Dr. David DodickDavid W. Dodick, MD
Orally administered atogepant, a small molecule CGRP receptor antagonist, demonstrated a statistically significant and clinically relevant reduction in mean migraine days compared with placebo while eliciting no treatment-related serious adverse events (AEs), according to findings from a phase 2b/3 study presented at the 2019 American Headache Society (AHS) Annual Meeting, July 11-14, 2019, in Philadelphia, Pennsylvania.

At the lowest dose of atogepant administered (10 mg once daily [QD], n = 92), there was a 4.00-day reduction in mean monthly migraine days compared with a reduction of 2.85 days in the placebo arm (adjusted P = .0236). This benefit remained consistent across 5 doses of atogepant explored in the study. At the largest dose (60 mg twice daily [BID], n = 87), there was a 4.14-day mean reduction in monthly migraine days (adjusted P = .0031).

"The primary efficacy end point of this study was met. All 5 atogepant groups showed statistically significant and clinically relevant reductions in mean migraine days across the 12-week treatment period," David W. Dodick, MD, Mayo Clinic, said during a presentation of the findings. "Atogepant was generally well-tolerated, with no treatment-related serious adverse events."

The phase 2b/3 study examined atogepant across a variety of doses with each compared with placebo during a 12-week double-blind treatment period that was followed by a 4-week safety evaluation. The atogepant doses examined were 10 mg QD (n = 92), 30 mg QD (n = 182), 60 mg QD (n = 177), 30 mg BID (n = 79), and 60 mg BID (n = 87). There were 178 patients in the placebo group.

The mean age of patients enrolled was 40 years, and a majority were female (86%). Prior acute treatments were received by 98% of participants and consisted of NSAIDs (67%) and triptans (36%). For patients who completed both periods of the study, the most common diagnosis was migraine without aura (50.4%), followed those with and without aura in 27.3% of patients. The mean time since first manifestation of migraines was 19.37 years, and 72% of patients had not received a prior preventive treatment. The average number of monthly migraine days at baseline was 7.67 per patient.

In the 30 mg QD group, there was a mean reduction of 3.76 monthly migraine days, resulting in an adjusted P of .0390 compared with placebo. Monthly migraine days were reduced by 3.55 days in the 60 mg QD group (adjusted P = .0390) and by 4.23 in the 30 mg BID group (adjusted P = .0034). Reductions in migraine occurred relatively quickly across groups. "Each dose group separated from placebo during the first 4 weeks," said Dodick.

A greater than or equal to 50% reduction in mean migraine days was experienced by approximately half of patients across the atogepant groups; however, this level of reduction was only statistically significantly observed at the highest doses of the oral agent. In the 30 mg BID group, 58% of patients had a ≥50% reduction in the number of mean monthly migraine days compared with 40% in the placebo group (adjusted P = .0339). Sixty-two percent of patients in the 60 mg BID group had a ≥50% reduction (adjusted P = .0097).

Monthly mean days requiring acute migraine medication use dropped across atogepant arms but only showed a statistically significant decline versus placebo in the two largest dose arms. The placebo group experienced a 2.42-day reduction in the use of acute medication compared with a reduction of 3.77 days and 3.64 days in the 30 mg BID and 60 mg BID groups, respectively. The adjusted P values for these groups versus placebo were .0339 and .0097, respectively.

Eighteen percent of patients discontinued treatment during the 12-week treatment period. The most common cause was withdrawal of consent (7%) followed by discontinuation due to AEs (5%). Of the 825 patients eligible for the safety analysis, 480 reported treatment-emergent AEs (TEAEs). Treatment-related TEAEs occurred in 16.1% of patients in the placebo group, compared with 18.3% in the 10 mg QD group, 21.3% at 30 mg QD, 22.6% for 60 mg QD, 20.9% for 30 mg BID, and 26.4% for 60 mg BID.

The most common TEAEs were fatigue, nausea, constipation, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and blood creatinine phosphokinase increase. Of these, fatigue, nausea, and constipation did appear to increase in a dose dependent manner, Dodick noted.

ALT and AST liver enzyme elevation was relatively uncommon and was observed in the placebo group at a similar frequency as the treatment arms. One possibly related case of ALT/AST increase of ≥3 times the upper limit of normal led to discontinuation of atogepant. "However, there were no potential cases of Hy's law reported," Dodick noted.

Additional phase 3 studies are currently exploring atogepant for episodic (NCT03777059) and chronic migraines (NCT03855137). For episodic migraine, the treatment is being tested at 10 mg, 30 mg, and 60 mg QD. For chronic migraine, a 30 mg BID dose is being explored along with 60 mg QD. Both studies also include matched placebo arms and are actively enrolling.

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REFERENCE
Goadsby PJ, Dodick DW, Ailani J, et al. Orally administered atogepant was efficacious, safe, and tolerable for the prevention of migraine: results from a phase 2b/3 study. Presented at: American Headache Society 2019, Philadelphia, PA, July 11-14, 2019.