Early onset of effect is rated as a highly important feature of migraine preventive treatment by patients and has been linked to improvements in adherence . A previous post hoc analysis of the phase 3 HALO trial examining early onset found greater early reductions in the mean number of monthly headache days of at least moderate severity, monthly average number of migraine days and mean number of monthly headache hours for CM patients treated with fremanezumab versus placebo . These subanalyses of early onset similarly found that preventive treatment with fremanezumab reduced MMD in EM patients and headache days of at least moderate severity in CM patients. Differences in efficacy endpoints between fremanezumab and placebo were sustained throughout the 4-week treatment period in these analyses. Further, the differential effect of fremanezumab versus placebo became evident during the first week of treatment and was even observed as early as the first day of injection in EM patients and the day after first injection in CM patients. These results suggest that fremanezumab has an early onset of action with clinical benefits for patients, with potential impact on patient satisfaction and adherence.
Two previous Phase 2b/3 studies in Japanese and Korean patients, which formed the basis of these subanalyses, established the efficacy of fremanezumab quarterly and monthly for periods up to 12 weeks [21, 22]. According to the primary endpoints, the reduction in the average number of migraine days (EM) or headache days of at least moderate severity (CM) per month during 12 weeks was significantly greater with fremanezumab monthly and fremanezumab quarterly than with placebo. Further, improvements in all secondary endpoints were also noted in both studies. Over long-term observation, both fremanezumab monthly and quarterly reduced the monthly number of migraine days in a 52-week, randomized, double-blind extension of the HALO trials . A subanalysis of these long-term HALO results similarly found that fremanezumab monthly and quarterly led to sustained improvements in monthly migraine days and headache days of at least moderate severity throughout 12 months in Japanese patients with CM and EM.
Without minimizing the importance of long-term efficacy, there is also a clear patient preference for early efficacy benefits for migraine prevention , which has been a limitation of existing oral preventive medications. Indeed, in a patient survey, speed of onset was rated as the second most important aspect of preventive treatment besides actual effectiveness . Switching between oral agents is a common practice to optimize therapy but persistence appears to actually worsen as patients cycle through agents .
Previously, early onset of efficacy has been shown with fremanezumab in CM patients , EM patients  and CM or EM patients with inadequate response to 2–4 prior migraine preventive treatment classes, including ≥1 inadequate response due to lack of efficacy [27, 28], erenumab in EM and CM patients  and galcanezumab in EM patients enrolled in the EVOLVE-1 and EVOLVE-2 studies , as well as in EM or CM patients with previous preventive medication failure . Results from the present subgroup analysis were consistent with these previous studies of fremanezumab and other anti-CGRP pathway monoclonal antibodies. In the previous post hoc analysis during the first 4 weeks of a primary trial of fremanezumab in CM patients, the statistically significant difference in LSM (95% CI) change in headache days of at least moderate severity per month between fremanezumab total and placebo (− 2.3 [− 3.0, − 1.7], P < 0.0001) was highly similar to the difference in CM patients in this analysis (− 2.51 [− 3.33, − 1.68], P < 0.0001) . In EM patients, corresponding differences in MMD between fremanezumab and placebo in this analysis were also significant for both fremanezumab monthly (− 3.13 [− 4.01, − 2.24], P < 0.0001) and fremanezumab quarterly (− 3.91 [− 4.80, − 3.02], P < 0.0001). Post hoc analyses of the FOCUS study in CM or EM patients with inadequate response to 2–4 prior migraine preventive treatment classes, including ≥1 inadequate response due to lack of efficacy also showed consistent results [27, 28]. In these analyses, the LSM (SE) change from baseline in the monthly average number of migraine days over the first 4 weeks of treatment was − 4.1 for both fremanezumab quarterly and fremanezumab monthly (versus − 0.6 for placebo, P < 0.0001 for both comparisons) . Onset of action was also rapid with a significant reduction in the odds of experiencing a migraine with fremanezumab versus placebo noted from Day 2 (1 day after first injection) to Day 7 .
Significant differences between active treatment and placebo were also observed at 4 weeks in studies of other anti-CGRP pathway monoclonal antibodies [16, 17, 19]. Further analyses for each week up to 4 weeks found significant reductions in WMD or headache days of at least moderate severity per week in EM and CM patients, respectively, from week 1 in the present analysis, which continued through to week 4. Onset of effect at week 1 was also identified in the previous post hoc analysis of fremanezumab , as well as in studies of erenumab and galcanezumab [16, 17, 19]. Finally, additional analyses of efficacy within the first week were conducted in the present and previous analyses. In the present subanalysis, the percentage of patients with either a migraine day (EM patients) or headache day at least moderate severity (CM patients) was noticeably lower in fremanezumab-treated patients from as early as the day of the first injection in EM patients treated with fremanezumab quarterly or the day after the first injection in CM patients and EM patients treated with fremanezumab monthly. This, as previously noted, is consistent with the results for fremanezumab in post hoc analyses of the FOCUS study . In the post hoc analysis of the phase 3b CONQUER study, onset of effect for galcanezumab was determined to occur the day following the first injection in EM or CM patients with previous preventive medication failures . Similarly, in the analysis of the EVOLVE-1 and EVOLVE-2 studies in EM patients, the estimated proportion of patients experiencing migraine was significantly lower with galcanezumab compared with placebo from the day after the first injection . Results for erenumab varied from day 3 to day 7 after injection depending on the dose and patient population .
Taken together, these results suggest that anti-CGRP pathway monoclonal antibodies, including fremanezumab, can provide early onset of action and thereby reduce the potential for patients to discontinue treatment. Discontinuation is a recognized disadvantage with oral preventive medications, which require daily adherence and titration to effect as well as potentially leading to headache chronification and medication overuse headaches through overuse of acute medications and tolerance [11, 14, 29]. Subanalyses of trials of anti-CGRP pathway monoclonal antibodies, including fremanezumab, have shown the potential of these agents to reduce the use of acute migraine treatment and lower the potential for medication overuse headaches [30, 31].
One of the main limitations of this subanalysis is that only Japanese and Korean patients were included. Nevertheless, the results are consistent with similar analysis from global study population. Further, this study is not powered to confirm treatment differences from placebo at early time points. Despite this limitation, substantial treatment differences were still demonstrated. Finally, assessment of migraine days and headache days of at least moderate severity were based on headache diary and therefore the influence of subjectivity in individual patient assessment cannot be ruled out.
In conclusion, fremanezumab shows a rapid onset of action in reducing migraine days and headache days at least moderate severity in EM patients and CM patients, respectively. Treatment effects were noted as early as the first day of injection in EM patients treated with fremanezumab quarterly and as early as the day after first injection in other patients. These results in Japanese and Korean patients align with those noted in subanalyses of fremanezumab and other anti-CGRP pathway monoclonal antibodies. In addition to the long-term efficacy and favorable safety and tolerability profile, the lack of need for titration, and flexible monthly or quarterly dosing schedule, the early onset of fremanezumab provides the potential to reduce barriers to adherence.