Prescription Conversion for Migraine Prevention in Veterans

Background: Several calcitonin gene-related peptide (CGRP) targeted therapies are available for migraine prevention. Minimal data are available to describe comparative efficacy among members of this drug class. Methods: This retrospective chart review evaluated the clinical efficacy after conversion from galcanezumab to fremanezumab. Patients with an active galcanezumab prescription for migraine prevention (March 1, 2022, to March 31, 2023) were enrolled in the neurology pharmacist clinic. Eligible patients were converted to fremanezumab with additional follow-up at 12 weeks. Changes in monthly migraine days (MMDs), monthly headache days (MHDs), headache pain intensity (0-10 scale), and a subjective report of overall change were assessed from baseline to follow-up after conversion. A Wilcoxon signed-rank test assessed statistical significance. Results: Seventy-four patients were analyzed following conversion from galcanezumab to fremanezumab. No statistically significant difference was found in headache or migraine frequency following medication change. The median MMDs reduced from 10 to 8 (P = .08), median MHDs reduced from 14 to 10 (P = .18), and median pain score remained unchanged at 8 (P = .01). Following conversion to fremanezumab, 63% of patients reported symptoms improved and 11% reported symptoms were unchanged.Conclusions: Efficacy remained stable following conversion from galcanezumab to fremanezumab for migraine prevention.Migraine is a leading cause of disability for younger adults, with a significant impact on function, productivity, and quality of life.[1] About 2.5% of patients with episodic migraine (EM) progress to chronic migraine (CM), a subtype of migraine associated with increased risk of comorbidities as well as high social and economic burden.[2] Preventive treatment can play a key role in EM and CM management.[3] Calcitonin gene-related peptide (CGRP) antagonists offer migraine-specific options for prevention. The US Food and Drug Administration has approved 4 monoclonal antibodies (mAbs) that target this pathway either by blocking the CGRP receptor (eg, erenumab) or binding the CGRP ligand (eg, fremanezumab, galcanezumab, eptinezumab).[4] Clinical trials and real-world data have compelling results, leading the American Headache Society to encourage these options to be considered among first-line treatments for migraine prevention.[5] Less is known about the comparative efficacy of individual CGRP-targeting treatments. Although observational studies have started to surface, many have compared anti-CGRP mAbs with oral small-molecule CGRP receptor inhibitors (ie, gepants) rather than changing between anti-CGRP mAbs.[6,7,8,9,10,11,12] With several CGRP-targeting therapies now available, changes in therapy may be needed due to various concerns (eg, tolerability, inadequate therapeutic response, or change in formulary). While some research describes efficacy following CGRP-targeting therapy changes after poor response to the initial agent, questions remain about the effectiveness of switching between CGRP-targeted mAbs in those on stable regimens.[13,14,15,16] The US Department of Veterans Affairs (VA) Pharmacy Benefits Management (PBM) has criteria for use with erenumab as the preferred first-line CGRP-targeting therapy for migraine prevention. After erenumab, other anti-CGRP mAbs may be considered without a clear order of preference. In March 2023, fremanezumab was named the preferred second-line anti-CGRP mAb prior to galcanezumab at Ralph H. Johnson Veterans Affairs Medical Center (RHJVAMC). Veterans were contacted and offered a transition from galcanezumab to fremanezumab. Some studies have evaluated conversion from galcanezumab to fremanezumab specifically.[17,18]A small prospective study of 21 patients found comparable treatment outcomes when switching from galcanezumab to fremanezumab.[17] A small single-center Japanese retrospective review found similar effectiveness in 20 patients who were initial responders to monthly galcanezumab and subsequently changed to quarterly fremanezumab injections.[18] To our knowledge, no formal studies or retrospective reviews evaluating a change in CGRP-targeting therapies have been published specifically in a veteran population. This research may be useful for other VAMCs considering cost-effective within-class medication changes. This retrospective chart review sought to add to this growing body of literature by evaluating the clinical efficacy following conversion from galcanezumab to monthly fremanezumab for migraine prevention at a VAMC. MethodsThe RHJVAMC neurology service consists of neurologists specializing in various subspecialty disorders, including a board-certified headache specialist, medical residents and fellows, neurology nurse practitioners, and 1 full-time neurology clinical pharmacy practitioner (CPP). The neurology CPP manages a neurology pharmacotherapy clinic where veterans are referred for comprehensive medication management (CMM). The CPP scope of practice includes medication changes, dose adjustments, discontinuations, and ordering medication-related laboratory tests. Veterans are referred to the neurology CPP by neurologists for CMM for neurologic conditions, including headache disorders. The RHJVAMC Neurology service approved this CPP-led conversion of CGRP-targeting therapy to reduce medication costs. This project evaluated changes in headache characteristics in patients switched from galcanezumab to fremanezumab for migraine prevention at the RHJVAMC neurology clinic. This was determined by the RHJVAMC facility project advisory group to be a quality improvement retrospective chart review following the local formulary medication conversion as part of routine care; therefore, submission to the institutional review board was not required. Patients aged ≥ 18 years who were seen at the RHJVAMC neurology clinic were included if they had a documented prescription for galcanezumab dosed at 120 mg monthly for migraine prevention, and a migraine diagnosis in accordance with the diagnostic criteria of the International Classification of Headache Disorders (ICHD-3).[19] Patients were excluded if they had a previous fremanezumab trial and/or failure, documented nonadherence to injectable therapy or discontinuation of anti-CGRP treatment, recent or upcoming transfer to another VAMC, declined conversion, a diagnosis of cluster headache without concomitant migraine headache disorder, an active prescription for galcanezumab 100 mg (300 mg monthly dose) for episodic cluster headache prevention, or the prescriber was not affiliated with RHJVAMC.Patients who met the inclusion criteria were contacted for a neurology CPP appointment. If the patient agreed with medication conversion, the neurology CPP entered a new prescription for fremanezumab 225 mg subcutaneous (SC) injection monthly to be initiated on the day the next galcanezumab dose was due. To ensure stable efficacy and tolerability with the conversion, patients were not offered a change to a fremanezumab 675 mg SC every 3 months until they completed a 12-week trial of once-monthly dosing. Data on quarterly fremanezumab dosing were not included in this analysis. Patients were scheduled for a telephone follow-up with the neurology CPP after 12 weeks to reassess the efficacy and tolerability of fremanezumab. Patients provided baseline headache characteristics at the initial consultation. Patients were encouraged but not required to keep a home headache journal. Headache characteristics were assessed at each neurology visit, including monthly migraine days (MMDs), monthly headache days (MHDs), and headache pain intensity (0, no pain; 10, debilitating pain). If a range of values was given for headache frequency or pain intensity, then the mean was recorded. Following fremanezumab conversion, headache characteristics were reassessed and the patient provided a subjective report of overall headache change as worsening, improving, or no change. At each visit, medication-related adverse events (AEs) were assessed and documented in the electronic health record. Adherence was self-reported and assessed through discrepancies in medication refill dates.Statistical AnalysisA retrospective chart review was completed for patients with an active prescription for galcanezumab 120 mg between March 1, 2022, and March 31, 2023, with subsequent conversion to fremanezumab 225 mg monthly. Baseline demographics were obtained, including age, sex, race, migraine classification, and previous medication trials documented for migraine prevention (eg, topiramate, divalproex, b-blockers, tricyclic antidepressants, selective serotonin-norepinephrine reuptake inhibitors, botulinum toxin, and erenumab). Change in MMDs and MHDs was assessed from baseline (time of medication conversion) to 12-week follow-up. The change in headache pain severity on the pain scale from baseline to follow-up was also assessed. Patient reports of overall change (ie, symptoms improved, worsened, or unchanged) and any adverse effects following fremanezumab initiation were also recorded for descriptive purposes. Statistical analysis was completed using SPSS software. Paired t tests were used to assess statistically significant changes in MMD or MHD. Changes in headache severity from baseline to follow-up were assessed using a Wilcoxon signed-rank test. A 2-tailed test with P < .05 determined statistical significance. Descriptive analysis was planned for all other endpoints, including patient-reported overall change in headache characteristics following conversion from galcanezumab to fremanezumab. ResultsBetween March 1, 2022, and March 31, 2023, 135 patients were identified with active prescriptions for galcanezumab 120 mg. Thirty patients were determined to be ineligible for conversion to fremanezumab: 14 had diagnosed primary cluster headache without migraine features, 8 had active migraine management by a non-VA neurologist, 3 previously tried fremanezumab, and 5 declined conversion. Of the 105 patients with an active galcanezumab prescription, 74 changed to fremanezumab (Figure 1). Thirty-one patients discontinued galcanezumab: 24 were nonadherent with galcanezumab and the patient/clinician decided not to start an alternative CGRP-targeting mAb, and 7 transferred to another VAMC. Forty-two patients (57%) were female, and 55 (74%) had CM. Fifty patients (68%) had failed ≥ 5 medications for migraine prevention at baseline, and 62 (84%) had previously tried erenumab (Table 1).Patients converted from galcanezumab to fremanezumab prescriptions for migraine prevention at Ralph H. Johnson Veterans Affairs Medical Center.At baseline, the mean (median) MMD was 11.0 (10) and MHD was 15.0 (14). Baseline data were not normally distributed; therefore, nonparametric tests were used to assess change at follow-up. At follow-up, patients reported reductions in mean (median) MMD to 9.7 (8) and MHD to 13.8 (10), though these changes were not statistically significant (Table 2, Figure 2). The mean pain score decreased from 7.8 to 7.3, but the median remained unchanged at 8, which was statistically significant (P = .01). Forty-seven patients (63%) reported improved efficacy following conversion, 19 (26%) reported worse efficacy, and 8 (11%) reported no change. Follow-up evaluation after conversion from galcanezumab to fremanezumab from baseline to follow-up; x indicates mean, line indicates median, and box indicates IQR (N = 74).Twelve weeks postconversion, 58 patients continued using fremanezumab, and 16 patients discontinued use (11 changed back to galcanezumab, 3 changed to atogepant as an alternative CGRP-targeting treatment for migraine prevention, and 2 stopped using a CGRP-targeting treatment). Over the 12-week assessment, 6 patients reported AEs, including 2 injection site reactions, 2 experienced constipation, 2 experienced insomnia, and 1 experienced hypersensitivity reaction. All AEs were considered mild without need for further intervention. All patients with AEs were offered a change back to galcanezumab, a different CGRP-targeting treatment, or another migraine preventive medication at the discretion of the neurology CPP or neurologist. While most neurology CPP follow-up assessments were conducted at 12 weeks, some were completed sooner. To assess for heterogeneity among these cohorts (ie, those with follow-up before 12 weeks vs those with follow-up at 12 weeks), a Mann-Whitney U test was performed. No significant differences were found among groups for change in MMD, MHD, or pain severity.DiscussionThis analysis found that switching from galcanezumab 120 mg monthly to fremanezumab 225 mg monthly for migraine prevention did not result in significant changes in efficacy. While the mean and median MMDs and MHDs decreased within 12 weeks postconversion, these changes were not statistically significant. The median headache pain intensity remained unchanged, and the significant P value found was likely due to variability in the IQR. The mean headache intensity pain score decreased by 0.6, although this degree of improvement is unlikely to be clinically significant. Some patients had a follow-up visit sooner than the initial 12-week postconversion follow-up due to patient requests related to perceived worsening of symptoms or AEs. No significant difference was found when results were analyzed according to follow-up timeframe at 12 weeks or < 12 weeks from the initial conversion. Although patient satisfaction was not formally assessed, patients were asked to subjectively describe their change in overall response following conversion to fremanezumab. Most reported that their symptoms were either improved (63%) or unchanged (11%). Only 26% of patients reported a worsening of overall response and were offered a change back to galcanezumab or alternative medication for migraine prevention. Few AEs were reported following conversion to fremanezumab, suggesting good overall tolerability, which is consistent with the literature.While some observational studies have described the effect of changing anti-CGRP mAbs after inadequate response to the initial agent, minimal evidence is available to describe the change in effect for those who are stable on an anti-CGRP mAb and switch to another mAb. Furthermore, there is minimal research on changes between anti-CGRP mAbs both targeting the ligand (eg, galcanezumab, fremanezumab, and eptinezumab) as opposed to changing between one medication targeting the CGRP ligand and another targeting the CGRP receptor (eg, erenumab, atogepant, and rimegepant).[13,14,15,16,17,18]This study adds to the growing body of research describing the real-world use and effect of CGRP-targeting treatments, and specifically provides hypothesis-generating data to suggest comparable efficacy between galcanezumab and fremanezumab. Results of this analysis are consistent with previous publications evaluating the change from galcanezumab to fremanezumab, but with a few notable differences.[17,18] The 74-patient sample in this analysis was larger than prior studies. Youn et al examined 20 patients who started fremanezumab 30 to 787 days after galcanezumab discontinuation; only 5 patients had a washout period < 60 days. In contrast, all patients in this analysis were directly converted to fremanezumab on the date the next galcanezumab injection was due (30 days).[17] Although Ihara et al evaluated the change from monthly galcanezumab to quarterly fremanezumab in 21 patients, all patients in this analysis were initially changed to monthly fremanezumab and only offered quarterly dosing after the initial 12 weeks of therapy.[18] In 2023, the VA and US Department of Defense published clinical practice guidelines for management of headache which strongly recommended erenumab, fremanezumab, or galcanezumab in the prevention of EM or CM. Erenumab is the initial medication preference per VA PBM, but either fremanezumab or galcanezumab can be considered as next-line anti-CGRP mAbs.[20] Local VA preference for either fremanezumab or galcanezumab may be proposed based on purchase availability, clinician preference, or local Pharmacy and Therapeutics Committee decisions based on pharmacoeconomic considerations. Few studies have data on real-world use of CGRP-targeting treatments in a veteran population. The VA criteria for use at the time of this project required patients to fail ≥ 3 medications for migraine prevention prior to approval of erenumab, and failure or intolerance of erenumab prior to another CGRP-targeting therapy for migraine prevention. Most patients in this analysis (84%) had previously failed erenumab, which was expected based on this formulary preference. Patients may have received approval for use of galcanezumab prior to an erenumab trial if there was a history of significant/severe constipation or for use in episodic cluster headache prevention. Many patients in this analysis may be considered treatment-refractory; 50 previously failed ≥ 5 preventive medications. Furthermore, 74% of veterans had CM, which may be more challenging to manage. The fact that stable headache frequency and severity were seen despite the change in anti-CGRP mAbs in this population is encouraging. A retrospective real-world analysis of 1003 patients found that fremanezumab was effective for migraine prevention regardless of type, even in difficult-to-treat migraine.[21] The present analysis also describes the impact after a local formulary conversion, and because stable headache outcomes were seen after this change, it may help clinicians feel more comfortable with medication changes in the setting of formulary changes or manufacturer backorders that affect medication supply. There is a high degree of variability in treatment response with many migraine medications, so a forced conversion from galcanezumab to fremanezumab was not imposed. All veterans were offered the option to remain on or switch back to galcanezumab at any time. LimitationsAs with any retrospective chart review, the possibility of missing or incomplete information from documentation exists and may impact the interpretation of these results. While patients were encouraged to maintain a home headache journal, this was not required and frequently the headache characteristics recorded in neurology CPP notes were based on patient self-reporting. Although medication adherence was assessed at the neurology CPP appointments, this information was not formally assessed as part of this retrospective review and may be an area of future study. Migraine diagnosis was required for inclusion, though patients may have also had other coexisting headache disorders which could impact the response rate with CGRP-targeting therapies. For example, some patients may have had a history of traumatic brain injury and posttraumatic headache disorder with migraine features that may be difficult to treat and refractory to many migraine preventives. More research is needed to determine the clinical significance of the reduction in headache frequency found in this review. Though the use of 50% response rates (ie, number of patients achieving a ≥ 50% reduction in migraine and/or headache days) was consistently used in prior research to assess headache efficacy, it was not used here as patients were stable on galcanezumab and may have already demonstrated an adequate treatment response.[3,22] Instead, this review focused on the change in headache and migraine frequency, as well as headache pain intensity, as markers for efficacy. We were encouraged that there was no significant change or worsening in headache frequency or pain intensity for most patients. Additionally, the patient perception of headaches improving or remaining unchanged postconversion in most patients is also reassuring, though the potential impact of the placebo effect (known to be high in headache therapy research) should also be considered. Randomized controlled trials adequately powered to detect a difference between these medications are needed to make more definitive conclusions. The results of this analysis help describe the real-world use of these medications in a veteran population and may be of value in describing the change between 2 anti-CGRP mAb agents. ConclusionsConversion to fremanezumab 225 mg did not result in a significant change in migraine or headache frequency, or headache pain severity within 12 weeks for patients treated with galcanezumab 120 mg. A decrease was seen in MMDs and MHDs, as well as mean headache pain intensity scores, though further research is needed to validate these observations. Few AEs were reported with the rotation to fremanezumab, all of which were considered mild. Findings of this single-center retrospective review suggest that switching from galcanezumab to fremanezumab is a feasible option if needed for migraine prevention.