Hirman, Joe

Abstract Objective This post hoc analysis in patients medically diagnosed with chronic migraine (CM) and medication‐overuse headache (MOH) evaluated reductions in the use of acute headache medication (AHM) and sustained changes in the diagnostic status of CM and MOH following eptinezumab treatment in the PROMISE‐2 study. Background Eptinezumab, a monoclonal antibody that inhibits calcitonin gene‐related peptide, is approved in the United States for the preventive treatment of migraine. A previous analysis showed that eptinezumab reduced monthly migraine days and was well tolerated in the subgroup of PROMISE‐2 patients diagnosed with both CM and MOH. Methods The phase 3, double‐blind, placebo‐controlled PROMISE‐2 study (NCT02974153) randomized adults with CM to eptinezumab 100 mg, 300 mg, or placebo (administered intravenously every 12 weeks for up to two doses). MOH was prospectively diagnosed at screening by trained physicians based on 3 months of medication history and International Classification of Headache Disorders‐3β criteria. This post hoc analysis evaluated changes in total and class‐specific days of AHM usage, the percentage of patients using AHM at or above MOH diagnostic thresholds, and the percentage of patients experiencing monthly headache and migraine day frequency below diagnostic thresholds for MOH and/or CM. Results In PROMISE‐2, 431/1072 (40.2%) patients with CM were diagnosed with MOH (eptinezumab 100 mg, n = 139; 300 mg, n = 147; placebo, n = 145) and were included in this analysis. Total monthly AHM use decreased from 20.6 days/month at baseline to 10.6 days/month over 24 weeks of treatment (49% decrease) with eptinezumab 100 mg, from 20.7 to 10.5 days/month (49% decrease) with eptinezumab 300 mg, and from 19.8 to 14.0 days/month (29% decrease) with placebo. Numerically greater decreases from baseline with eptinezumab were also observed for individual drug classes. In each study month, the percentages of patients who were below MOH thresholds were numerically higher for both eptinezumab doses compared with placebo, as were the percentages of patients experiencing headache and migraine frequency below CM thresholds. Of patients with available data across the entire treatment period, 29.0% (58/200) of patients treated with eptinezumab stopped meeting and remained below diagnostic thresholds for both CM and MOH during Weeks 1–24, as well as 6.3% (6/96) of patients who received placebo. Conclusions Across 24 weeks of treatment, eptinezumab reduced AHM use in patients diagnosed with CM and MOH. More than one‐fourth (29%) of patients treated with eptinezumab did not meet the diagnostic thresholds for either CM or MOH for the entire treatment period.

Abstract Objectives To describe the methodology and implications of the patient‐identified most bothersome symptom (PI‐MBS) measure used in the phase 3, multicenter, randomized, double‐blind, placebo‐controlled, and parallel‐group PROMISE‐2 trial and to evaluate the contribution of this measure to the assessment of the preventive migraine benefits of treatment. Background Although freedom from MBS is a coprimary endpoint in acute migraine treatment trials, its evaluation in preventive migraine trials is limited. The PROMISE‐2 study assessed a unique PI‐MBS measure as a secondary endpoint. Methods This was a secondary analysis of data from the PROMISE‐2 study. Adults with chronic migraine (CM) were randomized to receive intravenous (IV) eptinezumab 100 mg, eptinezumab 300 mg, or placebo, administered on day 0 and every 12 weeks. At the screening visit, patients were asked to verbally describe the MBS associated with their CM; the question format was open ended. At subsequent visits, patients were asked to rate the overall change in severity of their MBS from study inception to that time point, using a 7‐point ordinal scale ranging from “very much worse” (−3) to “very much improved” (+3). Patients completed the Patient Global Impression of Change (PGIC) assessment during the same visits, using an identical rating scale and recall period. Endpoints were summarized descriptively; post hoc correlations using the methodologies of Pearson and Spearman were calculated to evaluate relationships between PGIC and PI‐MBS and between PGIC and mean monthly migraine days (MMDs; primary efficacy endpoint in PROMISE‐2). Results Altogether, 1072 patients received treatment (eptinezumab 100 mg, n = 356; eptinezumab 300 mg, n = 350; placebo, n = 366) and were included in the analysis. There were 23 unique MBS identified; those reported by ≥10 patients included light sensitivity (18.7%), nausea/vomiting (15.1%), pain with activity (13.7%), pain (12.4%), headache (11.2%), sound sensitivity (7.3%), throbbing/pulsating pain (4.7%), cognitive disruption (4.1%), fatigue (2.4%), mood changes (1.5%), and sensitivity to smell (0.9%). Four weeks after the first dose (week 4), the rates of much or very much improvement in PI‐MBS were higher with eptinezumab 100 mg (45%) and 300 mg (57%) than with placebo (29%). Four weeks after the second dose (week 16), the proportions with much or very much improvement in PI‐MBS had increased to 58%, 65%, and 36%, respectively. At each time point, the percentages of patients with PGIC ratings of much or very much improved were similar to those for patient‐reported improvement in PI‐MBS. Patient ratings of changes in PI‐MBS and PGIC correlated strongly across time points (Pearson, r range, 0.83–0.88; Spearman, r range, 0.83–0.89); the absolute value of the correlations was greater than the correlation among changes in MMDs and PGIC (Pearson, r range, −0.49 to −0.52; Spearman, r range, −0.49 to −0.52). Conclusions Among patients with CM in the PROMISE‐2 study, a broad range of PI‐MBS was reported at baseline. Throughout the study, patients treated with eptinezumab reported greater improvement in their PI‐MBS severity compared with placebo recipients, and this improvement correlated strongly with PGIC findings. Collectively, these results indicate that PI‐MBS is a promising and novel outcome measure for preventive trials of CM and thus may provide a unique patient‐centered approach for identifying and measuring the burden of migraine symptoms that matter most to each patient, as well as the benefits of treatment.

Abstract Objective To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication‐overuse headache (MOH). Background Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene‐related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH. Methods PROMISE‐2 (NCT02974153) was a double‐blind, randomized, placebo‐controlled, phase 3 study that comprised a screening visit, a 28‐day pretreatment period, and a 32‐week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1–12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1–24. Results There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg ( n = 139), 300 mg ( n = 147), or placebo ( n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1–12, eptinezumab‐treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = −8.4, difference from placebo [95% confidence interval (CI)] = −3.0 [−4.56, −1.52], p < 0.0001 vs. placebo; 300 mg, change from baseline = −8.6, difference from placebo [95% CI] = −3.2 [−4.66, −1.78], p < 0.0001 vs. placebo; placebo, −5.4). Compared with placebo, more eptinezumab‐treated patients were ≥50% migraine responders (100 mg, 84/139 [60.4%]; 300 mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100 mg, 38/139 [27.3%]; 300 mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1–12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24‐week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo‐treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication‐overuse thresholds. Conclusions In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.

Objective To determine the onset of preventive efficacy with eptinezumab in patients with migraine. Background Eptinezumab is a monoclonal antibody inhibiting calcitonin gene‐related peptide approved as an intravenously administered treatment for the prevention of migraine. Methods Patients who received eptinezumab 100 mg, eptinezumab 300 mg, or placebo in PROMISE7‐1 (episodic migraine; 100 mg, n = 221; 300 mg, n = 222; placebo, n = 222) or PROMISE7‐2 (chronic migraine; 100 mg, n = 356; 300 mg, n = 350; placebo, n = 366) were included. Testing of the percentage of patients with a migraine on day 1 after dosing was prespecified and alpha‐controlled. In further exploration of this prespecified endpoint, a post hoc closed testing procedure, which controlled the false‐positive (type 1) error rate, provided a statistically rigorous evaluation of migraine prevention onset. The procedure involved up to 84 tests of significance, all of which were performed in sequence until the first nonsignificant result. Results For both studies, all tests for significance for eptinezumab 100 and 300 mg, from days 1‐84 through day 1 alone, achieved nominal significance ( P < .05), indicating that eptinezumab was fully effective beginning on day 1. Over each interval, the treatment effect was comparable to the effect over weeks 1‐12. Mean changes from baseline in monthly migraine days for the primary endpoint period ranged from −3.9 to −4.9, −4.1 to −4.9, and −2.2 to −3.2 for eptinezumab 100, 300 mg, and placebo, respectively, in PROMISE7‐1 and from −7.2 to −8.0, −7.9 to −8.2, and −4.3 to −5.6, respectively, in PROMISE7‐2. The difference from placebo (95% confidence interval) in day 1 treatment effect was −2.2 (−4.1, −0.3) and −2.5 (−4.4, −0.6) days/month for eptinezumab 100 and 300 mg, respectively, in PROMISE7‐1, and was −3.8 (−5.6, −2.0) and −4.0 (−5.8, −2.1) days/month for 100 and 300 mg, respectively, in PROMISE7‐2. Conclusions The migraine preventive effect of eptinezumab is rapid and sustained in patients with episodic or chronic migraine, with onset of optimal preventive efficacy observed on the day following the initial dose.

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. Methods This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Results The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo ( p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. Conclusions The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. Trial Registration ClinicalTrials.gov identifier: NCT02275117.