Secondary analysis boosts potential of atogepant for migraine prophylaxis in adults

In the secondary analysis of the phase III ADVANCE trial, responder rates were markedly higher with atogepant irrespective of dose than with placebo in adults with migraine.

“Responder rates … are regarded as more clinically meaningful than changes in monthly migraine-days (MMDs) … [as these] reflect the proportion of individuals achieving a relief threshold, an outcome readily communicated in clinical practice,” said the researchers.

The investigators now report the key secondary, α-controlled endpoint of ≥50-percent responder rate, and the ≥25-, ≥75-, and 100-percent responder rates in the 3-month mean of MMDs and by 4-week treatment intervals for atogepant vs placebo. A total of 902 participants (mean age 41.6 years, 89 percent female) were randomized equally into the atogepant 10, 30, or 60 mg, or placebo QD arms. Baseline mean MMDs were between 7.5 and 7.9 across all four arms. [JAMA Network Open 2022;5:e2215499]

The fractions of participants achieving ≥50-percent reduction in mean MMDs were greater with any atogepant dose (56, 59, and 61 percent for the respective 10, 30, and 60-mg doses) than with placebo (29 percent). The corresponding odds ratios (ORs) for the comparisons of each atogepant dose with placebo were 3.1, 3.5, and 3.8, all yielding statistical significance (p<0.001).

“The ORs suggest that the likelihood of experiencing ≥50-percent reduction in mean MMDs is ~3–4 times greater with atogepant than with placebo across the 12-week treatment period,” the researchers explained.

Similarly, atogepant of any dose trumped placebo in terms of the percentages of participants reporting ≥25-percent (73, 77, and 81 percent [10-, 30-, and 60-mg doses] vs 59 percent [placebo]; p<0.002) and ≥75-percent reduction in mean MMDs (30, 30, and 38 percent vs 11 percent; p<0.001).

The percentages of participants reporting 100-percent reduction in mean MMDs were 7.9 percent (p=0.004), 4.9 percent (p=0.02), and 7.7 percent (p=0.003) in the respective atogepant 10-, 30-, and 60-mg arms, trumping the 0.9-percent rate in the placebo arm. “A 100-percent reduction in MMDs represented individuals who reported no MDs from the day the participant received the first treatment dose through the end of week 12,” they said.

More than 50 percent of participants across all arms reported treatment-emergent adverse events, the most common being constipation and nausea. Nonetheless, atogepant was generally well-tolerated with no safety concerns reported.

About three-quarters of those on atogepant reported feeling much better/very much better, while up to 83 percent met treatment satisfaction responder criteria; the corresponding rates in the placebo arm were 46 percent and 55 percent. “Participant perceptions of treatment efficacy are important aspects for defining treatment success,” said the researchers.

Early, sustained response

“[It is important to note that] response to oral atogepant treatment was evident as early as the first 4 weeks and increased over time, demonstrating an early onset and sustained response,” the researchers stressed.

Except for atogepant 10 mg during weeks 5–8 in ≥25-percent responders, the significant efficacy of atogepant was seen in the first 4 weeks regardless of dose across all responder arms, highlighting the robust treatment effects achieved within the first month.

“[Overall, apart from the] rapid onset of action for atogepant, these data also suggest that responder rates continue to improve with extended treatment,” the researchers noted. “Higher atogepant doses appeared to produce the greatest responder rates, which can guide clinicians in individualizing starting doses.”

“These data more fully characterize the benefits of atogepant as a preventive migraine treatment and have meaningful applications to real-world practice, providing clinicians and patients with easier ways to communicate results that consider individual differences in response,” they concluded.

The findings also supplement the preliminary efficacy findings demonstrating reductions in the number of migraine and headache days with the drug.