Article
Combination of CRGP Antagonists Ubrogepant and Atogepant Proves Safe in Phase 1b Trial
Author(s):
A single dose of ubrogepant at its highest FDA-approved strength of 60 mg once daily had no statistically significant effect on atogepant pharmacokinetics.
Andrew Blumenfeld, MD
Recently published findings from a phase 1b, multicenter, open-label, fixed-sequence study showed that the combination approach of atogepant (Qulipta; AbbVie) and ubrogepant (Ubrelvy; AbbVie) at the highest FDA-approved dose strengths, was safe for patients with migraine, with no new concerns identified.
Atogepant, an oral calcitonin gene-related peptide (CGRP) receptor antagonist, gained approval as a preventive treatment of episodic migraine in September 2021, while ubrogepant, another CGRP receptor antagonist was approved for the acute treatment of migrane in December 2019. Led by Andrew Blumenfeld, MD, director of the Headache Center of Southern California, the trial’s primary objective was to assess pharmacokinetic (PK) interactions of the highest approved dose of each therapy, with ubrogepant administered on a fixed-dose schedule every 3 days.
A total of 31 patients were enrolled in March 2021, and 26 completed the study a few months later. The 5 patients who discontinued the study were either because they withdrew consent (n = 3), had an adverse event (AE) of rash (n = 1), or an AE of drug eruption (n = 1). Atogepant, administered in 60 mg QD, had plasma concentrations that were similar upon concomitant administration with a single 100 mg dose of ubrogepant.
All told, the point estimates for atogepant Cmax and area under the curve (AUC) were 104.09 (90% CI, 94.02-115.25) and 10.4.48 (90% CI, 97.59-111.86), respectively; thus, meeting the predefined DDI criteria of between 80% to 125% for no significant interaction. While investigators observed a 4% increase in steady-state Cmax and AUC of atogepant after single dose of ubrogepant, there was no change in median Tmax of atogepant (1.5 hrs) following administration alone or in combination with ubrogepant.
"This study showed that single-dose administration of ubrogepant had no significant effect on the steady-state PK of atogepant (e.g., point estimates were within the predefined no DDI criteria)," Blumenfeld et al wrote.
In terms of the PK profile of ubrogepant, plasma concentrations were higher following the combined approach of the therapies, with point estimates for ubrogepant Cmax and AUC of 12.563 (90% CI, 105.58-149.48) and 118.80 (90% CI, 108.69-129.84), respectively. These estimates extended beyond the upper bound 90% CI for the predefined DDI criteria for no interaction. Furthermore, the single-dose AUC and Cmax of ubrogepant increased by 19% and 26%, respectively, because of the concomitant administration of steady-stage atogepant.
In terms of safety, there were no observed deaths, serious AEs, or severe AEs while on treatment. Additionally, investigators observed no clinically meaningful between-group differences in mean clinical laboratory, vital sign, and safety 12-lead EEG parameters. There was 1 mild non-serious treatment-emergent AE (TEAE) of palpitation that was considered study drug related. All TEAEs were mild in severity, except for 1 moderate TEAE of vomiting following a single dose of ubrogepant; however, this was deemed not study drug-related.
Throughout the trial, there were no observed cases of alanine aminotransferase/asparate aminotransferase levels that reached at least 3 times the upper limit of normal or met the criteria for a potential Hy’s law case. No participants showed active suicidal behavior or suicidal ideation during the study, and no new safety signals were identified. Constipation, nausea, fatigue, back pain, abdominal pain, and neck pain made up the most frequently reported TEAEs, occurring in at least 10% of participants.
Constipation, which occurred in 52% of the cohort, was the most frequent TEAE reported. Patients reported constipation as mild in severity, and most cases were treated with either prune juice or over-the-counter laxative therapy within a median of 7 days. Of the 16 patients that reported constipation, 2 had a history of hypothyroidism and none describe medical history of constipation. Notably, there was a higher percentage of patients who reported constipation events at Study Site 3 (5 of 6; 83%) compared with sites 1 (8 of 21; 38%) and 2 (2 of 4; 50%).
"Concomitant administration of ubrogepant on day 7 and beyond with atogepant did not increase constipation events in the subsequent days compared to atogepant alone," Blumenfeld and his colleagues noted.1 "If the atogepant-ubrogepant combination synergistically increased constipation, then the rate of constipation would have increased over the course of the study; however, no constipation events were reported after day 18 in which participants had thus far received atogepant for 17 consecutive days with four cycles of ubrogepant (QD every 3 days)."
