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Atogepant proved effective, safe, and well-tolerated in refractory high-frequency episodic migraine and chronic migraine, according to a recent study.

The GIANT (atoGepant IN reAl life in iTaly) study demonstrated that atogepant—the first oral calcitonin gene-related peptide (CGRP) receptor antagonist approved for migraine prevention—is effective, safe, and well‐tolerated in refractory high-frequency episodic migraine (HFEM) and chronic migraine (CM)—showing rapid onset, reduced pain and disability, high satisfaction, and efficacy despite prior anti‐CGRP monoclonal antibodies (mAbs) failures, according to findings published in The Journal of Headache and Pain.

“These findings confirm and expand upon the efficacy and tolerability outcomes reported in RCTs (randomized controlled trials), offering valuable insights into the drug’s performance in clinical practice,” wrote study co-author Piero Barbanti, MD, PhD, San Raffaele Roma University, and colleagues.

Conducted across 16 headache centers in Italy under the Italian Migraine Registry, this investigation evaluated the effectiveness, safety, and tolerability of daily atogepant 60mg over 12 weeks in a cohort that closely mirrors routine clinical practice, according to the authors.

Rapid, Robust, Safe Reduction in Migraine Burden

A total of 183 adults with HFEM (8-14 migraine days/month) or CM (15 or more headache days/month) and three or more failed preventive treatments were enrolled; 82 completed the 12-week follow-up. The researchers reported that, by week 12, patients exhibited a mean reduction of 6.0 monthly migraine days (MMD) in HFEM and 11.2 monthly headache days (MHD) in CM (P<0.001 for both). Notably, efficacy was rapid: the first week of atogepant produced an average decrease of 2.5 migraine days (HFEM, –1.5; CM, –3.1; P<0.001).

“Clinical benefit was already detectable within the first week of treatment, an attribute that may enhance adherence and patient engagement, especially in individuals with previous treatment failures,” the authors stated.

According to study findings, secondary outcomes also improved markedly. Monthly analgesic intake dropped by 10.9 days, pain severity on the Numerical Rating Scale decreased by 2.7 points, and disability scores declined significantly (Headache Impact Test-6, –13.2; Migraine Disability Assessment, –61.1; Migraine Interictal Burden Scale-4, –5.4; all P<0.001).

“Clinically relevant outcomes included also the reversion from CM to episodic migraine in nearly 75% of patients and the resolution of medication overuse in over two-thirds within 12 weeks,” the authors wrote. “These findings support the role of atogepant in addressing factors such as central sensitization and maladaptive neuroplasticity that sustain migraine chronification.”

Treatment satisfaction was also high, based on study results, with 70.7% reporting being “much” or “very much” improved on the Patient Global Impression of Change. Responder rates at week 12 were 65.9% (≥50% reduction), 36.6% (≥75% reduction), and 6.1% (100% reduction).

“The ≥ 50% response rate observed in this real-world cohort (65.9%) exceeds that reported in the ELEVATE trial (51%), despite the inclusion of a more challenging population,” the authors continued. “Notably, 41.5% of our patients had previously failed treatment with anti-CGRP mAbs—typically an exclusion criterion in RCTs—yet 52.9% of them still achieved a ≥ 50% response rate.”

According to the authors, adverse events were infrequent and mild, occurring in 5.5% of participants, with only 1.6% discontinuing treatment due to side effects.

Limitiations & Implications

The authors acknowledged several potential limitations of the study:

1. Exclusion of patients with fewer than 8 MMD, limiting applicability to lower-frequency migraine populations;
2. The study sample includes more patients with CM than HFEM, limiting extrapolation to the latter group;
3. Small sample size and short follow-up, precluding firm conclusions on long-term safety and effectiveness; and
4. Lack of electronic headache diaries, offering a potential source of recall bias.

Nonetheless, the authors concluded “…the GIANT study documents the effectiveness, safety, and tolerability of atogepant for the prevention of HFEM and CM in a real-world population with multiple therapeutic failures and comorbidities. These findings extend RCT evidence by demonstrating early onset of effect, reductions in pain intensity and interictal disability, benefits in prior mAb non-responders, and high patient-reported satisfaction.”

The researchers concluded with a recommendation for further large-scale studies “…to confirm these results and to better define the place of atogepant within individualized migraine treatment strategies.”