Abstract
Background
Randomized clinical trials have demonstrated the efficacy and safety of eptinezumab. The aim of this study was to evaluate the effectiveness and safety of eptinezumab in a real-world setting among patients with difficult-to-treat migraine in France.
Methods
This is a one year-prospective real-word study including all consecutive adult patients from the Federation Hospitalo-Universitaire InovPain registry who received intravenous eptinezumab 100 mg.
Results
Three hundred and two patients (83.8% female / mean age of 48.0 ± 13.9 years) were included. Patients had at least 8 monthly migraine days, had failed at least 3 previous prophylactic treatments across amitryptiline, betablockers, botulinum toxin, candesartan, and topiramate and were Calcitonin Gene Related Peptide monoclonal antibodies naïve. Among them, 184 patients (60.9%) had chronic migraine and 118 (39.1%) had episodic migraine, whereas 229 patients (75.8%) presented a medication overuse. Regarding the primary endpoint, 50% responder rate at month 3, month 6, and month 12 was 35.4% (107/302), 39.0% (96/246), and 45.7% (63/138), respectively. ≥30% responder rate at month 3, month 6, and month 12 was 48.7% (147/302), 56.1% (138/246), and 63.0% (87/138), respectively. ≥75% responder rates at M3, M6, and M12 was 10.9% (33/302), 15.4% (38/246), and 23.2% (32/138), respectively. The effectiveness of eptinezumab was confirmed by significant changes in the values of all patient reported outcome measures at all assessment time points compared with baseline, demonstrating improvement in functional impact (Headache Impact Test-6), emotional impact (Hospital Anxiety Depression Scale), interictal burden (Migraine Interictal Burden Scale-4), and quality of life (Euro Qol-5 Dimensions descriptive system and visual analogue scale). According to Patient Global Impression of Change, the proportions of patients reporting being “much improved” or “very much improved” were 41.9% at month 3, 54.8% at month 6 and 74.4% at month 12. Overall, effectiveness appeared similar in episodic migraine and chronic migraine except at month12, where rates of 50% and 75% response were significantly higher in the chronic migraine (50% response: 53.8% vs. 34.5%, p = 0.025; 75% response: 30% vs. 13.8%, p = 0.026). Adverse events were uncommon and mostly mild, transient, and self-limited with few expected hypersensitivity reactions.
Conclusions
This French real-word study confirms the effectiveness and safety of eptinezumab in difficult-to-treat patients with migraine who and have failed non-specific preventive migraine treatments and are naïve to Calcitonin Gene Related Peptide monoclonal antibodies.
Clinical trial number
Not applicable.
Supplementary Information
The online version contains supplementary material available at 10.1186/s10194-026-02428-6.
Keywords: Migraine, Eptinezumab, Migraine prevention, Real-world evidence, Anti-CGRP monoclonal antibody-naive, Chronic migraine, Episodic migraine
Background
Advances in our understanding of migraine pathophysiology have led to the identification of calcitonin gene-related peptide (CGRP) as a key target for migraine treatment [1]. Consequently, a new class of drugs specifically designed to target CGRP, or its receptor has become available, including CGRP monoclonal antibodies (CGRP mAbs) and gepants [2]. Large randomized clinical trials (RCTs) and meta-analyses have provided strong evidence on the efficacy and safety of CGRP-targeting therapies [3, 4]. Despite this evidence, regulators and health-care payers still consider nonspecific drugs as the standard of care for migraine prevention and oppose reimbursement for CGRP-targeting therapies as first-line treatment, even in patients suffering from severe forms of migraine such as high-frequency episodic migraine (EM) or chronic migraine (CM). A shift in healthcare decision-making requires additional evidence and real-world data are particularly valuable because of their higher generalizability to clinical practice [5]. Although real-world data on CGRP-targeting therapies have been accumulating since their introduction, part of it was not collected in accordance with the International Headache Society guidelines for real-world studies [6], and fewer real-world data is available for CGRP-targeting therapies that last obtained marketing authorization, such as eptinezumab.
Eptinezumab is a humanized monoclonal antibody that binds CGRP and is administered intravenously, a route that distinguishes it from subcutaneous CGRP mAbs and confers rapid systemic bioavailability, quarterly dosing, and an early onset of therapeutic effect as early as the first day post-infusion [7]. Pivotal phase 3 RCTs have demonstrated the efficacy and safety of eptinezumab in EM [8], CM [9], migraine with previous failure for non-specific migraine drugs [10] and, more recently, migraine associated with medication overuse (MO) [11]. Since 2023 real-world evidence has begun to support these trial findings [12–26]. However, important limitations remain, as most existing real-world studies of eptinezumab have involved small patient populations and relied on retrospective data collection. Only three studies involved more than 100 patients and used prospective data collection in the United Kingdom [20], Greece [25], and Italy [26]. Furthermore, these more robust studies included a significant proportion of patients previously exposed to other CGRP mAbs, who may therefore have been non-responders to CGRP-targeting therapies.
In France, patient access to CGRP mAbs is extremely limited: subcutaneous CGRP mAbs and gepants are not reimbursed, and eptinezumab is currently the only available CGRP-targeting therapy, provided free of charge in selected hospitals for patients with severe migraine who have failed non-specific oral preventive treatments [27]. This unique situation makes it possible to consider conducting real-world studies of eptinezumab in migraine patients who are naïve to prior CGRP-targeted therapies.
In that respect, the aim of this study was to assess the effectiveness and safety/tolerability of eptinezumab over 12 months in a large cohort of patients with severe migraine (≥ 8 migraine days per month) enrolled in the prospective French FHU InovPain registry, who had experienced at least 3 prior treatment failure of amitriptyline, beta-blockers, botulinum toxin, candesartan, and topiramate, and had no prior exposure to CGRP mAbs.
Methods
Research context
This study was conducted within FHU InovPain, a research network dedicated to innovation in chronic refractory pain, including headache disorders. FHU InovPain has been described previously [28] and is based on a prospective patient registry designed to facilitate real-world observational research, particularly through the collection of data on newly approved treatments after marketing authorization.
Study design
This was a data analysis of a single-center, observational, longitudinal prospective cohort conducted at the Pain Department of Nice University Hospital. The study period extended from June 2023 to September 2025 and included all patients enrolled in the FHU InovPain registry who were naïve to CGRP mAbs prior to administration of eptinezumab for migraine prevention. Real-world effectiveness and safety/tolerability of eptinezumab were evaluated, with outcomes assessed at 3, 6, and 12 months after treatment initiation.
Participants
All consecutive patients in the FHU InovPain registry who received eptinezumab for migraine prevention had no prior exposure to CGRP-targeting therapies and had at least one documented follow-up assessment at month 3 were considered for enrolment.
The inclusion criteria for receiving eptinezumab at the Pain Department of Nice University Hospital were : (i) age over 18 years; (ii) a diagnosis of migraine according to the International Classification of Headache Disorders, 3rd edition [29]; (iii) at least 8 migraine days per month confirmed in a prospectively maintained headache diary for at least one month before treatment initiation; (iv) failure of at least 3 previous prophylactic non-specific migraine treatments across amitriptyline, beta-blockers, botulinum toxin, candesartan, or topiramate (efficacy failure after administration of drug for at least 2–3 months at generally accepted therapeutic doses / tolerability failure defined as discontinuation due to adverse event / contraindication). Compared to the criteria established by the French authorities [27], our criteria for access to eptinezumab are stricter in terms of prior treatment failure, as we limit the use of eptinezumab to patients with failure of at least 3 previous prophylactic non-specific migraine treatments across amitriptyline, beta-blockers, botulinum toxin, candesartan, or topiramate, whereas the French authorities authorize the use of eptinezumab as soon as patients with failure of 2 previous prophylactic non-specific migraine treatments failures, regardless treatments. Our stricter criteria were established due to institutional financial constraints.
The exclusion criteria for receiving eptinezumab et the Pain Department of Nice University Hospital were: (i) hypersensitivity to the active substance or any of its excipients; (ii) pregnancy or breastfeeding; and (iii) a history of cardiovascular disease (this criterion did not include patients with high blood pressure [HBP], provided it as well controlled by antihypertensive treatment).
Treatment
Patients received intravenous eptinezumab in routine clinical practice at our institution. Eptinezumab (Vyepti®, Lundbeck A/S) was administered at a dose of 100 mg every 12 weeks as a 30-minute infusion in a hospital setting, in accordance with standard clinical practice. In cases of insufficient response to the 100 mg dose, escalation to 300 mg was not performed due to institutional financial constraints. Concomitant preventive treatments, except for other CGRP mAbs and gepants, were permitted, and acute migraine medications could be used as needed.
Assessment
Baseline assessment was performed at treatment initiation (M0), and follow-up assessments were performed at month 3 (M3), 6 (M6), and 12 (M12). These assessments were conducted during outpatient visits corresponding to the first, second, third, and fifth eptinezumab infusions, respectively. During each outpatient visit, data was collected prior to the infusion, based on a prospectively completed headache diary covering the preceding month and on the standardized FHU InovPain questionnaire including all assessment items.
Following each outpatient visit, data were entered into the FHU InovPain registry database. Between visits, scheduled monitoring was performed to ensure data quality and verify the accuracy of the FHU InovPain registry entries.
At M0, baseline descriptive demographic and clinical data were recorded, including age, sex, migraine subtype (EM/CM), existence of aura, presence of continuous headache pain, concomitant preventive migraine treatments, previous failure of onabotulinumtoxinA, triptan resistance, MO, and body mass index (BMI).
At M0, M3, M6, and M12, assessment data were collected using the prospective paper headache diary and the FHU InovPain standardized questionnaire. Adverse events (AEs) were collected at M3, M6, and M12.
The prospective headache diary was used to record the monthly number of headache days (MHDs), migraine days (MMDs) and days with acute migraine treatment use during the month preceding each outpatient visit. A headache day was defined as any day on which the patient experienced headache, regardless of characteristics or duration. A migraine day was defined according to ICHD-3 criteria as a day with headache fulfilling criteria for migraine without aura, a day with symptoms fulfilling criteria for migraine with aura, or a day considered by the patient to be migraine at onset and relieved by migraine-specific acute medication [29]. Migraine subtype (EM or CM) and medication overuse were also defined according to ICHD-3 criteria [29].
For this study, patient-reported outcomes (PROs) included in the FHU InovPain standardized questionnaire were used to assess emotional impact, functional impact, interictal burden, quality of life, and patients’ overall perceived change.
Emotional impact was assessed using the Hospital Anxiety and Depression Scale (HADS), a 14-item self-report instrument comprising 2 subscales (HADS-A and HADS-D), each ranging from 0 to 21, with higher scores indicating greater symptom burden. HADS-A and HADS-D scores > 7 were considered indicative of clinically relevant anxiety and depressive symptoms, respectively [30].
Headache-related functional impact was evaluated using the Headache Impact Test-6 (HIT-6), with total scores ranging from 36 to 78, with higher scores indicating greater headache-related impact; scores were classified as little or no impact (36–49), some impact (50–55), substantial impact (56–59), and severe impact (≥ 60) [31].
Interictal burden was measured using the 4-item Migraine Interictal Burden Scale (MIBS-4), with total scores ranging from 0 to 12, with higher scores indicating greater interictal burden; scores were categorized as none (0), mild (1–2), substantial (3–4), and severe (≥ 5) [32].
Quality of life was evaluated using the EuroQol 5-Dimension questionnaire (EQ-5D), including the EQ-5D index and the EQ-5D visual analogue scale (EQ-5D VAS), with higher values indicating better perceived health status [33].
Patient global impression of change (PGIC) was assessed using a single-item 7-point scale ranging from “very much worse” to “very much improved.” Given the known placebo effect in migraine, the two highest categories (“much improved” and “very much improved”) were used as the threshold for defining clinical improvement [34].
Outcomes
The primary effectiveness endpoint was the 50% responder rate at M3, M6, and M12, defined as the proportion of patients achieving at least a 50% reduction in MMD compared with baseline. The response evaluation was done using the comparison of data collected during the 4 weeks before the initiation of eptinezumab treatment and data collected during the last 4 weeks of the three-month period between two eptinezumab infusions (at M3, M6 and M12).
Secondary effectiveness endpoints included the 30% and 75% responder rates at M3, M6, and M12, as well as changes from baseline in MMDs, MHDs, and the monthly number of days with acute migraine treatment use. Additional secondary endpoints included changes from baseline in headache-related impact assessed using HIT-6, emotional burden assessed using HADS-A and HADS-D, interictal burden assessed using MIBS-4 and quality of life assessed using the EQ-5D index and EQ-5D VAS. Further secondary outcomes included the evolution of PGIC and conversion from ‘MO’ to ‘non-MO’.
A prespecified subgroup analysis compared patients with EM and CM at baseline using the same effectiveness endpoints at each time point. Among patients classified as having CM at baseline, conversion to EM during follow-up was also evaluated.
Safety and tolerability outcomes included the occurrence of AEs during follow-up and discontinuations due to treatment-emergent adverse events (TEAEs).
Statistics
Statistical analyses were performed using standard statistical software R (version R-4.5.1). Continuous variables are presented as mean ± standard deviation (SD), and categorical variables as number and percentage. Distributional assumptions were assessed using the Shapiro–Wilk test.
Baseline comparisons between patients with CM and EM were performed using the unpaired Student’s t-test for approximately normally distributed continuous variables and the Mann–Whitney U test otherwise. Comparisons of categorical variables between subgroups were performed using the χ² test or Fisher’s exact test, as appropriate.
Responder rates are reported descriptively for the overall population at each follow-up time point. Comparisons of responder rates between CM and EM subgroups at each time point were performed using the χ² test or Fisher’s exact test, as appropriate.
Changes from baseline to follow-up in continuous outcomes were assessed using the paired Student’s t-test for approximately normally distributed variables and the Wilcoxon signed-rank test otherwise. This applied to MHDs, MMDs, monthly acute treatment days, HIT-6, HADS-A, HADS-D, EQ-5D index, EQ-5D VAS, MIBS-4. For subgroup analyses according to migraine subtype at baseline, within-group changes over time were assessed using the same approach. Changes from baseline to follow-up in dichotomous outcomes as medication overuse and migraine subtype, McNemar tests were performed.
Effectiveness analyses at M3, M6, and M12 were primarily performed using available-case analyses at each time point, including only patients with evaluable data for the corresponding outcome. Because availability of a documented M3 follow-up was part of the inclusion criteria, all included patients were evaluable for the 3-month assessment. In addition, sensitivity analyses using a last observation carried forward (LOCF) approach were performed for responder rates and diary-based outcomes, including MHDs, MMDs, and monthly acute treatment days, to assess the robustness of the results in the presence of treatment discontinuation and missing follow-up data.
All tests were two-sided, and p-values < 0.05 were considered statistically significant. No adjustment for multiple comparisons was performed; p-values should therefore be interpreted as nominal.
Ethics and regulatory considerations
This observational study did not require approval from the ethics committee. It was conducted as part of the FHU InovPain registry clinical research program, which received authorization from the French National Commission on Informatics and Liberty (Commission Nationale de l’Informatique et des Libertés; CNIL; CIL register no. 278, dated 11/09/2017). Patients were included only after providing written informed consent allowing their data recorded in the FHU InovPain registry database to be used for clinical research purposes.
This study was conducted in accordance with the STROBE guidelines [35].
Results
Demographics and clinical characteristics at baseline
Three hundred and two patients were included in the analysis. All 302 patients were evaluable for effectiveness and safety assessment at M3, whereas 246 and 138 patients were evaluable at M6 and M12, respectively. Reasons for non-evaluable status at M6 and M12 are shown in Fig. 1.
Fig. 1.
Flow-chart of patients from inclusion to study end, with initial evaluation at baseline (M0), follow-up assessments at month 3 (M3), month 6 (M6), and month 12 (M12), and reasons for non-evaluable status at M6 and M12
The cohort comprised 253 women (83.8%) with a mean age of 48.0 ± 13.9 years. At baseline, 184 patients (60.9%) had CM and 118 (39.1%) had EM. Migraine with aura was present in 54 patients (17.9%). Mean baseline MHDs and MMDs were 18.6 ± 7.7 and 17.0 ± 7.6, respectively. Continuous headache pain was reported by 102 patients (33.8%). Mean monthly acute treatment days were 16.2 ± 8.1. MO was present in 229/302 patients (75.8%).
Baseline demographic and clinical characteristics of the overall population and according to migraine subtype are detailed in Table 1.
Table 1.
Baseline demographic and clinical characteristics of the overall population and according to migraine subtype at baseline
| Characteristic | n valid | Total (n = 302) |
CM (n = 184) |
EM (n = 118) |
p-value |
|---|---|---|---|---|---|
| Sex, female, n (%) | 302 | 253 (83.8) | 143 (77.7) | 110 (93.2) | < 0.001 |
| Age, years | 302 | 48.0 ± 13.9 | 47.8 ± 14.6 | 48.3 ± 12.6 | 0.940 |
| Migraine subtype, n (%) | 302 | ||||
| CM, n | 302 | 184 (60.9) | — | — | — |
| EM, n | 302 | 118 (39.1) | — | — | — |
| Aura, n (%) | 298 | 54 (178.1) | 36 (19.9) | 18 (15.4) | 0.324 |
| MHD | 302 | 18.6 ± 7.7 | 23.5 ± 5.1 | 10.8 ± 3.3 | < 0.001 |
| MMD | 302 | 17.0 ± 7.6 | 21.4 ± 6.2 | 10.0 ± 3.0 | < 0.001 |
| MATD | 302 | 16.2 ± 8.1 | 19.9 ± 8.0 | 10.4 ± 3.9 | < 0.001 |
| Continuous headache pain, n (%) | 301 | 102 (34.9) | 96 (54.5) | 6 (5.2) | < 0.001 |
| MOH, n (%) | 302 | 229 (75.8) | 161 (87.5) | 68 (57.6) | < 0.001 |
| Simple overuse, n (%) | 302 | 118 (39.1) | 82 (44.6) | 36 (30.5) | 0.015 |
| Multiple overuse, n (%) | 302 | 112 (37.1) | 79 (42.9) | 33 (28.0) | 0.009 |
| Triptan overuse, n (%) | 302 | 188 (62.3) | 125 (67.9) | 63 (53.4) | 0.011 |
| Opioid overuse, n (%) | 302 | 15 (5.0) | 12 (6.5) | 3 (2.5) | 0.120 |
| Triptan resistance, n (%) | 299 | 41 (13.7) | 32 (17.6) | 9 (7.7) | 0.015 |
| Current preventive treatment, n (%) | 301 | 166 (55.1) | 101 (55.2) | 65 (55.1) | 0.986 |
| Previous onabotulinumtoxinA exposure, n (%) | 302 | 123 (40.7) | 93 (50.5) | 30 (25.4) | < 0.001 |
| Previous onabotulinumtoxinA failure among exposed, n (%) | 123 | 69 (56.1) | 53 (57.0) | 16 (53.3) | 0.726 |
| HIT-6 | 301 | 67.0 ± 6.4 | 67.2 ± 5.7 | 66.6 ± 7.5 | 0.693 |
| HADS-A | 301 | 10.0 ± 4.4 | 9.7 ± 4.4 | 10.4 ± 4.4 | 0.186 |
| Anxious symptoms, n (%) | 301 | 131 (43.45) | 78 (42.6) | 53 (44.9) | 0.695 |
| HADS-D | 301 | 7.3 ± 4.5 | 7.6 ± 4.8 | 6.9 ± 4.1 | 0.368 |
| Depressive symptoms, n (%) | 301 | 93 (30.9) | 52 (28.4) | 41 (34.7) | 0.246 |
| EQ-5D | 298 | 0.56 ± 0.29 | 0.50 ± 0.30 | 0.64 ± 0.25 | < 0.001 |
| EQ-5D VAS | 295 | 56.0 ± 18.7 | 53.9 ± 19.2 | 59.3 ± 17.4 | 0.017 |
| MIBS-4 | 287 | 6.3 ± 4.0 | 6.7 ± 4.0 | 5.7 ± 4.0 | 0.038 |
| BMI, kg/m² | 255 | 24.0 ± 4.2 | 24.1 ± 4.3 | 24.0 ± 3.9 | 0.960 |
| Overweight, n (%) | 256 | 69 (27.0) | 41 (26.5) | 28 (27.7) | 0.823 |
| Obesity, n (%) | 255 | 22 (8.6) | 14 (9.1) | 8 (7.9) | 0.745 |
Data are presented as mean ± SD or n (%), as appropriate Percentages were calculated using the number of valid observations for the corresponding variable. p-values refer to comparisons between patients with chronic migraine (CM) and episodic migraine (EM). BMI, Body Mass Index; CM, chronic migraine; EM, episodic migraine; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; HADS-D, Hospital Anxiety and Depression Scale-Depression; HIT-6, Headache Impact Test-6; EQ-5D, EuroQol 5-Dimension questionnaire; VAS, visual analogue scale; MATD, monthly acute treatment days; MHD, monthly headache days; MIBS-4, Migraine Interictal Burden Scale-4; MMD, monthly migraine days; MOH, medication overuse headache
Mean HIT-6 score was 67.0 ± 6.4. Mean EQ-5D index and EQ-5D VAS were 0.56 ± 0.29 and 56.0 ± 18.7, respectively. Mean MIBS-4 score was 6.3 ± 4.0. Mean HADS-A and HADS-D scores were 10.0 ± 4.4 and 7.3 ± 4.5, respectively; clinically relevant anxious symptoms were present in 131 patients (43.4%) and clinically relevant depressive symptoms in 93 (30.8%). Mean body mass index was 24.0 ± 4.2 kg/m² (n = 255), with overweight and obesity present in 69/255 (27.1%) and 22/255 (8.6%) patients, respectively.
Primary effectiveness endpoint
The proportion of 50% responders at M3, M6 and M12 was 35.4% (107/302), 39.1% (96/246) and 45.7% (63/138), respectively (Fig. 2).
Fig. 2.
Responder rates (≥ 30%, ≥ 50% and ≥ 75% reduction from baseline in monthly migraine days) at month 3 (M3), month 6 (M6), and month 12 (M12)
Secondary effectiveness endpoints
The proportions of ≥ 30% responders at M3, M6 and M12 were 48.7% (147/302), 56.1% (138/246) and 63.0% (87/138), respectively. The proportions of ≥ 75% responders at M3, M6 and M12 were 10.9% (33/302), 15.4% (38/246) and 23.2% (32/138), respectively (Fig. 2). Changes in continuous effectiveness outcomes over time are presented in Table 2, and the longitudinal evolution of diary-based outcomes is shown in Fig. 3.
Table 2.
Evolution of continuous effectiveness outcomes in the overall population
| Outcomes | M0 (302) |
M3 (302) |
M6 (246) |
M12 (138) |
|---|---|---|---|---|
| MHDs change/M0 |
18.6 ± 7.7 - |
14.1 ± 9.1* 4.5 ± 7.7 |
12.6 ± 9.0* 5.6 ± 8.0 |
10.8 ± 8.0* 7.1 ± 8.3 |
|
MMDs change/M0 |
17.0 ± 7.6 - |
12.5 ± 8.7* 4.4 ± 8.2 |
11.4 ± 8.6* 5.2 ± 8.3 |
9.2 ± 7.6* 7.0 ± 8.5 |
|
MATD change/M0 |
16.2 ± 8.1 - |
11.6 ± 9.1* 4.5 ± 8.0 |
10.5 ± 8.7* 5.2 ± 8.3 |
9.1 ± 7.7* 6.8 ± 8.4 |
|
HIT-6 change/M0 |
67.0 ± 6.4 - |
62.1 ± 8.4* 4.8 ± 8.3 |
60.0 ± 9.2* 7.0 ± 9.0 |
58.4 ± 8.8* 7.8 ± 8.3 |
|
HADS-A change/M0 |
10.0 ± 4.4 - |
9.2 ± 4.2* 0.8 ± 2.9 |
8.7 ± 4.3* 1.2 ± 3.3 |
8.1 ± 3.9* 1.6 ± 3.4 |
|
HADS-D change/M0 |
7.3 ± 4.5 - |
6.8 ± 4.6** 0.5 ± 3.2 |
6.5 ± 4.6* 0.8 ± 3.4 |
5.5 ± 4.0* 1.9 ± 3.5 |
|
EQ-5D i change/M0 |
0.6 ± 0.3 - |
0.7 ± 0.3* -0.1 ± 0.2 |
0.7 ± 0.3* -0.1 ± 0.2 |
0.7 ± 0.2* -0.1 ± 0.3 |
|
EQ-5D vas change/M0 |
56.0 ± 18.7 - |
62.3 ± 18.5* -6.0 ± 17.1 |
65.9 ± 19.0* -9.1 ± 18.7 |
69.5 ± 17.2* -12.7 ± 17.6 |
|
MIBS-4 change/M0 |
6.3 ± 4.0 - |
5.2 ± 4.0* 1.1 ± 3.5 |
4.6 ± 3.9* 1.5 ± 3.3 |
4.3 ± 3.8* 1.9 ± 3.9 |
Data are presented in mean ± standard deviation. Negative change-from-baseline values indicate an increase from baseline. *Wilconson signed rank test vs. M0, p < 0.001, ** Wilconson signed rank test vs. M0, p < 0.05. Change/M0, change from baseline; HIT-6, Headache Impact Test-6; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; HADS-D, Hospital Anxiety and Depression Scale-Depression; EQ-5Di, EuroQol 5-Dimension index utility; EQ-5Dvas: EuroQol 5-Dimension visual analogue scale; MATD, monthly acute treatment days; MHD, monthly headache days; MIBS-4, Migraine Interictal Burden Scale-4; MMD, monthly migraine days
Fig. 3.
Longitudinal evolution of key diary-based outcomes in the overall population. *Wilcoxon signed-rank test vs. M0: p < 0.001 MHDs, monthly headache days; MMDs, monthly migraine days
For MHDs, mean values decreased from 18.6 ± 7.7 at baseline to 14.1 ± 9.1, 12.6 ± 9.0, and 10.8 ± 8.0 at M3, M6, and M12, respectively. For MMDs, mean values decreased from 17.0 ± 7.6 at baseline to 12.5 ± 8.7, 11.4 ± 8.6, and 9.2 ± 7.6 at M3, M6, and M12, respectively. For monthly acute medication days, mean values decreased from 16.2 ± 8.1 at baseline to 11.6 ± 9.1, 10.5 ± 8.7, and 9.1 ± 7.7 at M3, M6, and M12, respectively. Differences from baseline were significant at all time points for MHDs, MMDs and monthly acute medication days (all p < 0.001).
For HIT-6 score, mean values decreased from 67.0 ± 6.4 at baseline to 62.1 ± 8.4, 60.0 ± 9.2 and 58.4 ± 8.8 at M3, M6 and M12, respectively. For HADS-A score, mean values decreased from 10.0 ± 4.4 at baseline to 9.2 ± 4.2, 8.7 ± 4.3 and 8.1 ± 3.9 at M3, M6 and M12, respectively. For HADS-D score, mean values decreased from 7.3 ± 4.5 at baseline to 6.8 ± 4.6, 6.5 ± 4.6 and 5.5 ± 4.0 at M3, M6 and M12, respectively. For MIBS-4 score, mean values decreased from 6.3 ± 4.0 at baseline to 5.2 ± 4.0, 4.6 ± 3.9 and 4.3 ± 3.8 at M3, M6 and M12, respectively. For EQ-5D index, mean values increased from 0.6 ± 0.3 at baseline to 0.7 ± 0.3, 0.7 ± 0.3 and 0.7 ± 0.2 at M3, M6 and M12, respectively. For EQ-5D VAS, mean values increased from 56.0 ± 18.7 at baseline to 62.3 ± 18.5, 65.9 ± 19.0 and 69.5 ± 17.2 at M3, M6 and M12, respectively. Differences from baseline were significant at all time points for HIT-6, HADS-A, MIBS-4, EQ-5D index and EQ-5D VAS (all p < 0.001), whereas for HADS-D the differences were significant at M3 (p < 0.05), M6 (p < 0.001) and M12 (p < 0.001).
According to PGIC, the proportions of patients reporting themselves as “much improved” or “very much improved” were 41.9% at M3, 54.8% at M6 and 74.4% at M12 (Fig. 4).
Fig. 4.
Distribution of patient global impression of change (PGIC) categories at month 3 (M3), month 6 (M6), and month 12 (M12) in the overall population
The proportion of patients with MO was reduced from 75.8% (229/302) at baseline to 41.9% (124/302), 36.4% (87/246) and 31.6% (43/138) at M3, M6 and M12, respectively (Fig. 5). Differences from baseline were significant at all time points (all p < 0.001).
Fig. 5.
Proportion of patients with medication-overuse at baseline (M0), month 3 (M3), month 6 (M6), and month 12 (M12) in the overall population. *McNemar test vs. M0: p < 0.001
Prespecified subgroup analysis according to baseline migraine subtype
Baseline demographic and clinical characteristics according to migraine subtype are presented in Table 1. Compared with patients with EM, those with CM were less frequently female (77.7% vs. 93.2%; p < 0.001) and had a greater headache burden, with higher MHDs (23.5 ± 5.1 vs. 10.9 ± 3.3; p < 0.001), higher MMDs (21.4 ± 6.2 vs. 10.0 ± 3.0; p < 0.001), and more monthly acute treatment days (19.9 ± 8.0 vs. 10.4 ± 3.9; p < 0.001). Patients with CM also more frequently reported continuous headache pain, MO, simple and multiple medication overuse, triptan overuse, and triptan resistance, and had lower EQ-5D index values, lower EQ-5D VAS scores, higher MIBS-4 scores, and higher systolic blood pressure. No significant between-group differences were observed for age, aura, HIT-6, HADS-A, HADS-D, current preventive treatment, previous onabotulinumtoxinA failure, overweight, obesity, or opioid overuse.
For the primary effectiveness endpoint, the proportions of 50% responders at M3, M6 and M12 were 35.9% (66/184), 41.4% (60/145) and 53.8% (43/80) in patients with CM, and 34.7% (41/118), 35.6% (36/101) and 34.5% (20/58) in patients with EM. Between-group differences were not significant at M3 (p = 0.842) or M6 (p = 0.364) but were significant at M12 (p = 0.025).
For the secondary responder endpoints, the proportions of 30% responders at M3, M6 and M12 were 48.4% (89/184), 53.8% (78/145) and 63.8% (51/80) in patients with CM, and 49.2% (58/118), 59.4% (60/101) and 62.1% (36/58) in patients with EM, with no significant between-group differences at any time point (p = 0.894, p = 0.383 and p = 0.840, respectively). The proportions of 75% responders were 10.3% (19/184), 16.6% (24/145) and 30.0% (24/80) in patients with CM, and 11.9% (14/118), 13.9% (14/101) and 13.8% (8/58) in patients with EM. These did not differ significantly at M3 (p = 0.676) or M6 (p = 0.566) but were significantly higher in the CM subgroup at M12 (p = 0.026).
Evolution of continuous effectiveness outcomes according to baseline migraine subtype are presented in Supplementary Table S1, and the longitudinal evolution of key diary-based outcomes in each subgroup is shown in Supplementary Fig. S1. In both subgroups, MHDs, MMDs and monthly acute treatment days decreased significantly from baseline at all follow-up time points (all p < 0.001). Patient-reported outcomes also improved in both subgroups. HADS-A decreased significantly from baseline at all time points in both groups, whereas HADS-D decreased significantly from M6 onward in patients with CM and from M3 onward in patients with EM.
MO decreased in both subgroups over time. In patients with CM, the proportion with MO decreased from 87.5% (161/184) at baseline to 53.6% (96/184), 48.9% (68/145) and 39.2% (31/80) at M3, M6 and M12, respectively. In patients with EM, the corresponding proportions were 57.6% (68/118), 23.9% (28/118), 19.0% (19/101) and 21.1% (12/58). Reductions from baseline were significant at all time points in both subgroups (all p < 0.001).
Conversion from chronic to episodic migraine
Among patients in the effectiveness population classified as having CM at baseline (n = 184), phenotypic conversion to EM was assessed at each follow-up visit using observed-case data. At M3, 87/184 patients (47.3%) no longer fulfilled criteria for CM and were classified as EM. Among baseline CM patients with available data at M6 (n = 145), 77/145 patients (53.1%) were classified as EM. Among baseline CM patients with available data at M12 (n = 80), 55/80 patients (68.8%) were classified as EM.
In the overall population, the proportion of patients classified as having EM increased from 39.1% at baseline to 65.0% at M3, 67.8% at M6 and 79.7% at M12, whereas the proportion classified as having CM decreased from 60.9% to 35.0%, 32.2% and 20.3%, respectively (Fig. 6). Differences from baseline were significant at all follow-up time points (McNemar test vs. M0: p < 0.001).
Fig. 6.
Proportion of patients classified as having episodic migraine or chronic migraine at baseline (M0), month 3 (M3), month 6 (M6), and month 12 (M12) in the overall population. *McNemar test vs. M0: p < 0.001
LOCF analysis
LOCF sensitivity analysis yielded results broadly consistent with those of the available-case analysis. In the overall population (N = 302), the proportions of ≥ 50% responders at M3, M6 and M12 were 35.4% (107/302), 36.1% (109/302) and 36.8% (111/302), respectively. The corresponding proportions of ≥ 30% responders were 48.7% (147/302), 53.6% (162/302) and 52.3% (158/302), whereas the proportions of ≥ 75% responders were 10.9% (33/302), 14.2% (43/302) and 16.6% (50/302), respectively. Mean MHDs decreased from 18.6 ± 7.7 at baseline to 14.1 ± 9.1, 13.3 ± 9.1 and 13.5 ± 9.3 at M3, M6 and M12, respectively. Mean MMDs decreased from 17.0 ± 7.6 at baseline to 12.5 ± 8.7, 12.1 ± 8.9 and 12.0 ± 9.1, respectively. Mean monthly acute treatment days decreased from 16.2 ± 8.1 at baseline to 11.8 ± 9.2, 11.5 ± 9.1 and 11.2 ± 9.2 at M3, M6 and M12, respectively. Differences from baseline remained significant at all time points for MHDs, MMDs and monthly acute treatment days (all p < 0.001). Detailed results of LOCF subgroup analyses according to migraine subtype at baseline are presented in Supplementary Table S2.
Safety and tolerability
AEs were uncommon and mostly mild, transient, and self-limited. Reported events included allergic and non-allergic AEs.
All of the non-allergic AEs occurred as early as the first eptinezumab infusion and recurred with each subsequent infusion. Some of these non-allergic AEs appeared during infusion and resolved spontaneously 24 h after the end of the infusion and included asthenia (n = 3, 1.0%), nausea (n = 1, 0.3%), scalp pruritus (n = 1, 0.3%), transient “brain fog” (n = 1, 0.3%), and transient symmetric lower-limb paresthesia (n = 1, 0.3%). Alopecia (n = 3, 1.0%) persisted between infusions. All these non-allergic AEs were mild in intensity.
Allergic AEs occurring during or immediately after eptinezumab infusion included bronchospasm (n = 3, 1%), pruritic erythematous rash (n = 1, 0.3%), urticaria (n = 3, 1.0%) concerning 6 patients (one patient presenting a bronchospasm associated with an urticaria). Three of the 6 concerned patients had a medical history of allergy (two with asthma and one with atopic dermatitis). Four of these allergic AEs occurred as early as the first infusion and two (both urticaria) occurred for the first time during the second infusion. Intensity was severe for three of these allergic AEs: one (generalized urticaria) leading to treatment discontinuation and two (pruritic erythematous rash and bronchospasm associated with urticaria) which led to the development of a desensitization protocol that made it possible to continue treatment.
Discussion
Our study is a real-world study to evaluate the effectiveness and safety of eptinezumab 100 mg in difficult-to-treat patients with migraine based on the prospective French InovPain registry.
Compared with previous large prospective real-world studies on eptinezumab conducted in the United Kingdom [20], Greece [25], and Italy [26], our study is distinguished by its larger sample size and its 12-month follow-up period. It is also the first prospective real-world study to evaluate eptinezumab exclusively in patients with migraine who were naïve to CGRP-targeting therapies. In this population of difficult-to-treat, CGRP-targeting therapy-naïve patients treated with eptinezumab 100 mg, our study has shown 50% responder rates (in terms of MMDs) of 35.4%, 39%, and 45.7% at M3, M6, and M12, respectively. To account for patients who discontinued treatment (mainly due to ineffectiveness) and those lost to follow-up, we conducted a LOCF analysis, which showed 50% responder rates of 35.4%, 36.1%, and 36.8% at M3, M6, and M12, respectively.
Comparison with previous prospective real-world studies on eptinezumab remains challenging because those studies involved smaller sample sizes, among which at least 50% of patients had failed previous CGRP mAbs [20, 25, 26]. Our findings may therefore be more appropriately compared with those of the DELIVER trial, a RCT that evaluated the efficacy of eptinezumab in a large population of patients who were difficult to treat with non-specific migraine therapies but had not previously failed CGRP-targeting treatments [10]. In that RCT, the 50% responder rate following initiation of treatment with 100 mg of eptinezumab was 42%, 52%, and 62.6% in weeks 1–12, 13–24, and 49–60, respectively [10, 36]. Those responder rates were higher than those observed in our study, but it should be noted that our patients likely had more prophylactic treatment resistance than those included in the DELIVER study. In DELIVER, the inclusion criterion regarding patients’ treatment history specified a prior failure of 2 to 4 treatments and less than 38% of included patients had at least 3 previous preventive treatment failures [10]. In contrast, all patients included in our study had failed at least three preventive treatments among amitriptyline, beta-blockers, candesartan, topiramate, and botulinum toxin before receiving eptinezumab. The population included in our study was also characterized by more severe migraine than the DELIVER population [12], in terms of MMDs (17.0 ± 7.6 vs. 13.8 ± 5.6), CM/EM ratio (60.9%/39.1% vs. 46%/54%), MO (75.8% vs. 13%), and HIT-6 scores(67.0 ± 6.4 vs. 66.6 ± 4.7).
Differences in assessment methodology may also have contributed to the lower responder rates observed in our study. Unlike DELIVER, which evaluated the average MMDs over the entire three-month period between two eptinezumab infusions, our study assessed only the last month of the three-month period. This approach may have reduced observed treatment response in patients experiencing a wearing-off effect toward the end of the dosing interval. Although wearing off was not specifically assessed in RCTs of eptinezumab, Alssadi et al. reported this phenomenon in 36.1% of patients treated with CGRP mAbs in a real-world cohort [37]. Similarly, approximately one-quarter of responders in our cohort reported a decline in therapeutic effect that consistently occurred during the last two weeks before reinfusion (data not presented because they are declarative and not supported by any quantitative analysis of prospective headache diary).
At the three assessment time points, the 30% responder rates (M3: 48.7% in principal analysis / 48.7% in LOCF analysis, M6: 56.1% in principal analysis / 53.1% in LOCF analysis, M12: 63% in principal analysis / 52.6% in LOCF analysis) and the 75% responder rates (M3: 10.9% in principal analysis / 10.9 in LOCF analysis, M6: 15.4% in principal analysis / 14.2 in LOCF analysis, M12: 23.2% in principal analysis / 16.6% in LOCF analysis) showed the same trend as the 50% responder rates, indicating that the effectiveness of eptinezumab was maintained over one year among responders. The effectiveness of eptinezumab was confirmed by significant changes in the values of all PRO measures at all assessment time points compared with baseline, demonstrating improvements in functional impact (HIT-6), emotional impact (HADS-A and HADS-D), interictal burden (MIBS-4), and consequently quality of life (EQ-5D index and EQ-5D VAS).
This reduction in the number of migraine days and in the burden of migraine resulted in a clinically relevant Patient Global Impression of Change, with 41.9%, 54.8%, and 74.4% of patients in the overall population reporting that they were ‘much improved’ or ‘very much improved’ at M3, M6, and M12, respectively.
Given its large sample size, our study allowed us to compare the effectiveness of eptinezumab in high-frequency EM (all patients included in our study experienced at least 8 migraine days per month) and CM. Overall, effectiveness appeared similar in both groups except at M12, where 50% and 75% responder rates were significantly higher in patients with CM than in those with high frequency EM (50% response: 53.8% vs. 34.5%, p = 0.025 and 75% response: 30% vs. 13.8%, p = 0.026).
Such improved effectiveness in CM had not been demonstrated in a subgroup analysis of the DELIVER study, which instead showed higher responder rates for patients with high-frequency EM than for those with CM, although no statistical comparison between groups was performed and this subgroup analysis was limited to weeks 1–12 and weeks 13–24 [38].
The effectiveness of eptinezumab in CM was further reflected by significant rates of conversion from CM to EM, as illustrated by the evolution of the CM/EM ratio: 60.9%/39.1% at baseline, 35%/65% at M3, 32.2%/67.8% at M6, and 20.3%/79.7% at M12. Similarly, the proportion of patients with MO decreased from 75.8% at baseline to 31.6% at 12 months.
The safety and tolerability of eptinezumab were good in our cohort. Allergic AEs were expected, as hypersensitivity reactions were reported in 23 (1.1%) patients among a pooled population of 2,076 patients with migraine treated with eptinezumab across 5 RCTs [39]. With 6/302 patients (half with a medical history of allergy) experiencing a hypersensitivity reaction, the proportion of patients who experienced this type of AEs in our cohort (2%) was slightly higher to that observed in controlled trials. In one patient, severe urticaria led to permanent discontinuation of eptinezumab treatment. In two other patients with severe allergic AE (one with pruritic erythematous rash and one with bronchospasm associated with urticaria), eptinezumab treatment was continued using a desensitization protocol previously developed and published by our group [40].
The primary strength of this study is its large sample size, making it currently the largest real-world study of eptinezumab in terms of patient number. A second major strength is that the study was conducted in accordance with the International Headache Society guidelines for real-world evidence studies [6], with Data Quality that may be considered Level 1 owing to the use of a structured data collection method, validated assessment measures and validated PRO instruments.
This study also has several limitations. First, its single-center design may call into question the generalizability of the findings to the broader French population. Another weakness is the use of a paper headache diary rather than an electronic diary, as recommended by the International Headache Society [6]. Similarly, our study may be criticized for assessing MHDs and MMDs only during the last 4 weeks of the three-month period between two eptinezumab infusions. This methodological choice was deliberate, given the low rate of adherence to headache diary completion among migraine sufferers, even those with frequent attacks [41].
Finally, it is important to note that our study focused solely on the 100 mg dose of eptinezumab. Due to financial constraints, escalation to the 300 mg dose was not possible. Consequently, we have no data to determine what proportion of non-responders to 100 mg would respond to 300 mg, or whether higher dosing could be a way to limit the wearing-off effect observed in some patients.
Conclusion
This French real-word study confirms the effectiveness and safety of eptinezumab in difficult-to-treat patients with migraine who had previously failed non-migraine specific treatments and are naïve to CGRP mAbs. For the international migraine community, these findings, which are consistent with those obtained with other CGRP mAbs, further support the clinical value of this innovative class of migraine therapies. More specifically for the French migraine community, these results give us hope that the ongoing negotiations will yield favorable outcomes, potentially leading to easier treatment access, particularly for patients with the most severe forms of migraine.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We would like to thank Ms. Leslie Gastaldi for her assistance in scheduling eptinezumab infusions for the patients in this cohort.
Author contributions
SFM and MLM conceived the study. TJ and MLM collected the data RF performed statistical analysis. SFM and MLM drafted the manuscript. All authors reviewed and approved the final manuscript.
Funding
This study was supported by FHU InovPain.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethic approval and consent to participate
This observational study did not require approval from the ethics committee. It was conducted as part of the FHU InovPain registry clinical research program, which received authorization from the French National Commission on Informatics and Liberty (Commission Nationale de l’Informatique et des Libertés; CNIL; CIL register no. 278, dated 11/09/2017). Patients were included only after providing written informed consent allowing their data recorded in the FHU InovPain registry database to be used for clinical research purposes.
Consent for publication
Not applicable.
Competing interests
SFM has no conflict of interest.RF had no conflict of interest.TJ had no conflict of interest.MLM received personal fees for consultancy activities from: Abbvie/Allergan, Amgen, Eli Lilly, IPSEN, Lundbeck, Medtronic, Novartis, Orion Pharma, Perfood, Pfizer, Reckitt-Benckiser, Savia, Bioelectronics, Teva, UPSA.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.