Abstract
BACKGROUND: Real-world evidence on atogepant remains limited. GIANT2 explores the 24-week real-life effectiveness of atogepant in patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM) under routine clinical conditions. METHODS: GIANT2 is a 24-week, prospective, multicenter, real-world, study including consecutive patients with HFEM or CM with ≥3 preventive treatment failures, treated with atogepant 60 mg once daily. Co-primary endpoints: proportions achieving ≥50% and ≥75% reductions in monthly migraine days for HFEM or monthly headache days for CM at weeks 21–24 versus baseline. Secondary endpoints: changes in migraine/headache days, analgesic intake, pain intensity, disability, patient global impression of change, 100% response rates, tolerability and safety. Response rates at weeks 21–24 were also evaluated in patients with prioranti-CGRP mAb failure. Exploratory analyses: proportion of >50% responders achieving >30% reduction in NRS scores and response rates in subgroups combining psychiatric comorbidities, CM, and medication overuse headache (MOH). RESULTS: Of 233 patients enrolled, 156 completed >24 weeks of treatment, with 37.2% having failed prior anti-CGRP mAbs. At weeks 21–24, 76.9% achieved a ≥ 50% response and 45.5% a ≥ 75% response, with ≥50% response more frequent in HFEM than CM (p = 0.005). A 100% response occurred in 5.1% of patients. All secondary endpoints improved significantly (p < 0.001) with greater benefits at week 24 than week 12. No difference in effectiveness was observed between mAb-naïve patients and those with prior mAb failures, who achieved ≥50% and ≥75% response rates of 70.7% and 39.7%. A combined ≥50% frequency reduction and ≥30% pain reduction was achieved by 54.5% of patients. Among patients with psychiatric comorbidities, 63.0% were ≥50% responders, while among CM patients rates were 62.1% in those with MOH and 40.0% in those with both psychiatric comorbidities and MOH (≥75% responder rates 42.4%, 37.0%, and 28.0%). Adverse events occurred in 11.2% of patients and led to discontinuation in 1.3%. CONCLUSIONS: GIANT2 shows that atogepant effectiveness increases from week 12 to 24 with a high proportion of responders and super-responders regardless of prior anti-CGRP mAb failure and reduces pain intensity in residual headaches in most patients. It is also effective in migraine subgroups combining psychiatric comorbidities, CM and MOH. TRIAL REGISTRATION: NCT06136442. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10194-026-02277-3.