Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials

Participants

Overall, 3345 participants were randomized across the five double-blind placebo-controlled studies and were included in the pooled analysis. Demographic and baseline characteristics of the 3345 participants are summarized in Table 1 (stratified by age groups) and in Additional file 1 (overall population).

Table 1 Demographics and baseline characteristics stratified by age group

The mean age of overall participants was 40.7 years; 83.6% were females (n = 2795), and 70.4% were white (n = 2356). The overall population reported 10.3 (SD ± 4.98) mean monthly migraine days (MMDs), 8.2% reported medication overuse, and 16.6% reported ≥ 3 prior preventive treatment failures (for age stratification please see Table 1). Nearly half (n = 1611, 48.2%) of the overall population reported 8–14 MMDs at baseline, while only 515 (15.4%) participants reported ≥ 15 MMDs. In total, 1755 (52.5%) participants reported no prior treatment failure. Older participants (≥ 60 years) reported a higher number of prior preventive treatment failures (PPTFs) compared with younger participants (< 40 years); the number of participants who reported ≥ 3 PPTFs was higher in the older age group (overall population, 556 [16.6%]; participants aged < 40 years, 186 [12.4%]; 40–49 years, 192 [18.0%]; 50–59 years, 138 [21.7%]; and ≥ 60 years, 40 [28.0%]).

Framingham CV risk factors are presented in Table 1 (stratified by age groups) and in Additional file 1 (overall population). At study baseline, nearly one-third (32.8%) of participants were non-smokers, 7.8% were former smokers, and 5.1% were current smokers (Additional file 1). In the overall population, incidence of diabetes (1.7%), coronary artery disease (0.2%), and cerebrovascular or peripheral artery disease (0.5%) was low, while 10.9% of participants had a prior history of hypertension. Although the preexisting medical history for vascular risk factors was low, there was a trend of increasing incidence of diabetes (2.1%), hypertension (23.8%), coronary artery disease (0.7%), and cerebrovascular or peripheral artery disease (3.5%) in older participants (≥ 60 years), which is typical for this age group (Additional file 1) [5].

As expected, the number of participants with comorbid conditions increased with age, starting with 75.7% aged < 40 years, 87.0% aged between 40–49 years, 92.3% aged 50–59 years, and 94.4% aged ≥ 60 years. Commonly reported comorbid conditions included migraine with aura (45.8%), migraine without aura (45.8%), anxiety (46.6%), depression (47.3%), and seasonal allergy (12.4%). Comorbid conditions were generally well balanced across treatment groups and age groups. Interestingly, comorbidities seemed to be higher in the erenumab 70 mg group across all age groups (data not shown).

Disposition

Overall, across the pooled analysis, 3176/3345 (94.9%) participants completed the DBTP and 169/3345 (5.1%) discontinued. Age did not influence the completion status of the DBTP (Fig. 2). The primary reason for discontinuation was participant decision (n = 110, 3.3%).

Fig. 2figure 2

Disposition of participants. *Subject decision was a sum of subject decision and subject/guardian decision. In the EMPOwER study, six randomized participants did not take the study medication and were not formally entered into the DBTP; these participants are counted under the “no study medication” category. Abbreviation: DBTP, double-blind treatment phase

Exposure

In total, 1972 participants received at least one dose of erenumab (1122 received 70 mg and 850 received 140 mg). Most participants received three doses of erenumab over the DBTP (n = 1895; of which 1075 received erenumab 70 mg, and 820 received 140 mg); 45 participants received two doses of erenumab, and 32 received one dose. Overall, the mean duration of exposure to either dose of erenumab (70 mg or 140 mg) was 11.9 weeks, and a total exposure of 449.2 patient-years to erenumab (70 mg or 140 mg).

Safety analysisOverall TEAEs

A summary of TEAEs by age group is presented in Table 2. Overall, 622/1349 (46.1%) participants who received placebo and 867/1972 (44.0%) participants who received erenumab reported at least one TEAE during the DBTP. The incidence of TEAEs by age group was similar in either dose group (70 mg or 140 mg): < 40 years, 44.0%; 40–49 years, 42.5%; 50–59 years, 46.5%; ≥ 60 years, 43.8%.

Table 2 Summary of TEAEs by age groups (safety analysis set, double-blind treatment phase)

A slightly higher incidence rate of TEAEs was observed in participants in the 50- to 59-year age group receiving 140 mg erenumab (80/158; 50.6%) compared with other age groups. A similar higher incidence rate of TEAEs was observed in participants in the ≥ 60-year age group receiving placebo (41/69; 59.4%). These differences are presumed to be normal variations and not driven by CV, cerebrovascular, and/or GI AEs (that are most common in older patients) or linked to any specific class of AEs (Table 2).

Most AEs were Grade 1 or Grade 2. Incidence of Grade 2 TEAEs was similar for both erenumab doses (70 mg or 140 mg) stratified by age group: < 40 years, 19.1%; 40–49 years, 19.5%; 50–59 years, 23.1%; ≥ 60 years, 27.4%. One participant receiving erenumab 70 mg (in the 40- to 49-year age group) and one participant receiving 140 mg (in the ≥ 60-year age group) reported one Grade 4 TEAE each.

No deaths were reported in any study during the DBTP. Incidence of treatment-related TEAEs was also balanced across both erenumab doses (70 mg or 140 mg) stratified by age group: < 40 years, 13.3%; 40–49 years, 11.7%; 50–59 years, 12.9%; ≥ 60 years, 12.3% (Table 2).

The most commonly reported TEAEs, occurring in ≥ 3.0% of participants in any age group, were viral upper respiratory tract infections and upper respiratory tract infections, which were common in all treatment groups (Table 3). In addition, participants aged ≥ 60 years reported fatigue, alopecia, back pain, ligament sprain, musculoskeletal stiffness, and sinusitis.

Table 3 TEAEs with incidence of ≥ 3.0% in any erenumab group (safety analysis set), by preferred term

Incidence of treatment-emergent SAEs by age group for both erenumab 70 mg and 140 mg doses was low: < 40 years, 0.9%; 40–49 years, 1.7%, and 50–59 years, 1.6%. No SAEs were reported in participants aged ≥ 60 years (Table 4). Most SAEs were reported in only one participant each across age group, except for migraine and uterine leiomyoma, which were reported in two participants in the 40- to 49-year age group and the 50- to 59-year age group, respectively.

Table 4 Treatment-emergent SAEs across age groups, by preferred term (safety analysis set)

There was no difference in the incidence of AEs leading to study drug discontinuation between erenumab-treated (total) and placebo-treated groups by age (Table 5). In participants aged ≥ 60 years, one participant in the erenumab 140-mg group discontinued treatment due to nausea.

Table 5 TEAEs causing study drug discontinuation across age groups, by preferred term (safety analysis set)

There were no notable imbalances among treatment groups in AEs, SAEs, or severity of AEs by age group during the double-blind treatment phase. Incidence of CV and cerebrovascular AEs were unremarkable across the age groups (Table 6). Notably, no CV and cerebrovascular AESIs were reported in the erenumab 140-mg group in participants aged ≥ 60 years, possibly due to the relatively lower number of participants receiving erenumab 140 mg as compared to erenumab 70 mg or placebo.

Table 6 Summary of cardiovascular and cerebrovascular AEs by age groups (safety analysis set) by preferred term

The incidence of GI AEs across age groups and treatment groups was low, with an overall incidence of 290 (8.7%). The only remarkable GI AE commonly found across the age groups was constipation (Table 7). Incidence of constipation was higher in the erenumab 140 mg group compared with erenumab 70 mg group (below 4% across age groups for both erenumab doses), and lowest in those receiving placebo across all age groups. Participants aged ≥ 60 years also reported other GI AEs including nausea, dyspepsia, and toothache. Incidence of nausea was similar across the treatment groups.

Table 7 Summary of GI AEs across age groups with incidence of ≥ 2.5% in any erenumab group by preferred term (safety analysis set)

The incidence of CV, cerebrovascular events, and constipation were comparable for both erenumab treatment groups and placebo within each age subgroup (Tables 6 and 7). Similar trends were seen across other age groups except for individuals aged ≥ 60 years who presented with a higher percent of CV and cerebrovascular events (4.2%) (Table 6).

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