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Preventive migraine treatment with eptinezumab reduced acute headache medication and headache frequency to below diagnostic thresholds in patients with chronic migraine and medication‐overuse headache

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.


INTRODUC TI ON
Medication-overuse headache (MOH) is a secondary headache disorder associated with excessive acute use of analgesics or other drugs used to treat migraine. 1 The International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria for a diagnosis of MOH is ≥15 headache days/month in a patient with a preexisting headache disorder, with >3 months of regular overuse of ≥1 drug that can be taken for acute and/or symptomatic treatment of headache or ≥15 days/month for nonopioid (simple) analgesics, or ≥10 days/month for triptans, ergots, opioids, and/or combination analgesics, as well as combinations of different classes of headache medications. 2 The resolution of MOH is typically regarded as reduction of acute medication below the levels defined by ICHD-3 thresholds for three consecutive months. 2 MOH occurs in 0.5%-7.2% of the total population (median estimate of 1%-2%), depending on the country and age range of the subjects in the various settings evaluated. MOH most commonly affects women, with a peak incidence in those who are 50-60 years of age. 1 The disorder may lead to considerable disability, medical and societal costs, as well as often making headache refractory to treatment. 1,[3][4][5] MOH is considered by many to be the most costly headache disorder.
Frequent medication use and increased headache frequency are common events among patients who experience migraine. 1 Clinic-based studies have shown an association between the frequent use of analgesics and the development of MOH. 6 Although not all patients who overuse acute headache medications (AHMs) will transform from episodic migraine to chronic migraine (CM) with MOH, an important goal of treatment is to prevent this transition. It is, however, not known whether the frequent intake of medication leads to MOH or whether patients with more frequent headaches take more medications. Furthermore, it is not clear whether patients who develop MOH have a genetic predisposition and hypersensitivity to pain stimuli that may indicate increased risk. 7 In addition, overuse of most acute medications, such as triptans, combination analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and others may increase the risk of MOH. 1 MRI studies of the brain structure of patients with MOH reveal evidence of structural and functional changes in the areas of the brain associated with pain and addiction. 8 Those abnormalities associated with pain appear to return to normal after MOH is resolved, but the areas associated with addiction may still be abnormal. An unmet need clearly exists to prevent MOH from developing, which may be achieved by using new treatments with high levels of sustained efficacy, high tolerability, and delivery methods that improve patient adherence to treatment. 9 Eptinezumab is a humanized IgG1 monoclonal antibody that selectively binds to and durably inhibits the calcitonin gene-related peptide (CGRP) ligand with high affinity. [10][11][12] Eptinezumab is approved in the United States for the preventive treatment of migraine in adults. 13 In pivotal phase 3 studies, eptinezumab 100 and 300 mg met the primary efficacy endpoint by significantly reducing mean monthly migraine days over Weeks 1-12, compared with placebo, in patients with episodic migraine (PROMISE-1 14 ) and CM (PROMISE-2 15 ). On average, the percentage of patients experiencing a migraine on the day following infusion was reduced by >50% in both studies and for both the 100 and 300 mg doses in both episodic migraine and CM, which was sustained across the 12-week treatment period. 16 Those receiving eptinezumab treatment were more likely to achieve ≥75% migraine response during Weeks 1-4 and Weeks 1-12 than were patients receiving placebo. A population pharmacokinetic analysis using data from eight trials of eptinezumab found that patient characteristics (including demographics and disease state) had no clinically significant effects on pharmacokinetic parameters, concluding that no dose adjustments were Based on the fact that MOH is highly prevalent in the CM population, a subgroup analysis of the patients with MOH was prespeci-

Study overview, design, and patients
The detailed methodology for PROMISE-2 (NCT02974153) has been published previously. 15 Briefly, PROMISE-2 was a randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of eptinezumab for migraine prevention in adults with CM.
Written informed consent was obtained from all participants prior to study initiation; consent forms used at each site were approved by the Independent Ethics Committee/Institutional Review Board for each study site in accordance with local legal requirements. Enrolled patients were treated with eptinezumab 100 mg, 300 mg, or placebo every 12 weeks for up to two doses. The subgroup of patients with CM in these analyses included those who were diagnosed at the screening visit as having MOH by the investigator.
The diagnosis of MOH was conducted as a prespecified measure for one of several subgroup analyses of the primary efficacy endpoint in PROMISE-2, and investigators were formally trained on how to diagnose MOH using the ICHD-3β classification guidelines. 18 Patients were prospectively diagnosed with MOH at screening based on 3 months of medication history in alignment with ICHD-3β criteria.
Limited use of barbiturates (including any combination containing butalbital) or prescription opioids (including single ingredient or combination medications containing opiates, opioids, tramadol, or tapentadol) was allowed if patients maintained a stable dose for 2 months prior to screening and dosing was not expected to exceed 4 days/month through Week 24. Patients using opioids or barbiturates >4 days/month prior to or during baseline were excluded from the study, as it was considered that frequent use of these drugs had the potential to make patients refractory to preventive treatments. Thus, no patients had MOH based exclusively on either of these drug classes. Active treatment for MOH (e.g., behavioral or psychological interventions, or pharmacological treatment other than the study drugs) was not a part of the PROMISE-2 study protocol.

Outcomes
Analyses in the MOH subgroup included the change in monthly AHM days, in total and by class (triptan, ergotamine, simple analgesics, combination analgesics [combination of drugs of different classes acting as analgesics or adjuvants], and opioids); the percentage of patients using AHM at or above MOH diagnostic thresholds, as well as the number of study months (4-week intervals) patients used AHM below MOH diagnostic thresholds; the percentage of patients experiencing a monthly headache and migraine day frequency below diagnostic thresholds for CM, as well as the number of study months patients reported migraine frequency below CM diagnostic thresholds; and the percentage of patients reporting AHM use and headache/migraine day frequency that were below both CM and MOH diagnostic thresholds, including the number of successive study months for which this was achieved.
MOH diagnostic thresholds were defined by ICHD-3β criteria (Table S1), which is ≥10 days/month of triptans, ergots, opioids, and/ or combination analgesics and/or ≥15 days/month of simple analgesics. For analysis of patients diagnosed with MOH, days of acute medication use were counted separately for each class. Within the ≥10 days/month group, if multiple drug classes were taken on a single day, the count was reported as a multiple of days. Thus, if 5 days of sumatriptan and 5 days of combination analgesics were taken per month, this would be counted as 10 days, and the diagnosis would be MOH. Simple analgesics were analyzed separately from other acute medications and used a 15 days/month cutoff. The CM diagnostic threshold was defined as ≥15 headache days/month, including ≥8 migraine days/month per ICHD-3 criteria. Additionally, if a migraine resolved in less than 4 hours because of triptan use, the classification of a "migraine day" is still applied.

Statistical analyses
Daily AHM use was captured in a daily eDiary, as were headache and migraine days. Use of AHM was captured each day regardless of whether a patient had a headache on that day. Descriptive statistics (including mean, standard deviation, and percentage) were used to report data. Analyses were performed using SAS software version 9.4 (SAS Institute, Inc., Cary, NC, USA). AHM use was analyzed over time for the full MOH population.
For analyses of specific drug classes, the patient population was limited to those who reported any use of the specific drug class during the baseline period. For analyses across dosing intervals (12 weeks), two methods were used to determine if a patient met diagnostic thresholds for MOH or CM; these comprised the average over the dosing interval (i.e., the average across the three 4-week intervals within Weeks 1-12) and an evaluation of each individual study month.
Missing data imputation was used for the endpoints related to headache and migraine days, as described in the primary report of PROMISE-2. 15 Briefly, the rate of headache and migraine was assumed to be the same on days when the diary was not completed as on days when it was completed. In cases where patients provided limited eDiary data in a given month (i.e., <21 days), the assumed migraine/headache rate was a weighted function of the data from the current month and prior month where the weight was a function of how much data were missing in the current month. As missing data were always imputed, results for headache and migraine endpoints were available for all patients at all time points.
Similar logic was used for the medication endpoints (i.e., medication usage rates days were assumed to be the same on days without data as those with data). However, in this case, if the eDiary was completed for ≥50% of days in the study month, any days the patient failed to complete the diary were assumed to be the same as the previous reported days, but if a patient failed to report medication data for ≥50% of days in a study month, the data were not imputed and were classified as missing.

Acute headache medication use by patients with MOH after treatment
Prophylactic and acute concomitant headache medication use during the study is shown in Table 2

Consistency of response and diagnostic resolution after treatment
The decreases in acute medication usage observed during the study resulted in patients no longer meeting the monthly MOH medication threshold based on ICHD-3β criteria. Across the study, the

Safety
Full details of the safety outcomes in PROMISE-2 have been reported. 15 No differences in treatment-emergent adverse events were seen between the MOH subgroup in these analyses and the overall PROMISE-2 study population.

DISCUSS ION
Reducing AHM use and its associated burden of overuse is an im- patients with MOH treated with onabotulinumtoxinA showed sustained improvements in migraine symptoms; however, it was not a placebo-controlled trial, and given that continued patient participation was likely linked to onabotulinumtoxinA efficacy, the results are more difficult to evaluate. 23 Two placebo-controlled studies of erenumab 27,28 and one of fremanezumab 29 included patients with medication overuse, but the ICHD diagnostic criteria were not formally applied for MOH; in these analyses of patients with acute medication overuse, no efforts were made to assess the sustained response over the entire study period. 27,28 Although the extent to which medication overuse contributes to migraine progression is often difficult to determine, 30  recommend starting migraine-preventive treatment along with education, and then gradual detoxification. 1 A third strategy is to treat MOH aggressively with migraine prevention, the acute use of short-term acute treatment such as antiemetics or corticosteroids, and patient education. 37 The key arguments for weaning prior to initiating migraine prevention is that (1) oral preventives may cause significant adverse events such as sedation or cognitive slowing, which could exacerbate withdrawal symptoms; and (2)

Limitations
Limitations of this analysis include those inherent in the nature of post hoc and exploratory analyses; all analyses herein were descriptive to reflect this limitation. Another factor to be considered when making inferences from these study data was that although thresholds for MOH were defined similarly in the ICHD-3β (2013) and ICHD-3 (2018) criteria for MOH, 2,18 there were some changes in drug definitions between the two sets of criteria (Table S1). In Furthermore, eptinezumab efficacy after subtracting the placebo value was >3 days, and the same response was observed for both the 100 and 300 mg doses.
Another limitation is that patients who used opioids for more than 4 days per month were excluded, because of their potential for higher rates of adverse events and poor outcomes. 6 As a result, a class of patients with MOH that can be found in the general population were omitted from this evaluation; however, another post hoc analysis of PROMISE-2 showed no change in the primary efficacy endpoint in patients who had no barbiturate or opioid use at any time during the study compared with those who did. 15 Opioid or barbiturate use, as well as the presence of significant mood or personality disorders, complicates the management of migraine with MOH and may warrant a different treatment strategy. 38 Finally, an integrated treatment plan for these patients was not provided, which could affect outcomes in a clinical setting.

Conclusions
In patients with CM diagnosed with MOH, preventive migraine treatment with eptinezumab, with either 100 or 300 mg doses, pro-