Phase 4 PEARL Study Confirms Long-Term Effectiveness of Fremanezumab in Preventing Chronic, Episodic Migraine

Messoud Ashina, MD, PhD, DMSc

Final data from the phase 4 PEARL real-world study presented at the 11^th Congress of the European Academy of Neurology (EAN 2025) Congress in Helsinki, showed that fremanezumab (Ajovy; Teva) was effective at reducing frequency, duration, and severity of migraine attacks in patients with chronic (CM) and episodic migraine (EP) over a 2-year period.¹

PEARL, or the Pan-European Real-World study, was a large-scale trial testing fremanezumab, an FDA-approved calcitonin gene-related peptide (CGRP)-targeting treatment, in 1140 patients with chronic or episodic migraine. Of these, 1129 were included in the effectiveness analysis (EM: 33.1%; CM: 66.9%; 87.2% female). Results showed that fremanezumab met its primary end point, with 66% of patients with EM and 51.6% of those with CM achieving at least a 50% reduction in Monthly Migraine Days (MMDs) during the first 6 months of treatment.

In the study, benefits from fremanezumab were noticed early in the treatment course and sustained over the 24-month treatment period. Patients had high adherence to the injectable treatment, with over 75% (854 of 1129) of patients completing the study duration. Fremanezumab, available in monthly or quarterly dosing, continued to show a safety and tolerability profile that was consistent with previous PEARL interim analyses and randomized controlled trials, further supporting its use as a migraine preventive.

"Over the last two years, we have observed the benefit of fremanezumab for sustained migraine prevention and its positive impact on patient outcomes,” Messoud Ashina, MD, PhD, DMSc, director of the Human Migraine Research Unit, Danish Headache Center, said in a statement.¹ "The PEARL study has provided valuable insight, not only into the pivotal role that fremanezumab can play in migraine prevention, but also in the importance of real-world studies in helping build our knowledge and shape clinical practice."

Fremanezumab became FDA-approved for the preventive treatment of migraine in 2018, becoming on the of the first antibodies to target the CGRP pathway. Its original approval was backed by data from 2 studies in the phase 3 HALO program, where the anti-CGRP monoclonal antibody demonstrated significant reductions in MMDs in both patients with EM and CM. The therapy was originally approved for adults with migraine; however, Teva seeks to expand its indication to include pediatric and adolescent patients aged 6-17 who weigh 45 kilograms or more.²

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The FDA formally accepted Teva’s supplemental new drug application for an expanded indication in April, using data from the phase 3 SPACE study (NCT03539393) as supportive evidence. SPACE, a double-blind, placebo-controlled, parallel-group trial, showed that fremanezumab was superior to placebo over a 12-week period, while maintaining a safety profile that was consistent with what was previously observed in adults.

SPACE comprised 237 pediatric patients, split into subgroups by age (6-11 years and 12-17 years), who had a history of less than 14 headache days a month. In the study, treatment with fremanezumab led to a statistically significant reduction in MMDs vs placebo (–2.5 vs –1.4; P = .0210), and a significant reduction in monthly headache days (MHD; –2.6 vs –1.5; P = .0172). In addition, investigators observed a significantly higher proportion of patients achieving at least a 50% response on fremanezumab vs placebo (47.2% vs 27.0%; P = .0016), with benefits that were similar across both age subgroups and between boys and girls.³

Since its 2018 approval, fremanezumab has been studied in numerous different contexts, including a 2024 real-world study that found no wearing off effect from the medication. Published in Cephalalgia, patients treated with 225 mg of fremanezumab showed no difference in migraine days during weeks 2 and 4 of treatment (P = .581), and did not differ from those on erenumab, another FDA-approved CGRP medication. Notably, an explorative analysis demonstrated no association between wearing-off and response rate in the total group (P = .935) or within the erenumab (P = .811) and fremanezumab (P = .981) groups.⁴

REFERENCES
1. Final Data from Teva’s PEARL Real-World Study Reinforce the Long-term Effectiveness of AJOVY® (fremanezumab) for the Prevention of Chronic and Episodic Migraine. News release. Teva Pharmaceuticals. June 23, 2025. Accessed June 23, 2025. https://www.globenewswire.com/news-release/2025/06/23/3103120/0/en/Final-Data-from-Teva-s-PEARL-Real-World-Study-Reinforce-the-Long-term-Effectiveness-of-AJOVY-fremanezumab-for-the-Prevention-of-Chronic-and-Episodic-Migraine.html
2. Teva Announces FDA Filing Acceptance for AJOVY® (fremanezumab) in Pediatric Episodic Migraine Prevention. News release. Teva Pharmaceuticals. April 7, 2025. Accessed June 23, 2025. https://www.globenewswire.com/news-release/2025/04/07/3056596/0/en/Teva-Announces-FDA-Filing-Acceptance-for-AJOVY-fremanezumab-in-Pediatric-Episodic-Migraine-Prevention.html
3. Teva Presents Positive Efficacy and Safety Data of AJOVY® (fremanezumab) for the Prevention of Episodic Migraine in Children and Adolescents from Phase 3 SPACE Trial. News release. Teva Pharmaceuticals. December 4, 2024. Accessed June 23, 2025. https://ir.tevapharm.com/news-and-events/press-releases/press-release-details/2024/Teva-Presents-Positive-Efficacy-and-Safety-Data-of-AJOVY-fremanezumab-for-the-Prevention-of-Episodic-Migraine-in-Children-and-Adolescents-from-Phase-3-SPACE-Trial/default.aspx
4. Florescu AM, Lannov LV, Younis S, et al. No wearing-off effect of erenumab or fremanezumab for chronic migraine prevention: a single-center, real-world, observational study. Cephalalgia. Published online January 12, 2024. doi:10.1177/03331024231222915