A retrospective audit of the real‐world safety and effectiveness profile of eptinezumab for treatment‐resistant chronic migraine in Australia

Authors: Lakshini Gunasekera, Shuli Cheng, Emma Foster, Shobi Sivathamboo, Terence O'Brien, Helmut Butzkueven, Jayashri Kulkarni, Elspeth Hutton

Abstract

Objective

To describe the real‐world safety, tolerability, and effectiveness of eptinezumab for chronic migraine prevention in Australia.

Background

Eptinezumab is a relatively new medication for treatment‐resistant chronic migraine prevention. It was only introduced onto the Australian Pharmaceutical Benefits Scheme in August 2023, so there are limited real‐world Australian data regarding its tolerability and effectiveness.

Methods

This is a single center retrospective audit of patients receiving eptinezumab for chronic migraine prevention between 1 September 2023 and 31 December 2024. Headache characteristics were compared at baseline and 3 months after eptinezumab administration. Primary outcomes were mean reductions in monthly headache days (MHD) and monthly migraine days (MMD). Secondary outcomes were mean monthly reductions in acute abortive medications, and adverse events.

Results

Of the 60 patients who received eptinezumab during the study period, a total of 54 patients with complete medical records and headache diaries were used in the statistical analysis. The majority were female (43/54, 80%) with mean age 41.7 years (SD 11.4). Three months after eptinezumab infusion, MMD reduced from 23.0 to 15.4 days (p value <0.001), and MHD reduced from 26.5 to 19.2 days (p value <0.001). Acute analgesic use decreased from 16.2 to 11.1 days (p value<0.001). The vast majority (94%, 51/54) had no immediate adverse events. Of 22 patients with 6‐month post infusion data, mean MMD and MHD decreased to 11.0 (p < 0.001) and 17.8 days (p < 0.001), respectively, from baseline. Statistically significant reductions to both co‐primary outcomes were achieved in those with pre‐existing medication‐overuse headache and those who had previously not responded to onabotulinumtoxinA, fremanezumab, and galcanezumab.

Conclusions

Our findings show that eptinezumab is a safe, well‐tolerated migraine prophylactic that decreases monthly migraine and headache days in a small sample of Australian patients with treatment‐resistant chronic migraine. Further prospective studies with larger sample sizes and longer follow‐up data are needed to confirm findings of this study.

INTRODUCTION

The pathophysiology of migraine is complex and includes alterations to both the central and peripheral nervous systems, the trigeminovascular system, the trigeminocervical complex, sterile neurogenic inflammation, and various neuropeptides. ^1^ Calcitonin gene‐related peptide (CGRP) in particular plays a significant role in migraine pathophysiology. ^1^ CGRP is a neuropeptide that is elevated during a migraine attack and is decreased after migraine‐specific acute and prophylactic medications are administered. ^1^ Its discovery in the late 1980s and 1990s as being contributory to migraine attacks led to development of therapeutics targeting this neuropeptide for migraine prevention. ^1^ Available anti‐CGRP therapies in Australia include galcanezumab and fremanezumab which are monthly subcutaneous injections against the CGRP molecule, eptinezumab which is a 3‐monthly intravenous infusion against the CGRP molecule, and erenumab which is a monthly subcutaneous injection against the CGRP receptor. ^2^ , ^3^ Due to the significant cost of anti‐CGRP monoclonal antibodies, their use is restricted in Australia to those with resistant chronic migraine. ^2^

In Australia, eligibility criteria for anti‐CGRP monoclonal antibodies require that a patient has a diagnosis of chronic migraine—at least 15 monthly headache days (MHD) with at least 8 of these being migraine days for at least 6 months. ^2^ In addition to this diagnosis, they must have had an inadequate response, intolerance, or contraindication to at least three prior oral migraine preventives. ^2^ The specific oral preventives that may be chosen as headache prophylactic agents amitriptyline, candesartan, nortriptyline, pizotifen, propranolol, sodium valproate, topiramate, and verapamil. ^2^ Continuation criteria stipulate that patients must have at least 50% reduction to baseline monthly migraine days (MMD) after one infusion in order to qualify for a second infusion. ^2^ These medications can only be prescribed by a neurologist or by a general practitioner in consultation with a neurologist. ^2^ , ^3^

Advanced therapies are expensive but fortunately the Pharmaceutical Benefits Scheme (PBS) in Australia subsidizes some medications available to the general population. Eptinezumab is the most recent migraine preventive therapy to receive subsidization from the PBS in Australia since August 2023. ^2^ This medication is given as a 100 mg infusion every 12 weeks. ^2^ The higher 300 mg 12‐weekly infusion is not subsidized by the Australian PBS ^2^ and, therefore, is not included in this retrospective audit. Erenumab is not available on the Australian PBS ^4^ so is presently only available on a private prescription whereas galcanezumab and fremanezumab are available on the PBS. ^3^

International studies have shown that eptinezumab is safe, well‐tolerated and effective in reducing MMD, MHD, and acute analgesic usage. ^5^ , ^6^ , ^7^ , ^8^ , ^9^ , ^10^ , ^11^ , ^12^ There is evidence that it can also convert chronic migraine into an episodic migraine phenotype that is more responsive to medications. ^13^ More importantly from a patient perspective, it improves patient quality‐of‐life and subjectively improves their most bothersome symptoms. ^14^

Given the relatively recent introduction of eptinezumab to the PBS in Australia, there is limited Australian data on its tolerability, safety, and effectiveness. Our study provides this information by performing a 12‐month retrospective audit of a tertiary headache center in Melbourne that commonly prescribes migraine advanced therapies. We hypothesized that the administration of eptinezumab to Australian patients with treatment‐resistant chronic migraine would lead to a statistically significant decrease in their mean MHD and mean MMD compared to their pre‐treatment baseline levels.

METHODS

Study design

This was a retrospective, single‐cohort, open‐label study of headache characteristics at baseline and 3 months after eptinezumab administration for chronic migraine prophylaxis.

Setting

This study was conducted in a tertiary hospital with a dedicated headache clinic in Melbourne, Australia, where approximately 800 patients per year receive headache treatment. This multi‐disciplinary center includes headache neurologists, a specialist headache nurse, a headache psychologist, and headache dietitian.

Participants

The inclusion and exclusion criteria for the study are below in Table 1.

Variables and data sources

We reviewed 12 months of clinical data of all patients referred for eptinezumab for chronic migraine between 1 September 2023 and 31 December 2024. The electronic medical record was used to extract patient demographics, headache diagnosis, baseline headache characteristics, and medication history. We examined clinical notes from the medical day stay unit to ascertain any immediate infusion‐related side effects within 24 h. Delayed infusion reactions after 24 h were noted during clinic follow‐up appointments at 3 months post infusion, and any relevant Emergency Department visits during the study period. Routine Headache clinic consultations were used to capture interval changes to headache characteristics based on patient headache diaries.

Study size

No statistical power calculation was conducted prior to the study. The sample size was based on the available data.

Statistical analysis

All statistical analyses were conducted using SPSS version 28.0 (IBM Corp., Armonk, NY, USA). Categorical variables were analyzed as counts with percentages. Continuous data were first split into two baseline and 3 or 6 months post eptinezumab administration. The raw data for each of these groups were visually observed with histograms. As the original data were paired and non‐parametrically distributed, both mean changes to MHD/MMD/acute medications with standard deviations and medians with interquartile ranges were analyzed using Wilcoxon‐signed rank tests. Sub‐group analyses were conducted using Mann–Whitney U tests due to independence of groups. All hypothesis tests were two‐tailed and considered significant at a p‐value <0.05. We assumed independence of each individual patient, but not for the paired differences. The raw paired data and differences (headache characteristics at baseline and post eptinezumab administration) were graphically checked using histograms and confirmed to be asymmetrically distributed. Non‐parametric statistical analysis was conducted for the paired differences. Means with standard deviation and median with interquartile ranges were both reported.

Ethics approval was from the Hospital Ethics Committee (Project 816/24). A waiver of consent was obtained due to the retrospective study design.

RESULTS

Patient disposition

A total of 64 patients were referred for eptinezumab infusion during the study period. Table 1 shows the inclusion and exclusion criteria for eptinezumab infusion. One of these referred patients received the infusion at a private hospital outpatient clinic, and a further three patients decided not to proceed with the infusion due to difficulty physically attending our institution's medical day stay unit. In total, 60 patients received the infusion during the study period. Complete headache diaries were available for 54 patients, thus only 54 patients were included in the statistical analysis. There were no missing data for the 54 patients included in the statistical analysis. Figure 1 summarizes patient disposition from referral to 6‐month analysis.

Baseline characteristics

All patients in the study (54/54, 100%) had a documented diagnosis of treatment‐resistant chronic migraine. Of these 54 patients, 43/54 (80%) were female with mean age 41.72 years (SD 11.4). Migraine duration prior to eptinezumab administration was >10 years in 44/54 (81%), and 5–10 years in 10/54 (19%). Medication‐overuse headache was present in over half (28/54, 52%). Acute analgesic use consisted of paracetamol (24/54, 44%), non‐steroidal anti‐inflammatory drugs (41/54, 76%), triptans (38/54, 70%), anti‐emetics (15/54, 28%), and opioids (14/54, 26%). Table 2 shows the baseline demographic data for the study population.

Three‐month outcome analysis

Three months after eptinezumab infusion, MMD reduced from 23.0 to 15.4 days (p value <0.001), and MHD reduced from 26.5 to 19.2 days (p value <0.001). Acute analgesic use decreased from 16.2 to 11.1 days (p value<0.001). These changes are graphically displayed in Figure 2.

Table 3 shows the interval changes to headache characteristics and acute analgesic use at baseline and after eptinezumab administration. Tables 4 and 5 further show that interval reductions to headache characteristics and acute analgesic use after eptinezumab administration held in the populations with and without concurrent headache prophylactic use, and in those with medication‐overuse headache.

Table 6 shows the changes to headache characteristics and acute analgesic use in the subpopulations who had previously not responded to galcanezumab, fremanezumab, erenumab, and onabotulinumtoxinA. Patients who had not responded to galcanezumab (n = 40) found that MHD, MMD, and acute analgesic use decreased by 7 days (p value < 0.001), 6 days (p value 0.003), and 5 days (p value 0.003), respectively. In patients who had not responded to fremenezumab (n = 44), MHD, MMD, and acute analgesic use decreased by 6.8 days (p value < 0.001), 7.6 days (p value < 0.001), and 4.1 days (p value 0.004), respectively. For patients who had not responded to onabotulinumtoxinA, we observed that MHD, MMD, and acute analgesic use decreased by 7.7 days (p value < 0.001), 8.3 days (p value < 0.001), and 5 days (p value < 0.001), respectively.

The 6‐month outcome analysis

Of the 54 patients who had an infusion of eptinezumab, two patients opted not to continue with a second infusion. There were 24 patients with <50% reduction to baseline MMD, so they did not qualify for a second infusion. This led to a total of 26 patients who did not proceed to a second infusion. A total of 28 patients were eligible for a second infusion and continued. Of these, only 22 maintained headache diaries and were included in the 6‐month post eptinezumab statistical analysis.

The 6‐month post eptinezumab follow‐up data (n = 22) are presented in Table 3. MHD, MMD, and acute analgesic use decreased by 8 days (p value 〈0.001), 12 days (p value 〈0.001), and 5 days (p value 0.013), respectively.

Unfortunately, we were unable to prescribe the higher 300 mg dose for those who were non‐responders to the lower 100 mg dose since the former is not subsidized by the Australian PBS. The higher dose is available on a private script but unfortunately cost was a barrier to patients accessing this medication.

Adverse events analysis

All 54 patients who had a first infusion attended a 3‐month follow‐up consultation. Of 54 patients who completed an eptinezumab infusion during the study period, the vast majority (51/54, 95%) did not have any immediate adverse events. The three documented adverse events mild vasovagal reaction that improved with leg elevation only, mild non‐anaphylactic allergic reaction responsive to oral antihistamines, and a mild non‐epileptic psychogenic seizure responsive to reassurance only in a patient with known functional neurological disorder. There were two delayed reactions reported after 24 h: subjective worsening of fatigue in a patient with known chronic fatigue syndrome, and mild generalized rash responsive to oral antihistamines. These changes are summarized in Figure 3.

Although 28 patients received a second infusion of eptinezumab, only 22 patients completed a second infusion and had complete headache diaries for 6 months. Data from these 22 patients were included in the statistical analysis. The vast majority (20/22, 91%) did not have any immediate infusion reactions. The two immediate reactions reported mild vomiting and mild pruritis responsive to antihistamines respectively. There were no delayed reactions. These adverse events are shown in Figure 3.

Analysis of responder rate

The 50% responder rate was 28/54 (52%). Responders to eptinezumab achieved at least 50% reduction to MMD from baseline. There were no significant differences to responsiveness based on sex (p value 0.752). We further analyzed responders to non‐responders using binary outcomes (yes/no) for the following ischemic heart disease (no patients), hypertension (p value 0.291), hyperlipidaemia (p value 0.073), diabetes mellitus (p value 0.279), cerebrovascular disease (p value 1.000), obesity (p value 0.752), depression (p 0.426), anxiety (p value 0.602), fibromyalgia (p value 0.412), attention‐deficit hyperactivity disorder (p value 0.066), endometriosis (female only, p value 0.070), and functional neurological disorder (p value 0.633).

DISCUSSION

This study fills the gap in the Australian literature regarding real‐world safety, tolerability, and effectiveness of eptinezumab for chronic migraine prevention. An international systematic review and meta‐analysis including over 2700 patients has shown that eptinezumab is safe, well‐tolerated, and effective in reducing MMD, and increasing quality of life in both episodic and chronic migraine. ^15^ Unfortunately in Australia, there is no PBS subsidization for eptinezumab use in episodic migraine and the higher 300 mg dose is also unavailable. ^2^

Our study, which contains comparable demographic data to the international literature, has shown that eptinezumab reduces MMD and MHD at both 3 months and 6 months post eptinezumab infusion. Over half of our study population had medication‐overuse at baseline and confirms findings in the international literature that eptinezumab is efficacious despite concomitant medication overuse. ^16^ , ^17^ , ^18^ , ^19^ In a similar vein to previous studies, ^20^ we have shown that acute medication use also decreases after eptinezumab use despite concurrent medication‐overuse headache, which is often a reason for lack of observed effectiveness of headache prophylactic agents. Unlike the original PROMISE2 trial, ^21^ our cohort did not exclude opioid overuse over 5 days per month so our results show significance despite being a more treatment‐resistant population. We have also shown in our study that eptinezumab is useful in those who have not responded to other advanced therapies such as onabotulinumtoxinA, galcanezumab, and fremanezumab which is useful when counseling patients prior to eptinezumab.

The effectiveness of eptinezumab in those who have not responded to other CGRP therapies is controversial in the literature; there is evidence that eptinezumab may work despite failure of other anti‐CGRP therapies, ^22^ while other studies show that non‐responders to the subcutaneous CGRP injections are unlikely to respond to an intravenous medication of the same class of drug. ^23^ Our sample size of patients who had tried all three available anti‐CGRP therapies of galcanezumab, fremanezumab, and erenumab was small (6/54, 11%) but shows meaningful results. Of note, these same patients had also previously not responded to onabotulinumtoxinA. Of these patients, a third (2/6, 33%) had no change to their baseline; a third (2/6, 33%) improved from daily migraine to zero monthly migraine/headache days; and a third (2/6, 33%) showed improvements that fell just short of a 50% reduction from baseline.

Confounding effects are noted for patients on concurrent headache preventives, but we also note their prescription for dual purposes; all three patients on concurrent candesartan had co‐existing migraine and hypertension. While this clouds interpretation of our results regarding the true treatment effect of eptinezumab, it reflects the limitations of a real‐world study in which this infusion is used as adjunctive therapy in those who may wish to continue (or need to continue) other oral headache preventives.

A limitation of this study is that results may not be extrapolatable to other populations where comprehensive headache clinics such as ours are unavailable. Our specialized headache clinic includes headache neurologists, a headache psychologist, a headache nurse, and a headache dietician. This multidisciplinary care contributes to increased patient education, optimizing acute treatments, and also non‐pharmacological treatments. However, we believe that the patient population requiring eptinezumab likely warrants a higher level of time, resources, and multidisciplinary care since they have not responded to less advanced therapies. This medication is also likely to be prescribed and administered in specialist centers, so it is useful to see the real‐world effectiveness that can be achieved in such centers despite patients not responding to other preventives.

Our study is also limited by a small sample size and retrospective data collection. To increase the reliability of treatment effect seen in this small sample size that was available to us, we ensured that there were no missing data points in the cohort used in the final statistical analysis. Authors elected to omit six medical records for patients receiving an eptinezumab infusion and attending a follow‐up appointment at 3 months due to incomplete headache diaries. The retrospective nature of data collection and lack of a control arm reduces the ability to infer causation. The subgroup analyses for patients who had not responded to other advanced therapies, for example, should be interpreted with caution given the small sample size. The treatment effect may also be magnified due to the administration of this medication through a specialized headache center whereby patients are educated about managing lifestyle contributions to headache, or the relative novelty of the medication, which may confer a placebo effect or magnified subjective treatment benefit.

Future prospective studies with larger sample sizes and longer follow‐up data are needed to assist clinicians in the management of this chronic condition that may require eptinezumab infusions over several years.

CONCLUSION

This study shows that eptinezumab is a safe, well‐tolerated, and efficacious medication in Australians with chronic migraine. Although limited by a small sample size, our findings have shown reductions to MHD, MMD, and acute medications after eptinezumab use. Future studies with prospective data collection and longer follow‐up are needed to confirm our positive preliminary observations.

AUTHOR CONTRIBUTIONS

Lakshini Gunasekera: Conceptualization; investigation; writing – original draft; methodology; writing – review and editing; formal analysis; project administration. Shuli Cheng: Conceptualization; writing – review and editing; supervision. Emma Foster: Writing – review and editing; supervision. Shobi Sivathamboo: Supervision; writing – review and editing. Terence O'Brien: Writing – review and editing; supervision. Helmut Butzkueven: Supervision; writing – review and editing. Jayashri Kulkarni: Writing – review and editing; supervision. Elspeth Hutton: Conceptualization; writing – review and editing; supervision.

CONFLICT OF INTEREST STATEMENT

Shuli Cheng, Emma Foster, Shobi Sivathamboo, Terence O'Brien, and Jayashri Kulkarni have no conflicts of interest. Lakshini Gunasekera has received funding from the Victorian Government Catalyst Grant program for investigation of hormonal therapies for menstrual migraine. Helmut Butzkueven has received institutional (Monash University) funding from NHMRC (L1 Investigator Grant), MRFF Australia, MSAustralia, The Trish Foundation, The Pennycook Foundation, Biogen, F. Hoffmann‐La Roche Ltd., Merck, Alexion, CSL, UCB & Novartis; carried out contracted research for Novartis, Merck, F. Hoffmann‐La Roche Ltd. & Biogen; taken part in speakers' bureaus for Biogen, UCB, Novartis, F. Hoffmann‐La Roche Ltd. & Merck (honoraria paid to Institution) and has received conference support from Merck and Novartis. Elspeth Hutton has served on advisory boards for Sanofi‐Genzyme, Novartis, Teva, Eli Lilly, Allergan, Lundbeck, been involved in clinical trials sponsored by Novartis, Teva, Xalud, Cerecin, and has received payment for educational presentations from Allergan, Teva, Eli Lilly and Novartis.