Participants

A total of 1550 participants were analyzed across the 2 pooled RCTs (Supplemental Fig. 1A; Table 1) and 1424 participants in the pooled LTS trials (Supplemental Fig. 1B; Table 1). Of the LTS trial participants, 792 were previously enrolled in an RCT (MD-01: 107; ADVANCE: 685). Demographic and baseline characteristics are summarized in Table 2.

Table 2 Demographic and baseline characteristicsTreatment-emergent adverse events

TEAEs for the pooled safety population are summarized in Table 3. In the RCTs, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 TEAEs. In the LTS trials, 792/1228 (64.5%) atogepant participants and 154/196 (78.6%) SC participants experienced ≥ 1 TEAEs.

Table 3 Summary of treatment-emergent adverse events for the pooled safety population

The most commonly reported TEAEs (≥ 5%) with once-daily atogepant were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). The majority of the TEAEs were mild or moderate in severity (Table 4).

Table 4 Treatment-emergent adverse eventsTreatment-related TEAEs and serious TEAEs

Most TEAEs were considered not related to the study drug by the investigator in the RCTs and LTS trials. In the RCTs, 228/1142 (20.0%) atogepant participants and 50/408 (12.3%) placebo participants experienced ≥ 1 treatment-related TEAEs (TR-TEAEs). In the LTS trials, 158/1228 (12.9%) atogepant participants experienced ≥ 1 TR-TEAEs. The most commonly reported TR-TEAEs (> 2%) in atogepant participants were constipation (RCTs: 4.7% [54/1142]; LTS trials: 3.0% [37/1228]), nausea (RCTs: 4.0% [46/1142]; LTS trials: 2.0% [24/1228]), and fatigue (RCTs: 1.7% [19/1142]; LTS trials: 1.1% [14/1228]) (Table 5).

Table 5 Most common treatment-related treatment-emergent adverse events

Serious TEAEs in the RCTs were reported in 7 (0.6%) atogepant participants compared with 4 (1.0%) in the pooled placebo group. In the LTS trials, 47 (3.8%) atogepant participants and 7 (3.6%) SC participants reported any serious TEAE (Table 3). With the exception of 1 case of optic neuritis, all serious TEAEs were considered by the investigator to be unrelated to study treatment. The case of optic neuritis occurred in a 23-year-old woman who received atogepant 10 mg once daily; magnetic resonance imaging of the brain and orbits, and visual-evoked potential results were normal, and the optic neuritis resolved without any sequela. Serious TEAEs are summarized in Table 6. In the LTS trials, 2 deaths were reported, 1 due to homicide and 1 due to beta-hemolytic streptococcal infection (toxic shock syndrome), both of which were deemed unrelated to atogepant per the investigator.

Table 6 Serious treatment-emergent adverse eventsTreatment discontinuations

In the pooled RCTs, the proportions of participants with TEAEs leading to discontinuation were 3.5% (40/1142) with atogepant and 2.7% (11/408) with placebo. In the pooled LTS trials, 4.3% (53/1228) of atogepant participants and 2.6% (5/196) of SC participants discontinued due to TEAEs (Table 3). No dose–response relationship was observed for TEAEs leading to discontinuation. The AEs that most led to discontinuation in RCTs were constipation (0.5%), nausea (0.5%), and fatigue/somnolence (0.5%). The AEs that most led to discontinuation in the LTS trials were nausea (0.5%) and dizziness (0.3%).

AEs of interest

AEs of interest included AEs commonly reported with atogepant and ones that are of interest to health care professionals (Table 4).

Constipation

Constipation was reported in 6.1% (70/1142) of atogepant participants in the RCTs and in 5.0% (62/1228) of atogepant participants in the LTS trials. Most cases of constipation were mild or moderate in severity and there was no clear dose dependency. There were no SAEs of constipation, including no constipation-related complications (eg, hospitalization, ileus). Few TEAEs of constipation resulted in discontinuation (RCTs: 0.5% [6/1142], LTS trials: 0.2% [2/1228]). Most cases (RCTs: 71.4% [50/70], LTS trials: 45.2% [28/62]) occurred within the first 2 weeks after treatment initiation, and the majority (RCTs: 64.3% [45/70], LTS trials: 87.1% [54/62]) resolved by the end of the study, either spontaneously or with over-the-counter treatment.

Nausea

Nausea was reported at rates of 6.6% (75/1142) in the RCTs and 4.6% (57/1228) in the LTS trials. The majority of cases were mild in severity. No SAEs of nausea occurred. Few instances of nausea led to discontinuation (RCTs: 0.4% [5/1142], LTS trials: 0.5% [6/1228]). Most cases (RCTs: 54.7% [41/75], LTS trials: 36.8% [21/57]) occurred within the first 2 weeks after treatment initiation, and the majority (RCTs: 94.7% [71/75], LTS trials: 96.5% [55/57]) of cases resolved by the end of the study.

Hepatic safety

Hepatic safety was evaluated thoroughly in all clinical trials through AE reporting and lab monitoring. An external clinical adjudication committee provided a blinded review and adjudication of all post-treatment elevations of ALT or AST ≥ 3 × ULN to assess their causal relationship to atogepant. In the RCTs, 1.3% (15/1142) and 1.1% (12/1142) of atogepant participants experienced a TEAE of increased ALT or AST, respectively (placebo: ALT, 2.2% [9/408]; AST, 2.0% [8/408]). In the LTS trials, 1.3% (16/1228) and 1.6% (20/1228) experienced a TEAE of increased ALT or AST, respectively (SC: ALT, 2.0% [4/196]; AST, 2.6% [5/196]) (Table 4).

There were no potential Hy’s law cases. In the RCTs, the rates of ALT or AST elevation ≥ 3 × ULN were similar between those who received atogepant (1.0% [11/1126]) and those who received placebo (1.8% [7/399]). In the LTS trials, ALT or AST elevation ≥ 3 × ULN was observed in 1.4% (17/1214) with atogepant and 3.2% (6/190) with SC. The adjudication committee determined most cases to be unlikely related to atogepant and a few to be probably or possibly (8 cases in RCTs and LTS trials) related to atogepant. Among the possible/probable cases, confounding factors were also identified in all but 1 case.

Weight changes

In the RCTs, the percentages of participants with a weight decrease of a clinically significant weight loss of ≥ 7% at any time point during the 12 weeks were 3.8% for atogepant 10 mg, 3.2% for atogepant 30 mg, and 4.9% for atogepant 60 mg, compared with 2.8% for placebo. At week 12, the percentage changes from baseline for atogepant 10 mg, 30 mg, and 60 mg were 0.12, − 0.51, and − 1.02. In the LTS trials, the percentages of clinically significant weight loss were 14.7% for those treated with SC and 24.1% for those treated with atogepant 60 mg once daily. At week 4 and week 40, the percentage changes from baseline for atogepant 60 mg were − 0.42 and − 2.38, respectively, in the 52-week LTS trial, and − 0.76 and − 2.09, respectively, in the 40-week LTS trial. Weight loss appeared to be dose- and duration-dependent.

The percentages of atogepant participants who reported a TEAE of decreased weight were 0.4% in the RCTs and 2.6% in the LTS trials (Table 4). Discontinuation due to weight loss as a TEAE was rare (0 in the RCTs and 2 participants in the LTS trials). An exploratory analysis revealed no clear relationship between weight change and nausea or vomiting, but a slightly higher incidence of decreased appetite was observed in weight-loss responders.

Cardiac Disorders and Hypertension

In the RCTs and LTS trials, cardiac disorders were uncommon TEAEs. Hypertension was reported by 0.4% (5/1142) of atogepant participants and 0% of placebo participants in the RCTs, and by 1.9% (23/1228) of atogepant participants and 1.0% (2/196) of SC participants in the LTS trials (Table 4). There were no serious cases of hypertension in any of the clinical trials. One participant in each of the pooled RCTs and pooled LTS trials discontinued due to hypertension. No cases in the RCTs were considered treatment related. One nonserious case of mild hypertension in the LTS trials was considered related to atogepant treatment by the investigator. Blood pressure was measured at each participant visit, and the data collected across RCTs and LTS trials did not reveal any clinically relevant changes in blood pressure. Other cardiac disorders (including atrioventricular block first degree, atrioventricular block second degree, left bundle branch block, left atrial enlargement, palpitations, postural orthostatic tachycardia syndrome, and supraventricular extrasystoles) were experienced by 1.4% (16/1142) of atogepant participants and 1.0% (4/408) of placebo participants in the RCTs and by 1.3% (16/1228) of atogepant participants and 2.6% (5/196) of SC participants in the LTS trials.