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. 2025 Dec 15;32(12):e70460. doi: 10.1111/ene.70460

Early and Sustained Shift in Headache Day Frequency Following Eptinezumab Treatment in Adults With Migraine for Whom 2–4 Previous Preventive Treatments Have Failed: A Post Hoc Analysis of the Randomized DELIVER Trial

Cristina Tassorelli 1,2,✉, Amaal J Starling 3, Susanne F Awad 4, Xin Ying Lee 5, Line Pickering Boserup 4, Divya Asher 5, Seema Soni‐Brahmbhatt 5, Bjørn Sperling 4, Peter J Goadsby 6,7
PMCID: PMC12704021  PMID: 41395928

ABSTRACT

Background

This post hoc analysis examined the reduction in monthly headache days (MHDs) by frequency category shifts and associated improvements following eptinezumab treatment.

Methods

The DELIVER trial evaluated eptinezumab in adults with migraine for whom 2–4 previous preventive treatments failed. During a 24‐week, double‐blind, placebo‐controlled period followed by a 48‐week extension period, participants received IV eptinezumab 100 mg, 300 mg, or placebo every 12 weeks, with all receiving eptinezumab beginning Week 25 (dose‐blinded). Participants were categorized by MHD frequency: > 14, 8–14, 4 to < 8, 1 to < 4, 0. MHD category shifts were evaluated in the total population and several subgroups (including participants with > 14 baseline MHDs and early ≥ 50% responders). In participants reporting < 8 MHDs after all doses, the associated changes in headache intensity and disease status were evaluated.

Results

Of randomized participants, 88% (782/890) completed the trial. The percentage of participants randomized initially to eptinezumab who reported < 4 MHDs was 23% (138/592) over Weeks 1–12 and 47% (236/498) over Weeks 61–72; 9% reported 0 MHDs after the final dose. Of participants randomized initially to eptinezumab who shifted from ≥ 8 MHDs at baseline to < 8 over Weeks 1–12, 71% (170/241) reported < 8 MHDs for the rest of the trial; of those who shifted from > 14 to < 8 MHDs, 66% (49/74) reported < 8 MHDs for the rest of the trial. Reduction to < 8 MHDs was associated with robust improvements in headache intensity and disease burden.

Conclusions

Eptinezumab was associated with sustained reduction in MHD category, with some achieving headache/migraine freedom in patients with a history of preventive treatments that failed.

Trial Registration

ClinicalTrials.gov (identifier: NCT04418765; https://www.clinicaltrials.gov/ct2/show/NCT04418765) and EudraCT (identifier: 2019‐004497‐25; https://www.clinicaltrialsregister.eu/ctr‐search/search?query=2019‐004497‐25)

Keywords: anti‐CGRP, eptinezumab, headache, migraine, preventive treatment

This post hoc analysis of data from the DELIVER trial—which had an 88% completion rate across the placebo‐controlled and extension periods—suggests that eptinezumab administration in people with the most burdensome migraine subtypes (chronic and high‐frequency episodic migraine) induces a shift of MHDs towards less burdensome subtypes. For most participants, this shift occurs within the first 12 weeks (Dose 1) and is sustained across 72 weeks of continued eptinezumab treatment.

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1. Introduction

Headache frequency varies widely among individuals living with migraine [1, 2, 3], and higher headache frequency is associated with reduced quality of life and higher economic/societal burden (e.g., healthcare resource utilization and lost productivity) [4, 5, 6, 7, 8]. Thus, reducing headache frequency through the optimization of preventive treatments has the potential to improve the lives of affected individuals and reduce the burden of disease on all those impacted by migraine. The International Headache Society (IHS) recommends that preventive treatment be considered for people with migraine experiencing one or more of the following: ≥ 4 monthly headache days (MHDs; or ≥ 2 MHDs if they are debilitating migraine days), self‐reported impact of migraine on life (professional, social, or personal), frequent use of acute treatments for migraine attacks, and inadequate migraine relief from optimized acute treatment [9, 10]. Once initiated, current standards for success of preventive migraine treatment are often based on either a percentage reduction in MHDs or in monthly migraine days (MMDs; MHDs with migraine features) [11]; however, percentage reductions can be associated with disparities in residual migraine burden due to the influence of baseline severity [10]. The IHS advocates for more optimized and patient‐centered treatment goals in migraine prevention, with the ultimate goal of headache/migraine freedom, emphasizing the importance of focusing on targeting a low number of MHDs rather than just percentage improvements [10].

Indicated for the preventive treatment of migraine in adults, eptinezumab is an intravenously (IV) administered anti‐calcitonin gene‐related peptide (CGRP) monoclonal antibody. The phase 3b DELIVER trial evaluated the efficacy and safety of eptinezumab for migraine prevention in adults with migraine for whom 2–4 previous preventive treatments have failed. Quarterly IV administration of either eptinezumab 100 or 300 mg reduced headache frequency and impact in this population, with benefits sustained for up to 72 weeks of treatment [12, 13, 14, 15, 16]. The current post hoc analysis was performed to explore changes in MHD frequency across the 72‐week DELIVER trial, including early (Weeks 1–12) and sustained (from Weeks 13–24 to 61–72) shifts from more severe to less severe MHD frequency categories and to evaluate the associated long‐term improvement in headache severity and participants' overall impression of change.

2. Methods

2.1. Trial Design and Participants

DELIVER was a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group clinical trial designed to assess the efficacy and safety of eptinezumab for migraine prevention in participants with migraine and a history of previous preventive treatments that have failed. The trial included a 28–30‐day screening period, 24‐week placebo‐controlled period, and 48‐week dose‐blinded extension period. The full trial design and methodology, including the protocol and statistical analysis plan, are published [12, 13]. All participants provided written informed consent before any trial procedures. This trial is registered on ClinicalTrials.gov (identifier: NCT04418765) and EudraCT (identifier: 2019‐004497‐25).

The DELIVER trial was approved at each participating site by the corresponding ethics committee or institutional review board. All clinical work was conducted in compliance with current Good Clinical Practices as defined in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines, local regulatory requirements, and the Declaration of Helsinki. All participants provided written informed consent prior to any trial procedures.

The trial enrolled adults (18–75 years) with episodic migraine (EM) or chronic migraine (CM), as defined in the International Classification of Headache Disorders, 3rd edition (ICHD‐3) [17], and documented evidence of 2–4 previous preventive treatments that had failed in the prior 10 years. Eligible EM was confirmed as ≥ 4 MMDs and ≤ 14 MHDs during the 28‐day screening period, with CM confirmed as ≥ 8 MMDs and > 14 MHDs. Documented evidence of previous preventive migraine medication failures had to provide proof of 2–4 treatments that failed due to inadequate efficacy, safety/tolerability reasons, or contraindications, with ≥ 1 failure due to inadequate efficacy following ≥ 3 months of treatment with the locally recommended dose. Compliance with the electronic headache diary (eDiary) during the screening period (≥ 24 of 28 days completed) was required.

Individuals were excluded if any previous treatment targeting the CGRP pathway had evidence of failure; failure of valproate/divalproex or botulinum toxin that was not the latest preventive medication prior to trial inclusion (consistent with guidance from Gemeinsamer Bundesausschuss, the German Federal Joint Committee for reimbursement); confounding and clinically significant pain syndromes; diagnosis of temporomandibular disorder; history or diagnosis of other headache types; history of clinically significant cardiovascular disease; uncontrolled and/or untreated psychiatric condition; or use of preventive migraine medication ≤ 1 week prior to the screening visit. Participants were permitted to use acute migraine treatments, provided the current dose levels had been stable for ≥ 12 weeks prior to screening [12, 13]. Medication‐overuse headache (per ICHD‐3 [17]) was permitted, unless opioid use exceeded 4 days per month.

2.2. Interventions

Participants were randomized (1:1:1) to receive eptinezumab 300 mg, eptinezumab 100 mg, or placebo IV every 12 weeks for the first 24 weeks; randomization was stratified by MHDs at baseline (≤ 14 or > 14 MHDs) and by country. After 24 weeks, participants initially assigned eptinezumab continued their assigned dosing regimen for the 48‐week dose‐blinded extension period, while participants initially assigned placebo were randomized to eptinezumab 100 or 300 mg in a dose‐blinded manner.

2.3. Outcomes and Subgroups

Daily throughout the trial, participant‐completed eDiary entries recorded the occurrence, start/stop times, associated pain intensity (mild, moderate, or severe), and associated acute medication use of each headache episode. Outcome measures analyzed here included categorical analysis of the number of MHDs for the placebo‐initiated and eptinezumab‐initiated arms and, for the eptinezumab‐initiated arm, included sustained MHD frequency category response, proportion of headache episodes with severe pain intensity, and Patient Global Impression of Change (PGIC) responder rates. The eDiary was used to derive all outcome measures except for PGIC.

A headache day was defined as any day with a headache that lasted ≥ 30 min and/or met the criteria for being a migraine. The criteria for a migraine day were defined previously in the published DELIVER trial and are modified from IHS guidelines [11, 12].

2.3.1. MHD Frequency Category Shifts

Participants were categorized by number of MHDs as follows: > 14, 8–14, 4 to < 8, 1 to < 4, and 0 (similar to prior analyses [4, 18, 19, 20]). To be included in the 0‐MHDs category, a participant had to report 0 headache days for each 4‐week period within the respective 12‐week dosing interval; all other categories represent the average. The percentage of participants within each MHD category was calculated at baseline and for each 12‐week dosing interval (i.e., the 12‐week period between each IV infusion). This analysis was conducted in the total population and in the following subgroups: participants with > 14 MHDs at baseline, participants with 8–14 MHDs at baseline, participants who were ≥ 50% migraine responders (i.e., experienced ≥ 50% reduction in MMDs) over Weeks 1–12; and for CM participants who experienced ≥ 30% MMD reduction over Weeks 1–12. The first two subgroup definitions represent numeric thresholds associated with CM (> 14 MHDs) and high‐frequency episodic migraine (HFEM; 8–14 MHDs) [4, 18, 19, 20, 21]; the latter two definitions represent numeric thresholds associated with sufficient response per clinical guidelines (≥ 50% for general migraine population and ≥ 30% for CM) [22, 23], with the timeframe in consideration that some treatment guidelines and reimbursement regulations recommend stopping or reevaluating use of eptinezumab if sufficient response is not reported within the first 12 weeks of use [23, 24, 25].

2.3.2. Sustained MHD Response

Sustained MHD response was analyzed by calculating the number of remaining 12‐week dosing intervals (i.e., the 12‐week period between each IV infusion) with < 8 or < 4 MHDs, depending on the subgroup, in participants who had MHD response (< 8 or < 4 MHDs) over Weeks 1–12. The 8‐MHD cutoff represents a numeric threshold often used to distinguish HFEM [21]. The 4‐MHD cutoff represents a numeric threshold used to distinguish low‐frequency EM (≥ 4 MHDs) [21] as well as people with migraine considered eligible for preventive treatment (≥ 4 MMDs) [24, 26, 27]. Three analyses to calculate sustained MHD response were performed: [1] In the subgroup with ≥ 8 baseline MHDs and who reported < 8 MHDs over Weeks 1–12, the number of 12‐week dosing intervals over Weeks 13–72 with < 8 MHDs was calculated; [2] In the subgroup with > 14 baseline MHDs and who reported < 8 MHDs over Weeks 1–12, the number of 12‐week dosing intervals over Weeks 13–72 with < 8 MHDs was calculated; [3] In the subgroup with ≥ 50% migraine response over Weeks 1–12 and who reported < 4 MHDs over Weeks 1–12, the number of 12‐week dosing intervals over Weeks 13–72 with < 4 MHDs was calculated.

2.3.3. Impact of Response on Pain Severity and PGIC

The final set of analyses evaluated the impact of early (first dose) and sustained MHD response on other efficacy outcomes, including the proportion of headache episodes with severe pain intensity and PGIC responder rates. The PGIC responder rate was defined as the proportion of participants reporting “much improved” or “very much improved” in response to the question about their perceived change in disease status since the start of the trial. These efficacy outcomes were analyzed at baseline (or Week 12 for PGIC) and over Weeks 61–72 (or Week 72 for PGIC) in the same subgroups as the sustained MHD response analysis but who were further grouped by their sustained response (i.e., < 8 MHDs over Weeks 1–12 and all remaining dosing intervals, < 8 MHDs over Weeks 1–12 but not all remaining dosing intervals, and ≥ 8 MHDs over Weeks 1–12 [with remaining dosing intervals not analyzed]).

2.4. Statistical Analysis

No sample size calculations were performed for these post hoc analyses. All analyses used the full analysis set (i.e., all randomized participants who received trial medication and had ≥ 1 valid 4‐week MMD assessment over Weeks 1–12). The percentage of participants within each MHD frequency category was analyzed in all participants with sufficient observed MHD values for the respective timepoint. Analyses of the percentage of participants with sustained MHD response (and related analyses of the impact of sustained MHDs on other efficacy outcomes) were conducted in participants who had sufficient observed MHD values for all timepoints during the extension period.

Eptinezumab doses were pooled for most analyses to improve the robustness of the results; participants receiving eptinezumab 100 or 300 mg for all six doses were pooled, and participants who received placebo before switching to eptinezumab 100 or 300 mg for the extension period were pooled. Descriptive statistics are presented, with no statistical testing performed. Analyses were conducted using R Core (version 4.1.2; R Foundation for Statistical Computing, Vienna, Austria) and RStudio (version 4.1; RStudio, PBC, Boston, MA, USA).

3. Results

3.1. Participants

There were 890 participants in the full analysis set (eptinezumab, n = 592; placebo, n = 298). A total of 865/890 (97%) participants completed the placebo‐controlled treatment period, of which 90% (782/865) completed the 48‐week dose‐blinded extension period, resulting in an overall completion rate of 88% (782/890) for the entire trial. Full demographic and clinical characteristics have been published [12, 13]; briefly, participants were predominantly white (854/890, 96%) and female (800/890, 90%), with a mean (SD) age of 43.8 (10.6) years. At baseline, 88/890 (10%) participants reported 4 to < 8 MHDs, 397/890 (45%) reported 8–14 MHDs, and 405/890 (46%) reported > 14 MHDs.

3.2. MHD Categories Change Over Time and Sustained MHD Response

3.2.1. Total Efficacy Population

Among participants randomized to eptinezumab for the full trial, there was an increase in the percentage of participants reporting < 4 MHDs from the first dose (Weeks 1–12: 23% [138/592]) to the final (sixth) dose (Weeks 61–72: 47% [236/498]; Figure 1A). During the final 12 weeks, 45/498 (9%) participants reported 0 MHDs (headache freedom). The proportion of participants experiencing < 8 MHDs increased from 10% (58/592) at baseline to 53% (316/592), 63% (362/573), and 73% (365/498) following the first, second, and final eptinezumab doses, respectively.

FIGURE 1.

FIGURE 1

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Shift in MHD frequency category among participants who (A) received eptinezumab throughout the placebo‐controlled and extension periods or (B) initially received placebo and were switched to eptinezumab for the extension period. Percentages may not add to 100% due to rounding. Results for both eptinezumab doses (100 mg and 300 mg) were pooled. MHDs, monthly headache days.

The percentage of participants in the placebo arm reporting < 4 MHDs was 5% (15/298) over Weeks 1–12 and 10% (29/295) over Weeks 13–24, increasing to 31% (89/290) following the first eptinezumab dose (Weeks 25–36; Figure 1B). During Weeks 61–72 (after 4 eptinezumab doses), 47% (122/262) of participants reported < 4 MHDs, whereas 9% (23/262) reported 0 MHDs. The proportion of participants experiencing ≥ 8 MHDs was reduced from 90% (268/298) at baseline to 37% (108/290) over Weeks 25–36 and 28% (73/262) over Weeks 61–72.

3.2.2. Participants With > 14 Baseline MHDs

Among participants with > 14 baseline MHDs receiving eptinezumab for all doses, 66% (179/271) reported ≤ 14 MHDs following their first dose (Weeks 1–12), 74% (192/260) reported ≤ 14 MHDs following their second dose (Weeks 13–24), and 81% (181/223) reported ≤ 14 MHDs after the final dose (Weeks 61–72) (Figure 2A). Furthermore, 27% (74/271), 40% (105/260), and 58% (129/223) of these participants reported < 8 MHDs following the first, second, and final eptinezumab doses, respectively. Over Weeks 61–72, 33% (73/223) reported < 4 MHDs, wherein 23% (52/223) reported 1 to < 4 MHDs and 9% (21/223) reported 0 MHDs. Limiting to participants with MHD data at all timepoints, 29% (74/258) of participants with > 14 baseline MHDs receiving eptinezumab for all 6 doses had < 8 MHDs over Weeks 1–12, and of this subset, 66% (49/74) reported a sustained response at < 8 MHDs for all 12‐week dosing intervals (Table S1).

FIGURE 2.

FIGURE 2

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Shift in MHD frequency category among participants with > 14 baseline MHDs who (A) received eptinezumab throughout the placebo‐controlled and extension periods or (B) initially received placebo and were switched to eptinezumab for the extension period. Percentages may not add to 100% due to rounding. Results for both eptinezumab doses (100 mg and 300 mg) were pooled. MHDs, monthly headache days.

The percentage of participants with > 14 baseline MHDs in the placebo arm who reported ≤ 14 MHDs was 43% (58/134) over Weeks 1–12 and 42% (55/131) over Weeks 13–24 (Figure 2B); following their first eptinezumab dose (Weeks 25–36), the percentage increased to 67% (87/130), reaching 80% (92/115) following their final (fourth) dose (Weeks 61–72). The percentage reporting < 8 MHDs increased from 10% (13/134) and 19% (24/131) over Weeks 1–12 and 13–24 following placebo administration, respectively, to 36% (47/130) and 51% (59/115) following their first and fourth eptinezumab doses (Weeks 25–36 and 61–72), respectively. During Weeks 61–72, 29% (34/115) of participants reported < 4 MHDs, of which 6% (7/115) reported 0 MHDs.

3.2.3. Participants With 8–14 Baseline MHDs

Among participants with 8–14 baseline MHDs receiving eptinezumab for all doses, 71% (172/242) reported < 8 MHDs over Weeks 1–12, 79% (187/237) over Weeks 13–24, and 85% (177/209) over Weeks 61–72 (Figure 3A). There were 56% (117/209) and 9% (19/209) of participants who reported < 4 MHDs and 0 MHDs, respectively, over Weeks 61–72.

FIGURE 3.

FIGURE 3

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Shift in MHD frequency among participants with 8–14 baseline MHDs who (A) received eptinezumab throughout the placebo‐controlled and extension periods or (B) initially received placebo and were switched to eptinezumab for the extension period. Percentages may not add to 100% due to rounding. Results for both eptinezumab doses (100 mg and 300 mg) were pooled. MHDs, monthly headache days.

Of participants with 8–14 baseline MHDs randomized to placebo, 41% (53/130) and 55% (71/130) reported < 8 MHDs over Weeks 1–12 and 13–24, respectively, following placebo administration (Figure 3B). The percentage of participants reporting < 8 MHDs was 81% (103/127) following the first eptinezumab dose (Weeks 25–36) and sustained at 85% (98/115) over Weeks 61–72. The proportion of participants with < 4 MHDs was 56% (64/115) over Weeks 61–72, whereof 9% (10/115) reported 0 MHDs.

3.2.4. Participants With ≥ 8 Baseline MHDs

Of participants with ≥ 8 baseline MHDs (including both 8–14 and > 14 MHDs) receiving eptinezumab for all 6 doses, 49% (241/492) had < 8 MHDs over Weeks 1–12; of this subset, 71% (170/241) reported a sustained response at < 8 MHDs for all remaining 12‐week dosing intervals (Table S1).

3.2.5. Participants With First‐Dose Response to Eptinezumab

Of 271 participants receiving eptinezumab for all 6 doses who reported ≥ 50% migraine response (i.e., ≥ 50% reduction in MMDs) over Weeks 1–12, > 85% reported < 8 MHDs throughout any given dosing interval (Figure 4A). Over Weeks 1–12, 48% (131/271) experienced < 4 MHDs, increasing to 68% (165/243) over Weeks 61–72, whereof 16% (38/243) reported 0 MHDs. Limiting to participants with MHD data at all timepoints, of participants receiving eptinezumab for all 6 doses who experienced ≥ 50% migraine response over Weeks 1–12, 49% (129/264) reported < 4 MHDs over Weeks 1–12, and of these, 60% (77/129) reported a sustained response at < 4 MHDs for all 12‐week dosing intervals (Table S1).

FIGURE 4.

FIGURE 4

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Shift in MHD frequency among participants who received eptinezumab throughout the placebo‐controlled and extension periods and (A) were ≥ 50% responders over Weeks 1–12 or (B) had > 14 baseline MHDs and were ≥ 30% responders over Weeks 1–12. Percentages may not add to 100% due to rounding. Results for both eptinezumab doses (100 mg and 300 mg) were pooled. Panel A: ≥ 50% responders were defined as participants with ≥ 50% reduction in monthly migraine days. A ≥ 50% reduction in monthly migraine days does not necessarily reflect an equal proportional reduction in monthly headache days. Panel B: ≥ 30% responders were defined as participants with ≥ 30% reduction in monthly migraine days. MHDs, monthly headache days.

Among participants with > 14 baseline MHDs who were ≥ 30% migraine responders over Weeks 1–12 following eptinezumab treatment, 87%–93% experienced ≤ 14 MHDs across any given dosing interval (Figure 4B). Over Weeks 1–12, 42% (74/178) reported < 8 MHDs, and 12% (21/178) reported < 4 MHDs. Over Weeks 61–72, 42% (65/155) reported < 4 MHDs, and 12% (19/155) reported 0 MHDs.

3.3. Association of Early and Sustained MHD Response to Eptinezumab With Episode Severity and PGIC Rating

In participants receiving eptinezumab for all 6 doses who had ≥ 8 baseline MHDs and experienced < 8 MHDs for all 12‐week dosing intervals (n = 170), the percentage of headache episodes with severe pain (eDiary‐derived) decreased from 44% at baseline to 11% over Weeks 61–72, and the percentage of PGIC responders increased from 83% at Week 12 to 93% at Week 72 (Figure 5).

FIGURE 5.

FIGURE 5

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Association of maintaining < 8 MHDs on headache severity and PGIC response in participants with ≥ 8 MHDs at baseline receiving eptinezumab for all 6 doses. Results for both eptinezumab doses (100 mg and 300 mg) were pooled. MHDs, monthly headache days; PGIC, Patient Global Impression of Change.

4. Discussion

This post hoc analysis of 72‐week data from the DELIVER trial suggests that eptinezumab led to early and sustained reductions in headache frequency of sufficient magnitude to mark the transition from more burdensome migraine subtypes (HFEM and CM) to less burdensome subtypes, including headache freedom, for many participants. Many participants had a downward shift in MHD frequency following their first eptinezumab dose, with more participants reporting lower MHD frequency as eptinezumab treatment continued. Subgroup analyses showed that participants with high baseline MHDs experienced clinically relevant shifts (e.g., < 8, < 4, or 0 MHDs). First‐dose (Weeks 1–12) response to eptinezumab treatment was associated with a higher level of sustained response and improved outcomes, as evidenced by [A] a greater rate of < 4 MHDs, including headache freedom, over Weeks 1–12 and over Weeks 61–72 in participants with ≥ 50% migraine response after the first eptinezumab dose compared with the overall population and [B] a greater rate of sustaining < 8 MHDs for the entire trial in participants with < 8 MHDs after the first eptinezumab dose. Of note, a sustained reduction to < 8 MHDs with all six eptinezumab doses was associated with fewer severe headache episodes and higher PGIC responder rates.

Prior studies have examined shifts in diagnostic classification with other anti‐CGRP monoclonal antibodies, namely galcanezumab and erenumab, which are subcutaneously administered monthly. Of galcanezumab‐treated participants with 8–14 baseline MHDs in the EVOLVE trials (randomized, double‐blind, placebo‐controlled [28, 29]), 82% reported < 8 MHDs during 6 month and 54% reported < 4 MHDs [30]. Of galcanezumab‐treated participants with CM in the REGAIN trial (3‐month placebo‐controlled period followed by 9‐month open‐label extension [31]), 55% shifted to < 8 MMDs and/or < 15 MHDs (for ≥ 3 consecutive months and the rest of trial), 33% to < 8 MMDs, and 14% to < 4 MMDs; it was not reported when the response started relative to baseline. Two Italian real‐world studies of galcanezumab and erenumab captured shifts to lower headache frequencies. In a 12‐month study, > 70% of galcanezumab‐treated participants reported < 15 MMDs all 12 months evaluated and 14% to 26% reported < 4 MMDs [32]. In a 6‐month study, the conversion rate from CM (≥ 15 MHDs) to EM (< 15 MHDs) in erenumab‐treated participants increased from 48% at Month 1 to 71% at Month 5, but decreased to 66% at Month 6; 68% were at EM frequency levels for Months 4–6 of the study [33]. In the same study, the percentage of participants with < 4 MHDs was 11% at Month 1, 20% at Month 5, and 17% at Month 6, with 16% reporting < 4 MHDs for each of Months 4–6 [33].

Almost half of participants receiving all six eptinezumab doses reported < 4 MHDs during the final dosing interval, with nearly 10% reporting zero. Experiencing < 4 MHDs aligns numerically with the American Headache Society and IHS recommendations for considering, offering, or optimizing preventive migraine treatment [9, 22]. The IHS also recognizes low migraine/headache frequency as an emerging proxy for treatment success that is accessible, easy to monitor, and closely correlated with quality of life [10]. The advocacy for setting higher standards for migraine prevention rests on the pitfalls of a traditional ≥ 50% MMD reduction, which may not fully restore quality of life or appreciate the residual migraine burden for patients [10]. Furthermore, previous post hoc eptinezumab data suggested that reducing headache frequency to ≤ 4 MHDs was a strong indicator of positive patient‐reported outcomes [34], and a cross‐sectional European survey found that ≥ 4 MHDs was associated with lower quality of life, worse productivity, and higher healthcare resource utilization than 1–3 MHDs [18]. Considering < 4 MHDs as an optimal preventive treatment target, these analyses demonstrated that eptinezumab can achieve optimal prevention in nearly 50% of participants. For individuals still experiencing ≥ 4 MHDs with preventive treatment, further optimization may be warranted, such as modifying acute and preventive treatment regimens or adding non‐pharmacological treatment [22].

Current clinical guidelines and reimbursement regulations are typically based on the achievement of defined percentage‐reduction thresholds (e.g., ≥ 50% reduction in headache frequency for people with EM and ≥ 30% reduction in headache frequency for the CM population), with assessment following the first or second eptinezumab dose [22, 23, 24, 35, 36]. First, anchoring treatment response to absolute values for MHD frequency, as done in the current analyses, may be a more accurate assessment of post‐baseline burden than percentage reductions in MHD frequency. Because percentage reductions are inherently influenced by baseline MHDs, people with higher baseline MHDs may experience higher residual burden than those with lower baseline MHDs, despite a similar percentage reduction in MHD frequency [10]. Second, the results of this analysis suggest that, while many participants reported those thresholds following just one dose, clinically meaningful shifts in headache frequency can occur at later time points with continued administration in patients who did not respond optimally following the first or second dose.

4.1. Limitations

The results described in this work should be interpreted with consideration of the known limitations of post hoc analyses. Long‐term extension trials have the limitations of responder trials in which continued enrollment favors positive outcomes, and participant awareness of receiving active treatment during the extension period may bias the results toward positive results. Moreover, only participants with complete data for each analysis were included, so missing data were not considered to produce the potential risk of exclusion bias. Differences in response by dose level (100 mg vs. 300 mg) were not evaluated within these analyses; however, results for migraine responder rates by dose level using data from the DELIVER trial have been published previously [14]. Finally, analyses were limited to changes in headache frequency; relationships between these shifts and changes in other important migraine characteristics were only partially examined.

5. Conclusion

In adults with migraine for whom 2–4 prior preventive treatments have failed, eptinezumab treatment resulted in more participants with < 8 or < 4 MHDs compared with placebo, with nearly 10% of participants reporting headache freedom. Eptinezumab treatment induced a diagnostic shift toward lower‐frequency headache types in most participants. Most participants with > 14 MHDs at baseline reported < 8 MHDs following the first dose and across the 72 weeks of treatment. Most participants reporting < 8 MHDs with the first eptinezumab dose sustained this response for the entire 72‐week treatment period, and having < 8 MHDs over all dosing intervals was associated with a decreased percentage of headache episodes with severe pain and a high percentage of PGIC responders. Overall, the analysis provides strong evidence supporting the early and long‐term effectiveness of eptinezumab for migraine prevention, with some even achieving headache freedom.

Author Contributions

Cristina Tassorelli: conceptualization (equal), investigation (lead), writing – original draft preparation (equal), writing – review and editing (equal). Amaal J. Starling: conceptualization (equal), writing – review and editing (equal). Susanne F. Awad: conceptualization (equal), formal analysis (equal), validation (equal), writing – original draft preparation (equal), writing – review and editing (equal). Xin Ying Lee: conceptualization (equal), formal analysis (equal), validation (equal), writing – original draft preparation (equal), writing – review and editing (equal). Line Pickering Boserup: conceptualization (equal), supervision (equal), writing – original draft preparation (equal), writing – review and editing (equal). Divya Asher: conceptualization (equal), writing – original draft preparation (equal), writing – review and editing (equal). Seema Soni‐Brahmbhatt: conceptualization (equal), supervision (equal), writing – review and editing (equal). Bjørn Sperling: conceptualization (equal), supervision (equal), writing – original draft preparation (equal), writing – review and editing (equal). Peter J. Goadsby: conceptualization (equal), writing – original draft preparation (equal), writing – review and editing (equal).

Funding

The trial and medical writing support were sponsored and funded by H. Lundbeck A/S. In collaboration with the academic authors, the sponsor participated in the design and conduct of the trial and in the collection, management, analysis, and interpretation of the data. The preparation, review, and approval of the manuscript were undertaken by all authors and by a professional medical writer and editor funded by the sponsor. All authors and H. Lundbeck A/S prepared, reviewed, and approved the final version of the manuscript and made the decision to submit the manuscript for publication.

Consent

The authors have nothing to report.

Conflicts of Interest

Cristina Tassorelli, over the last 36 months, has received honoraria for participation in advisory boards or for lecturing from AbbVie, Dompé, Eli Lilly, Ipsen, Lundbeck, Medscape, Pfizer, and Teva; has been a Principal Investigator or collaborator in clinical trials sponsored by AbbVie, Biohaven, Eli Lilly, Ipsen, Lundbeck, Pfizer, and Teva; and has received grants from the European Commission and the Italian Ministry of Health. Amaal J. Starling, over the last 36 months, has received consulting fees from AbbVie, Allergan, Amneal, Axsome Therapeutics, eNeura, Everyday Health, Lundbeck, Med‐IQ, Medscape, Miller Medical, Satsuma, and WebMD. Susanne F. Awad, Line Pickering Boserup, and Divya Asher are full‐time employees of H. Lundbeck A/S or one of its affiliate companies. Xin Ying Lee was a full‐time employee of H. Lundbeck A/S during data analysis and initial manuscript stages. She is currently an employee of Novo Nordisk, which was not involved in nor has a competing interest with this study. Bjørn Sperling is a full‐time employee of and owns stock/options in H. Lundbeck A/S. Peter J. Goadsby reports, over the last 36 months, personal fees for consulting from AbbVie, Eon Biopharma, Aurene, CoolTech LLC, Dr. Reddy's, Eli Lilly, Epalex, Kallyope, Linpharma, Lundbeck, Pfizer, PureTech Health LLC, Satsuma, Shiratronics, Teva, and Vial; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, Vector Metric; fees for educational materials from CME Outfitters and WebMD; publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate, and Wolters Kluwer; and a patent for magnetic stimulation for headache assigned to eNeura without fee.

Supporting information

Table S1: Sustainability of early response among participants who received eptinezumab for all 6 doses.

ENE-32-e70460-s001.docx (56.6KB, docx)

Acknowledgments

Medical writing and manuscript preparation support was funded by H. Lundbeck A/S and provided by Mary Tom, PhD, Nicole Coolbaugh, CMPP, and Brittany Friedson, PhD, of The Medicine Group LLC (New Hope, PA, USA) in accordance with Good Publication Practice guidelines.

Tassorelli C., Starling A. J., Awad S. F., et al., “Early and Sustained Shift in Headache Day Frequency Following Eptinezumab Treatment in Adults With Migraine for Whom 2–4 Previous Preventive Treatments Have Failed: A Post Hoc Analysis of the Randomized DELIVER Trial,” European Journal of Neurology 32, no. 12 (2025): e70460, 10.1111/ene.70460.

Data Availability Statement

In accordance with EFPIA's and PhRMA's “Principles for Responsible Clinical Trial Data Sharing” guidelines, Lundbeck is committed to responsible sharing of clinical trial data in a manner that is consistent with safeguarding the privacy of participants, respecting the integrity of national regulatory systems, and protecting the intellectual property of the sponsor. The protection of intellectual property ensures continued research and innovation in the pharmaceutical industry. Deidentified data are available to those whose requests have been reviewed and approved through an application submitted to https://www.lundbeck.com/global/our‐science/clinical‐data‐sharing.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1: Sustainability of early response among participants who received eptinezumab for all 6 doses.

ENE-32-e70460-s001.docx (56.6KB, docx)

Data Availability Statement

In accordance with EFPIA's and PhRMA's “Principles for Responsible Clinical Trial Data Sharing” guidelines, Lundbeck is committed to responsible sharing of clinical trial data in a manner that is consistent with safeguarding the privacy of participants, respecting the integrity of national regulatory systems, and protecting the intellectual property of the sponsor. The protection of intellectual property ensures continued research and innovation in the pharmaceutical industry. Deidentified data are available to those whose requests have been reviewed and approved through an application submitted to https://www.lundbeck.com/global/our‐science/clinical‐data‐sharing.

Articles from European Journal of Neurology are provided here courtesy of John Wiley & Sons Ltd on behalf of European Academy of Neurology (EAN)

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