There is limited real-world evidence on the use of fremanezumab for the preventive treatment of migraine, especially among patients with DTT migraine. The current clinician panel–based retrospective chart review study provides a timely and comprehensive assessment of the effectiveness of fremanezumab in a real-world setting across a variety of patient subgroups, including those with potentially DTT migraine. MMD and MHD reductions observed in the current subgroup analyses supported the effectiveness in patients with EM or CM and those with DTT migraine, based on the presence of MO, GAD, MDD, or prior CGRP pathway–targeted mAb exposure.
Regardless of the type of migraine (EM or CM), reductions from baseline in MMD and MHD were observed within 1 month after initiating fremanezumab treatment, with continued improvement demonstrated over 6 months of treatment. The proportion of patients with ≥ 50% reduction in MMD also increased from Month 1 to Month 6 of fremanezumab treatment in both the EM and CM subgroups, and discontinuation rates were low regardless of the subgroup studied. These real-world effectiveness results complement those from the randomized, double-blind, placebo-controlled, phase 3 HALO studies, which reported significant reductions in MMD with fremanezumab versus placebo over 3 months of treatment in patients with EM or CM [15, 16]. Likewise, over the course of a 12-month extension study, the proportion of patients with ≥ 50% reduction in MMD also increased over time and discontinuation rates were low . In the randomized, double-blind, placebo-controlled, phase 3b FOCUS study, which included a similar population to the current real-world study (patients with EM or CM with inadequate response to 2 to 4 prior classes of migraine preventive treatments), patients who received fremanezumab had significant reductions in MMD compared with those assigned to placebo over 3 months of treatment and the proportion of patients with ≥ 50% reduction in MMD increased over an additional 3-month open-label extension [17, 21]. Compared with phase 3 trials [15,16,17], which showed least-squares mean changes from baseline in MMD ranging from − 3.4 to − 5.0 over 3 months for patients with EM or CM, the current study demonstrated even larger mean changes from baseline in MMD at 3 months in patients with EM or CM (− 4.7 to − 7.9), highlighting the effectiveness of fremanezumab in the real-world setting. These differences in real-world and clinical trial outcomes are in line with those observed for other CGRP pathway–targeted mAbs erenumab and galcanezumab [22,23,24,25,26,27,28].
The current study also demonstrated reductions in MMD and MHD with fremanezumab treatment for patients diagnosed with MO. These real-world outcomes support the findings of previous subgroup analyses of the randomized, double-blind, placebo-controlled, phase 3 HALO study in patients with MO (n = 587) . In a subgroup of patients with MO from the HALO study, fremanezumab resulted in significantly greater mean reductions from baseline in MMD at Month 3 with both quarterly and monthly dosing compared with placebo, with mean changes from baseline in MMD ranging from − 4.8 to − 5.2 at 3 months . Given that secondary headache from MO is common among patients with migraine , these findings from both clinical trial and real-world settings support the benefits of fremanezumab treatment among patients with MO, which may be associated with more DTT migraine. Results from the current study indicate even greater reductions in MMD in patients with MO versus in clinical trials [18, 29], with a mean change from baseline in MMD of − 7.0 at 3 months, again reflecting the utility of fremanezumab in real-world practice.
Reductions in MMD and MHD with fremanezumab treatment for subgroups of patients with comorbid MDD or GAD were also reported in the current study, and improvements in the severity of these conditions were reported by approximately half of patients each with comorbid MDD or GAD. These results corroborate findings from a subgroup analysis of patients with comorbid moderate to severe depression (based on scores of ≥ 10 on the Patient the Health Questionnaire-9 [PHQ-9]; n = 229) from the phase 3 HALO study . In that subgroup of patients with CM and comorbid moderate to severe depression, fremanezumab treatment resulted in significant reductions in MMD, as well as non-significant reductions in PHQ-9 scores, indicating a decrease in the severity of depressive symptoms . Given the 5-fold higher risk for MDD and 3- to 5-fold higher risk for anxiety disorders among patients with migraine compared with healthy individuals [31,32,33], these findings, which showed improvement in migraine symptoms with fremanezumab in both real-world and clinical trial settings, as well as reductions in the severity of MDD and GAD with fremanezumab treatment in the current real-world study, show that fremanezumab may reduce the symptom burden of both migraine and these psychiatric comorbidities. Results from the current study versus the previous HALO CM study indicate slightly better outcomes for those with MDD (mean reductions from baseline in MMD, − 9.9 overall at 6 months versus − 6.5 with quarterly dosing and − 8.2 with monthly dosing at 6 months) . This again supports fremanezumab as an effective treatment in clinical practice for patients with migraine and depression.
There has previously been a lack of evidence for the effectiveness of CGRP pathway–targeted mAbs in patients switching from another prior CGRP pathway–targeted mAb. Although effectiveness and reasons for switching were assessed in this newly explored and highly relevant subgroup of patients switching to fremanezumab from another prior CGRP mAb, there were several factors that were not taken into account, including the duration of prior CGRP pathway–targeted mAb treatment, which CGRP mAb had been used, or if there was any washout period between treatments. Among patients who received prior CGRP pathway–targeted mAbs, the most common reasons for switching from another CGRP pathway–targeted mAb to fremanezumab were inadequate response to treatment and side effects. During the post-index period, patients who had switched from a prior CGRP pathway–targeted mAb experienced substantial reductions in MMD with fremanezumab treatment during the 6-month post-index period. Only 12% of patients who received a prior CGRP pathway–targeted mAb discontinued fremanezumab treatment after the index dose, most often due to poor response. These results suggest that fremanezumab is effective and well tolerated in patients with migraine who had failed a different CGRP pathway–targeted mAb and therefore that treatment failure to 1 CGRP pathway–targeted mAb does not predict treatment failure to another. This finding supports previous evidence showing that patients who had prior failure of a CGRP pathway–targeted mAb treatment achieved a clinical benefit by switching to another CGRP pathway–targeted mAb [34,35,36]. In a previous retrospective cohort study by Overeem and colleagues that included 25 patients who did not respond to erenumab and switched to either galcanezumab or fremanezumab, MHD were significantly reduced by Month 3 after switching and approximately 12% of patients achieved a ≥ 50% reduction in MHD . In the current study, in the subgroup switching to fremanezumab from another prior CGRP mAb, the proportion of patients achieving a ≥ 50% reduction in MMD at Month 3 (45.5%) was substantially higher; however, the patient characteristics in the previous cohort study by Overeem and colleagues differed from the current study, with many patients in that prior study reporting daily headache .
There are several strengths in the design of this study. The real-world setting of this online physician chart review closely reflects the true clinical landscape of migraine. The broad range of clinicians (e.g., neurologists, general practitioners, NPs, PAs, psychiatrists) included in this study may more accurately reflect real-world use of fremanezumab and enhance the generalizability of these results. In addition, the large patient sample size allowed for a number of subgroup analyses to be conducted, including the currently presented analyses in populations by migraine type or with DTT migraine (MO, MDD, GAD, or prior CGRP pathway–targeted mAb exposure). Furthermore, the inclusion of patients with a physician-confirmed migraine diagnosis and collection of both health care provider– and patient-reported outcomes have given a comprehensive view into the clinical outcomes across the broad population of patients with migraine. The results from this real-world study further support the effectiveness of fremanezumab as demonstrated in previous clinical trials [15,16,17], including in patients with DTT migraine [17,18,19, 30], and contribute to the real-world data on fremanezumab and other CGRP pathway–targeted mAbs [22, 24, 37,38,39,40,41,42,43,44,45].
This real-world study had limitations that need to be considered. Retrospective real-world studies are subject to bias and confounding factors, problems that are controlled for in randomized controlled trials. For the subgroups with MDD or GAD, the diagnosis was based only on the diagnosis noted in the chart, which was not required to be made by a qualified mental health professional and was not based on any specific definition or guidance in the current study. Thus, there is the potential that these diagnoses were not completely accurate for all patients included in those subgroups. Moreover, data collection efforts were limited by the availability of clinical data in the medical charts. With that said, observed discontinuation rates were relatively low (~ 8%), suggesting that discontinuation is not the cause of the limited availability of certain data. While measurements were conducted at monthly time points, it is unlikely that patients would be seen in the clinic every month, limiting availability of data at any individual month to those who came for follow-up in that month. Likewise, patients may have fewer follow-up visits if they experience a favorable therapeutic effect with fremanezumab and improvement in their symptoms. Other reasons may include physicians’ lack of reporting of the outcomes assessed at the follow-up appointments or the possibility that these follow-ups were not conducted in person. Although adherence to treatment, discontinuation rates, and reasons for discontinuation were reported over the full follow-up period, the length of this time frame varied among patients. As noted in the statistical analysis section, effectiveness outcomes clustered patients with available assessments within ± 15 days of each time point reported (e.g., Month 1, Month 2) due to heterogeneity in the assessment times observed in real-world practice. As a result, not all patients were included in the analyses for each time point and sample sizes varied accordingly. In addition, the mean follow-up period of 7 months was relatively short, with effectiveness outcomes evaluated over 6 months due to low follow-up numbers at later time points. Reporting rates declined over the course of the study; however, this decrease over time in the proportion of patients who responded to each outcome was not necessarily due to discontinuation of treatment, as described previously. In addition, certain outcomes that may have been of interest for some of the subgroups, including detoxification prior to initiating fremanezumab or the proportion of patients reverting from MO to no MO with fremanezumab treatment in the MO subgroup, were not collected in the eCRF. In line with real-world clinical practice, some patients in the current study were using concomitant preventive medications with fremanezumab, which could potentially have had an impact on observed effectiveness outcomes; however, preventive medication use decreased after fremanezumab initiation. MMD and MHD also decreased substantially after fremanezumab initiation, indicating that the addition of fremanezumab treatment led to improvements in both outcomes. Furthermore, approximately 20% of patients in the HALO CM pivotal study were using concomitant preventive medication ; efficacy, including reduction in MHD, was comparable in subgroups of patients from HALO CM with and without preventive medication use .