Patient demographic characteristics:
Table 1: Baseline clinical characteristics of study patients who completed 4-month follow-up
Figure 1: Cohort use of previous migraine prophylactics
Of 289 total patients, we report the outcomes of 182 patients who completed 3 injections and 4-month follow-up. Baseline characteristics of these patients and prior prophylactics used are summarised (Table 1, Figure 1).
a) Cohort fremanezumab efficacy outcomes:
Table 2a: Changes in monthly headache days, monthly migraine days, crystal-clear headache-free days, analgesia use and HIT-6 score post-fremanezumab treatment
Table 2b: Numbers and proportions of patients achieving ≥30%, >50% and >75% reductions from baseline monthly headache days and baseline monthly migraine days post-fremanezumab treatment
Table 2c: Numbers and proportions of patients achieving MHD <15 in any month, MMD <8 in any month, MHD <15 in any month and MMD <8 in any month, and number and proportion of patients with 0 baseline headache-free days achieving ≥1 headache-free days post-fremanezumab treatment
Figure 2: Cohort changes in monthly headache days, migraine days and crystal-clear headache-free days post-fremanezumab treatment
Figure 3: Changes in acute analgesia and triptan use and HIT-6 score post-fremanezumab treatment
At 4-month follow-up, median MHD reduction from baseline was 9 days, MMD reduction was 10 days and HFD increase was 9 days (all p<0.0001) (Table 2a, Figure 2a–c). 38 (45%) of 84 patients without baseline headache-freedom achieved ≥1 HFD post-fremanezumab (Table 2c, Figure 2d). These demonstrate significant MHD, MMD and HFD improvements after 3 fremanezumab doses.
We assessed correlation between baseline MHD and MMD and individual patient response magnitudes. Baseline MHD negatively correlated with % MHD reduction (r = -0.410, R2 = 17%, p<0.0001) and % MMD reduction (r = -0.155, R2 = 2%, p=0.0416) (Figure 2e, f). Baseline MMD demonstrated no correlation with % MMD reduction (r = -0.119, p=0.13, data not shown). Therefore, fewer baseline headache days statistically associated with superior % MHD and MMD reduction responses, with minimal clinical significance. Baseline MMD bore no correlation with % MMD reduction magnitude.
We next evaluated ≥30%, >50% and >75% MHD and MMD reduction from baseline to quantify the proportion of patients meeting UK continuation criteria and who experienced significant fremanezumab responses (Table 2b, Figure 2g). 105 (58%), 70 (39%) and 31 (17%) patients achieved ≥30%, >50% and >75% MHD reduction. 145 (80%) patients achieved ≥30% MMD reduction, thereby meeting UK fremanezumab continuation criteria. 124 (68%) and 76 (42%) achieved >50% and >75% MMD reduction. 46 (25%) achieved ≥30% MMD reduction without achieving ≥30% MHD reduction (not shown). Overall, sizeable proportions of patients experienced large-magnitude MHD and MMD improvements, with greater response for MMD reduction and 80% patients eligible for treatment continuation beyond 3 months.
To contextualise real-world fremanezumab utility, we evaluated the proportion of patients achieving MHD <15 days or MMD<8 days in any treatment month (Table 2c, Figure 2h). 82 (45%) patients achieved MHD <15 days in any treatment month, indicating reversion to headache frequency of EM for ≥1 months. 119 (65%) achieved MMD <8 days in any treatment month, indicating migraine frequency reduction to a level manageable with acute analgesia without risking MO. Moreover, 67 (37%) achieved both outcomes. Therefore, within 3 months of fremanezumab initiation, substantial proportions of our cohort demonstrate early headache improvement towards EM reversion and migraine frequency reduction to one safely manageable with abortive therapies.
Post-fremanezumab, median AMD reduction was 5 days, TD reduction was 0 days and HIT-6 reduction was 14.5 (all p<0.0001) (Table 2a, Figures 3a–c). These demonstrated significantly reduced acute analgesia and triptan use to a frequency below that which predisposes to MO, and significantly improved quality-of-life.
b) Fremanezumab efficacy in patients with and without baseline headache-freedom:
Table 3a: Baseline clinical characteristics of patients with and without baseline headache-freedom
Table 3b: Treatment outcomes post-fremanezumab in patients with and without baseline headache-freedom
Figure 4: Treatment outcomes in patients with and without baseline headache-freedom
We compared treatment outcomes between patients with and without baseline headache-freedom. Patients without baseline headache-freedom exhibited significantly greater baseline MHD, MMD and HFD but similar other baseline characteristics, including proportion with baseline medication-overuse and HIT-6 score (Table 3a). Both groups achieved significant post-fremanezumab MHD, MMD, HFD and HIT-6 improvements (all p<0.0001). Patients with baseline headache-freedom experienced significantly greater median MHD reduction and HFD gain compared to those without, with significantly greater percentages achieving ≥30%, >50% and >75% MHD reductions, MHD <15 days in any month, MMD <8 days in any month, and both outcomes, but no significant difference in median MMD reduction or percentages achieving significant MMD reductions. Similar percentages of patients stopped medication-overuse post-fremanezumab in both groups (Table 3b, Figure 4a–j). Therefore, those with baseline headache-freedom demonstrate greater headache improvement independent of medication-overuse reductions, suggesting baseline headache-freedom as a potential response prognosticator.
c) Fremanezumab efficacy in onabotulinumtoxinA-unresponsive patients:
Table 4a: Baseline clinical characteristics of onabotulinumtoxinA-unresponsive patients
Table 4b: Treatment outcomes in onabotulinumtoxinA-unresponsive patients
We evaluated treatment efficacy in 166 onabotulinumtoxinA-unresponsive patients (Table 4a). Overall, fremanezumab induced significant headache, migraine, headache-free days and HIT-6 improvements in onabotulinumtoxinA-refractory patients (Table 4b).
d) Fremanezumab efficacy in patients with and without baseline analgesia medication overuse:
Table 5a: Clinical characteristics of patients with and without baseline analgesia MO
Table 5b: Treatment outcomes in patients with baseline MO
Table 5c: Treatment outcomes in patients without baseline MO
Table 5d: Treatment outcome comparisons in patients with and without MO
We next compared treatment outcomes between patients with and without baseline MO. The two groups exhibited similar baseline characteristics including MHD, MMD, HFD and HIT-6 score (Table 5a). Post-fremanezumab, 58 (82%) with baseline MO reverted to non-MO with cessation of non-opioid and triptan overuse. Both groups achieved significant improvement in all outcomes, with no significant inter-group differences in median improvement for any outcomes (Tables 5b, c, d). Overall, fremanezumab demonstrated similar efficacy in patients with and without MO.
e) Factors associated with fremanezumab response:
Table 6a: Univariate and multivariate logistic regression analysis of patient factors associated with achieving ≥30% MMD reduction from baseline post-treatment and fremanezumab continuation
Table 6b: Univariate and multivariate logistic regression analysis of patient factors associated with achieving MHD <15 days/month in any treatment month post-fremanezumab
We investigated potential predictive factors for treatment responses, including ≥30% baseline MMD reduction (enabling fremanezumab continuation), and MHD<15 in any month (Table 6a, b). ≥30% baseline MMD reduction associated with baseline HFD (OR 2.789, p=0.0461) and HIT-6 score (OR 0.918, p=0.0282) in multivariate regression analysis, indicating baseline headache-freedom and lower HIT-6 scores independently associated with ≥30% MMD response. Achieving MHD <15 in any treatment month associated with baseline HFD ≥1 (OR 4.564, p=0.0003) and MMD (OR 0.923, p=0.008) in multivariate regression analysis, signifying baseline HFD ≥1 and lower baseline MMD independently associated with headache frequency reversion to that of EM in any treatment month. Other characteristics including migraine duration, medication-overuse, previous prophylactics or onabotulinumtoxinA were not associated with either outcome.
f) Safety and tolerability:
37 (20%) patients discontinued fremanezumab due to inefficacy. Injection site irritation and rash was the only AE reported in 5 (3%) patients. No patients discontinued fremanezumab due to AEs (data not shown).