Research Summary

Safety of Combined Atogepant and Ubrogepant Use in US Adults with Episodic Migraine: TANDEM Study Results

Edited by:
Ashton L. Stahl

Key Highlights

  • In the US TANDEM study, 12 weeks of concomitant atogepant 60 mg once daily and ubrogepant 100 mg as needed were shown to be safe and well tolerated in adults with episodic migraine.
  • No increase in the incidence or types of treatment-emergent adverse events (TEAEs) was observed with more frequent ubrogepant use.
  • Across both treatment periods, 9.9% of participants discontinued atogepant or ubrogepant because of TEAEs, and no new safety signals were identified.

The TANDEM study, published in Headache, examined whether the use of 2 calcitonin gene-related peptide (CGRP) receptor antagonists, atogepant for prevention and ubrogepant for acute treatment, could be safely combined in routine care for US adults with episodic migraine. The primary objective was to characterize the safety and tolerability of adding ubrogepant to ongoing atogepant preventive therapy.

In this multicenter, open-label, phase 4 trial, adults aged 18-80 years with a ≥ 1-year history of migraine (with or without aura), 4-14 migraine days per month, and < 15 headache days per month were enrolled. After screening, participants entered 2 consecutive 12-week treatment periods followed by a 4-week safety follow-up.

During Treatment Period 1 (Weeks 1-12), participants received atogepant 60 mg once daily and used their own non-gepant acute medications for breakthrough attacks. In Treatment Period 2 (Weeks 13–24), atogepant 60 mg once daily was continued, and ubrogepant 100 mg was taken as needed for breakthrough migraine (up to 8 attacks per 4-week interval). An optional second ubrogepant dose or non-gepant acute medication between 2 and 24 hours was permitted if attacks did not resolve or recurred. Safety monitoring included treatment-emergent adverse events (TEAEs), serious adverse events, discontinuations, vital signs, electrocardiograms, laboratory tests, and specific hepatic evaluations.

Study Findings

Of the 352 screened participants, 263 were enrolled; 262 formed Safety Population 1 (atogepant only), and 218 formed Safety Population 2 (atogepant plus ubrogepant). Most participants were female (about 82%) and White (about 79%), with a mean age of approximately 44 years and a mean body mass index of 29.6 kg/m².

Across the entire treatment period, treatment-emergent adverse events (TEAEs) occurred in 174 of 262 participants (66.4%). In Treatment Period 1, 49.6% experienced a TEAE; in Treatment Period 2, 43.1% did as well. The most common TEAEs (≥ 5% across the whole study) were COVID-19 (11.1%), fatigue (7.6%), nausea (6.9%), decreased appetite (6.5%), constipation (6.1%), and upper respiratory tract infection (5.3%). Overall, 26 participants (9.9%) discontinued atogepant or ubrogepant due to TEAEs, with constipation, nausea, and decreased appetite among the most frequent reasons.

The mean number of ubrogepant use days over 12 weeks in Period 2 was 6.6 (standard deviation 5.0) among those who took at least 1 dose. TEAEs occurred in 40% of the participants who did not use ubrogepant and 44.1% of those who did. Within ubrogepant users, TEAE rates were similar across low (1-3 days), moderate (4-9 days), and high (≥ 10 days) ubrogepant-use subgroups, and similarly across low-, moderate-, and high-dose subgroups, with no clinically relevant increase in TEAEs with greater use.

Hepatic safety assessments identified 3 cases of alanine aminotransferase or aspartate aminotransferase ≥ 3 times the upper limit of normal during Treatment Period 1 only; all were adjudicated as unlikely to be related to atogepant. No such elevations occurred during concomitant atogepant and ubrogepant use. Fewer than 3% of participants had potential clinically significant changes in blood pressure or pulse, and no Hy’s law cases occurred. Weight decreases ≥ 7% from baseline were observed in 13.2% of participants during at least one postbaseline visit; rates were 6.2% in Treatment Period 1 and 12.9% in Treatment Period 2, which the authors noted were within expected ranges for up to 24 weeks of atogepant treatment.

Clinical Implications

According to the study authors, the TANDEM trial met its primary objective. It demonstrated that concomitant use of atogepant 60 mg once daily for preventive treatment and ubrogepant 100 mg as needed for acute treatment of breakthrough migraine over 12 weeks was safe and well-tolerated in adults with episodic migraine. The overall safety profile of the combination was consistent with the known safety of each agent used alone, and no new safety signals emerged.

The authors also report that there were no apparent increases in the incidence, type, or severity of TEAEs, with higher numbers of ubrogepant use days or doses during the concomitant treatment period. Sensitivity analyses suggested that differences in TEAE rates between treatment periods were not attributable to participants discontinuing due to adverse events. However, the authors note that the open-label design, short concomitant treatment duration, and relatively homogeneous study population limit generalizability and underscore the need for longer-term studies.

Expert Commentary

“In summary, the concomitant use of ubrogepant for the acute treatment of breakthrough migraine attacks and atogepant for the preventive treatment of episodic migraine in this study was safe and well tolerated, with no clinically relevant increases in the incidence, type, or severity of treatment-emergent adverse events and no new safety signals identified,” the researchers concluded.

Reference

Ailani J, Lipton RB, Blumenfeld AM, et al. Safety and tolerability of ubrogepant for the acute treatment of migraine in participants taking atogepant for the preventive treatment of episodic migraine: Results from the TANDEM study. Headache. 2025;65(6):1005-1014. doi:10.1111/head.14871.