezumab is an anti-calcitonin gene-related peptide (CGRP) monoclonal antibody approved for the preventive treatment of migraine. In the phase 3 RELIEF study, eptinezumab resulted in shorter time to headache pain freedom and time to absence of most bothersome symptom (MBS; including nausea, photophobia, or phonophobia) compared with placebo when administered during a migraine attack. The objective of this exploratory analysis was to examine the earliest time points that eptinezumab separated from placebo (P < .05) on headache- and migraine-associated symptoms when administered during a migraine attack. METHODS: RELIEF, a multicenter, parallel-group, double-blind trial, occurred from November 7, 2019, through July 8, 2020. Adults considered candidates for preventive treatment were randomized to eptinezumab 100 mg (N = 238) or placebo (N = 242) administered intravenously over 30 min within 1-6 h of migraine onset. Outcome measures included headache pain freedom/relief and absence of MBS, patient's choice of photophobia, phonophobia, or nausea, at regular intervals from 0.5 to 48 h after infusion start. Censoring was applied at time of acute rescue medication use. RESULTS: At hour 1, more eptinezumab-treated patients achieved headache pain freedom (9.7%), headache pain relief (38.7%), and absence of MBS (33.2%) versus placebo (4.1%, 26.9%, and 22.1%, respectively; P < .05 all), with separation from placebo (P < .05) through hour 48. Eptinezumab separated from placebo (P < .05) at hour 1 in absence-of-photophobia (29.4% vs 17.0%) and absence-of-phonophobia (41.2% vs 27.2%) and through hour 48. Initial separation from placebo (P < .05) in absence-of-nausea occurred at end-of-infusion (0.5 h; 36.7% vs 25.4%, respectively). CONCLUSION: Preventive treatment with eptinezumab initiated during a migraine attack resulted in more patients achieving headache pain freedom/relief and absence of MBS, with separation from placebo (P < .05) as early as 0.5-1 h following the start of infusion. Rapid resolution of headache- and migraine-associated symptoms by a peripherally acting, intravenously administered antibody suggest a peripheral site of pharmacological action for CGRP blockade. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04152083 .

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: H Lundbeck.

Evaluating the clinical utility of the patient-identified most bothersome symptom measure from PROMISE-2 for research in migraine prevention.

OBJECTIVE: To assess the utility of the novel patient-identified (PI) most bothersome symptom (MBS) measure from PROMISE-2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. BACKGROUND: Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI-MBS could improve clinical decision-making. METHODS: In PROMISE-2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses (n = 1072). PI-MBS was an exploratory outcome requiring each patient to self-report their MBS in response to an open-ended question. At baseline and week 12, patients rated overall improvement in PI-MBS. The relationships among PI-MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9-12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6-item Headache Impact Test total, EuroQol 5-dimensions 5-levels visual analog scale, and 36-item Short-Form Health Survey component scores were assessed. RESULTS: Treatment groups had similar baseline characteristics and reported a total of 23 unique PI-MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI-MBS at week 12 correlated with changes in MMDs (ρ = -0.49; p < 0.0001) and other patient-reported outcomes. Controlling for changes in MMDs, PI-MBS improvement predicted other patient-reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI-MBS were 0.31 (p < 0.0001 vs. placebo) and 0.54 (p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. CONCLUSIONS: Improvement in PI-MBS at week 12 was associated with improvement in other patient-reported outcome measures, and PI-MBS may be an important patient-centered measure of treatment benefits in patients with chronic migraine.

Reduction in migraine-associated burden after eptinezumab treatment in patients with chronic migraine.

OBJECTIVE: To examine changes in the occurrence, severity, and symptoms of headache episodes in patients with chronic migraine following eptinezumab treatment. METHODS: PROMISE-2 was a double-blind, placebo-controlled, parallel-group trial that randomized adults with chronic migraine to eptinezumab 100 mg, 300 mg, or placebo IV every 12 weeks for up to 24 weeks (2 infusions). Headache episodes (migraine and non-migraine) and their characteristics were reported in daily electronic diaries during the 28-day baseline and throughout the 24-week treatment period. RESULTS: A total of 1072 patients were included in this post hoc analysis. Mean monthly headache days decreased by 8.9 (100 mg) and 9.7 (300 mg) compared to a 7.3 decrease in placebo over the first 4-week interval post initial dose and reductions were maintained throughout the 24-week treatment period. Mean monthly headache episodes also decreased by 8.4 (100 mg) and 9.0 (300 mg) compared to a decrease of 7.1 with placebo. The proportion of headache episodes that were migraine attacks decreased by 11.2% (100 mg), 12.4% (300 mg), and 3.9% (placebo), and among remaining headaches decreases in severe pain, nausea, phonophobia, photophobia, and physical activity limitations were numerically greater than placebo. CONCLUSIONS: Patients with chronic migraine treated with eptinezumab decreased the monthly severity and frequency of headache days and episodes more than placebo. Beyond decreased headache frequency, patients treated with eptinezumab reported a reduction in the percent of remaining headache episodes that were migraine attacks, as well as a decrease in burdensome symptoms of headache episodes, indicating additional decreased headache severity after eptinezumab treatment.Trial registration: ClinicalTrials.gov Identifier: NCT02974153; registered November 23, 2016.

Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2.

BACKGROUND: This post hoc subgroup analysis evaluated the efficacy and safety of eptinezumab for migraine prevention in patients with migraine and self-reported aura. METHODS: PROMISE-1 (NCT02559895; episodic migraine) and PROMISE-2 (NCT02974153; chronic migraine) were randomized, double-blind, placebo-controlled trials that evaluated eptinezumab for migraine prevention. In both studies, the primary outcome was the mean change from baseline in monthly migraine days over Weeks 1-12. Patients in this analysis included those who self-reported migraine with aura at screening. RESULTS: Of patients with episodic migraine, ∼75% reported a history of aura at screening; of patients with chronic migraine, ∼35% reported a history of aura. Changes in monthly migraine days over Weeks 1-12 were -4.0 (100 mg) and -4.2 (300 mg) with eptinezumab versus -3.1 with placebo in patients with episodic migraine with aura, and were -7.1 (100 mg) and -7.6 (300 mg) with eptinezumab versus -6.0 with placebo in patients with chronic migraine with aura. Treatment-emergent adverse events were reported by 56.0% (100 mg), 57.4% (300 mg), and 55.4% (placebo) of patients. CONCLUSIONS: The preventive migraine efficacy of eptinezumab in patients in the PROMISE studies who self-reported aura was comparable to the overall study populations, demonstrating a similarly favorable safety and tolerability profile.Trial registration: ClinicalTrials.gov Identifiers: NCT02559895 and NCT02974153.

Eptinezumab treatment initiated during a migraine attack is associated with meaningful improvement in patient-reported outcome measures: secondary results from the randomized controlled RELIEF study.

BACKGROUND: Demonstrating therapeutic value from the patient perspective is important in patient-centered migraine management. The objective of this study was to investigate the impact of eptinezumab, a preventive migraine treatment, on patient-reported headache impact, acute medication optimization, and perception of disease change when initiated during a migraine attack. METHODS: RELIEF was a randomized, double-blind, placebo-controlled trial conducted between 2019 and 2020 in adults with ≥1-year history of migraine and 4-15 migraine days per month in the 3 months prior to screening. Patients were randomized (1:1) to a 30-min infusion of eptinezumab 100 mg or placebo within 1-6 h of a qualifying migraine attack onset. The 6-item Headache Impact Test (HIT-6) and 6-item Migraine Treatment Optimization Questionnaire (mTOQ-6) were administered at baseline and week 4, and the Patient Global Impression of Change (PGIC) at week 4. A post hoc analysis of these measures was conducted in patients who reported headache pain freedom at 2 h after infusion start. RESULTS: Of 480 patients enrolled and treated, 476 completed the study and are included in this analysis. Mean baseline HIT-6 total scores indicated severe headache impact (eptinezumab, 65.1; placebo, 64.8). At week 4, the eptinezumab-treated group demonstrated clinically meaningful improvement in HIT-6 total score compared with placebo (mean change from baseline: eptinezumab, - 8.7; placebo, - 4.5; mean [95% CI] difference from placebo: - 4.2 [- 5.75, - 2.63], P < .0001), with greater reductions in each item score vs placebo (P < .001 all comparisons). Change in HIT-6 total score in the subgroup with 2-h headache pain freedom was - 13.8 for the eptinezumab group compared with - 4.9 for the placebo group. mTOQ-6 total score mean change from baseline favored eptinezumab (change, 2.1) compared with placebo (1.2; mean [95% CI] difference: 0.9 [0.3, 1.5], P < .01). More eptinezumab-treated patients rated PGIC as much or very much improved than placebo patients (59.3% vs 25.9%). CONCLUSIONS: When administered during a migraine attack, eptinezumab significantly improved patient-reported outcomes after 4 weeks compared with placebo, with particularly pronounced effects in patients reporting headache pain freedom at 2 h after infusion start. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04152083 . November 5, 2019.

Eptinezumab for migraine prevention in patients 50 years or older.

OBJECTIVE: To evaluate the efficacy and safety of eptinezumab versus placebo in patients ≥50 years old with episodic (EM) or chronic migraine (CM). MATERIALS AND METHODS: This post hoc analysis included data from two phase 3, parallel-group, randomized, double-blind, placebo-controlled studies in adults with EM (PROMISE-1) or CM (PROMISE-2). Patients ≥50 years at baseline treated with eptinezumab 100 mg, 300 mg, or placebo were pooled from both studies to evaluate efficacy and safety. RESULTS: A total of 385/1960 (19.6%) EM and CM patients who were ≥50 years old at baseline (range, 50-71 and 50-65 years, respectively) received eptinezumab 100 mg (n = 132), 300 mg (n = 127), or placebo (n = 126) over Weeks 1-12. Reductions in mean monthly migraine days (MMDs) in ≥50-year-old EM patients were -3.8 (100 mg) and -4.4 (300 mg) with eptinezumab versus -2.6 with placebo. In ≥50-year-old CM patients, mean changes in MMDs were -7.7 (100 mg) and -8.6 (300 mg) with eptinezumab versus -6.0 with placebo. Changes in MMDs were comparable to total study results. A ≥50% MMD reduction over Weeks 1-12 was achieved by 57.9% of eptinezumab-treated versus 35.7% of patients who received placebo, and a ≥75% reduction by 30.5% versus 13.5%, respectively. The incidence of treatment-emergent adverse events (TEAEs) in EM and CM patients ≥50 years old was similar across treatment groups, with ≥96% of TEAEs mild or moderate in severity. CONCLUSIONS: Treatment with eptinezumab was efficacious, tolerable, and safe in patients ≥50 years with EM or CM, congruent with results from the overall study population.