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Clinical Trial
. 2025 Dec;46(12):6907-6921.
doi: 10.1007/s10072-025-08484-1. Epub 2025 Oct 1.

Long-term real-world effectiveness and safety of fremanezumab in 1140 patients with migraine and at least 6 months of treatment: third interim analysis of the pan-European PEARL study

Messoud Ashina  1   2 , Dimos D Mitsikostas  3 , Faisal Mohammad Amin  4   5 , Pinar Kokturk  6 , Christoph J Schankin  7 , Gurdal Sahin  8 , Patricia Pozo-Rosich  9   10 , Paul J Dorman  11 , Tomáš Nežádal  12 , Anne Christine Poole  13 , Isabel Pavão Martins  14 , Marja-Liisa Sumelahti  15 , Verena Ramirez Campos  16 , Andrew H Ahn  16 , Hasan Akcicek  6 , Cristina Tassorelli  17   18
Affiliations
Clinical Trial

Long-term real-world effectiveness and safety of fremanezumab in 1140 patients with migraine and at least 6 months of treatment: third interim analysis of the pan-European PEARL study

Messoud Ashina et al. Neurol Sci. 2025 Dec.

Abstract

Introduction: Real-world data on the long-term use of fremanezumab for migraine prevention remain limited. This third interim analysis of the PEARL study addresses this gap by investigating the long-term effectiveness, safety, and tolerability of fremanezumab for up to 12 months of treatment.

Methods: PEARL is a 24-month, prospective, observational, Phase 4 study conducted in 11 European countries. Eligible participants were adults (≥ 18 years) diagnosed with chronic or episodic migraine who received subcutaneous fremanezumab (225 mg monthly or 675 mg quarterly) and completed ≥ 6 months of treatment. The primary endpoint was defined as the proportion of participants achieving a ≥ 50% reduction in monthly migraine days (MMD) during the 6-month period following treatment initiation. Secondary endpoints included mean change from baseline to Month 12 in: average MMD, acute migraine medication use, and migraine-related disability scores, as measured by the Migraine Disability Assessment and the 6-item Headache Impact Test. Safety was assessed through the collection of adverse events.

Results: At data cut-off (22 September 2022), 968 of 1140 enrolled participants were included in the effectiveness analysis with 58.5% achieving the primary endpoint. Sustained reductions in MMD, acute medication use, and disability scores were observed over 12 months, and no new safety signals were detected.

Conclusions: Findings from this third interim analysis of PEARL provide compelling evidence for the long-term effectiveness of fremanezumab in a large, real-world patient population. The results support the continued use of fremanezumab as a preventive strategy for migraine and underscore the value of integrating real-world evidence into migraine management.

Trial registration number: EUPAS35111.

Keywords: Calcitonin gene-related peptide; Chronic; Episodic; Migraine; Real-world data; Real-world evidence.

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Conflict of interest statement

Declarations. Ethics approval and informed consent: The PEARL study protocol was approved by the Independent Ethics Committee/Institutional Review Board in the 11 participating European countries, as required by local law, and all relevant local data protection laws were followed. As PEARL is a non-interventional, prospective study, no study procedures were performed beyond the participants’ care in real-world clinical practice. Informed consent was obtained from all participants as part of the study inclusion criteria; participants agreed for their clinical data to be recorded anonymously and had the right to withdraw their consent at any time during the study. Competing interests: Messoud Ashina has received personal fees and declares PI/collaborator in clinical trials for AbbVie, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; and institutional research grants from the Lundbeck Foundation, the Novo Nordisk Foundation, Lundbeck, and Novartis. Dimos D. Mitsikostas has received fees and travel grants from Allergan, Amgen, Bayer, Biogen, Cefaly, electroCore, Eli Lilly, Genesis Pharma, Merck Serono, Merz, Mylan, Novartis, Roche, Sanofi Genzyme, Specifar, and Teva Pharmaceuticals. Faisal Mohammad Amin has received personal fees for lecturing and/or participation in advisory boards from AbbVie, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; and research grants from the Lundbeck Foundation. Pinar Kokturk, Verena Ramirez Campos, and Hasan Akcicek are employees and/or shareholders of Teva Pharmaceuticals. Christoph J. Schankin declares consulting, advisory boards, presentations, and travel support from AbbVie, Allergan, Almirall, Amgen, Eli Lilly, Grünenthal, Lundbeck, MindMed, Novartis, Pfizer, and Teva Pharmaceuticals; part-time employment with Zynnon; and research support from the Baasch-Medicus Foundation, the Eye on Vision Foundation, the German Migraine and Headache Society, the Swiss Heart Foundation, Teva Pharmaceuticals, Visual Snow Initiative, and Visual Snow Syndrome Germany e.V. Gurdal Sahin declares advisory boards and/or PI in clinical trials for AbbVie, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; and research support from Vinnova (Sweden’s innovation agency), Lund University, and the Swedish Neurological Association. Patricia Pozo-Rosich declares grant/research support from AbbVie, AGAUR, EraNet NEURON, Instituto Investigacióón Carlos III, MINECO, Novartis, RIS3CAT FEDER, and Teva Pharmaceuticals; and consultancy or education for AbbVie, Amgen, Dr. Reddy’s, Eli Lilly, Lundbeck, Novartis, Organon, Pfizer, and Teva Pharmaceuticals. Paul J. Dorman declares lecture fees, advisory boards, educational support, and research with AbbVie, electroCore, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals. Tomáš Nežádal declares consulting, speaking fees, and travel grants from Eli Lilly, Glenmark, Lundbeck, Novartis, Organon, Pfizer, St. Jude Medical, Teva Pharmaceuticals, and UCB; and advisory boards and PI in clinical trials for AbbVie, Amgen, Eli Lilly, Lundbeck, Neurocrine, Novartis, Teva Pharmaceuticals, and UCB. Anne Christine Poole declares advisory boards, clinical studies, and/or lecturing for AbbVie, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals. Isabel Pavão Martins declares consultancy or education and/or PI in clinical trials for AbbVie, Allergan, Eli Lilly, Lundbeck, Novartis, Organon, Pfizer, Teva Pharmaceuticals, and Zambon. Marja-Liisa Sumelahti declares lectures, advisory boards, educational support, and research with AbbVie, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals. Andrew H. Ahn is a former employee of Teva Pharmaceuticals. Cristina Tassorelli declares consulting or speaking fees and/or travel grants, advisory boards, symposia, and/or PI/collaboration in clinical trials for AbbVie, Chordate, Dompé, Eli Lilly, Ipsen, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; PI in clinical trials for AbbVie, Chordate, Eli Lilly, Ipsen, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; and research grants from AbbVie, the European Commission, the Italian Ministry of Health, the Migraine Research Foundation, and the Italian Multiple Sclerosis Foundation.

Figures

Fig. 1
Fig. 1
The progress of participants through the PEARL study. Baseline is defined as the 28-day period prior to initiating treatment with fremanezumab; eligible participants have ≥ 21 days of data from this 28-day period in their headache diary. Fremanezumab is initiated within 3 months of the first visit (V0). Ashina M, Mitsikostas DD, Amin FM, Kokturk P, Schankin CJ, Sahin G, Pozo-Rosich P, Dorman PJ, Nežádal T, Poole AC, Martins IP, Sumelahti M-L, Ramirez Campos V, Ahn AH, Lyras L, Tassorelli C. Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study. Cephalalgia. 2023;43(11):3331024231214987. Copyright @ 2024 by Sage Publications. Reprinted by Permission of Sage Publications. CM chronic migraine, EM episodic migraine
Fig. 2
Fig. 2
Participant inclusion process. Data cut-off date: 22 September 2022. FAS full analysis set
Fig. 3
Fig. 3
Proportion of participants reaching ≥ 50% reduction in MMD during the 6 months after fremanezumab initiation. At data cut-off, not all data for this endpoint were available and participants with missing data have been excluded. CM chronic migraine, EM episodic migraine, MMD monthly migraine days
Fig. 4
Fig. 4
Mean change from baseline in MMD at Months 1, 3, 6, 9, and 12. At data cut-off, not all data for this endpoint were available and participants with missing data have been excluded. The number of participants prematurely discontinuing this study and the number of participants that had not yet reached the relevant observation timepoint, as well as delays in data being entered into the electronic data capture system, contributed to a drop in participant numbers over time. CM chronic migraine, EM episodic migraine, MMD monthly migraine days
Fig. 5
Fig. 5
Proportion of participants reaching ≥ 50% reduction in MMD at Months 1, 3, 6, 9, and 12 after fremanezumab initiation. At data cut-off, not all data for this endpoint were available and participants with missing data have been excluded. The number of participants prematurely discontinuing this study and the number of participants that had not yet reached the relevant observation timepoint, as well as delays in data being entered into the electronic data capture system, contributed to a drop in participant numbers over time. CM chronic migraine, EM episodic migraine, MMD monthly migraine days
Fig. 6
Fig. 6
Mean change from baseline in acute medication use at Months 1, 3, 6, 9, and 12. At data cut-off, not all data for this endpoint were available and participants with missing data have been excluded. The number of participants prematurely discontinuing this study and the number of participants that had not yet reached the relevant observation timepoint, as well as delays in data being entered into the electronic data capture system, contributed to a drop in participant numbers over time. CM chronic migraine, EM episodic migraine
Fig. 7
Fig. 7
Mean change from baseline in migraine-related disability scores at Months 1, 3, 6, 9, and 12: (a) MIDAS score* and (b) HIT-6 score*. *Possible MIDAS scores ranged from 0–270 and possible HIT-6 scores ranged from 36–78, with higher scores indicating more severe disability for both scales. At data cut-off, not all data for this endpoint were available and participants with missing data have been excluded. The number of participants prematurely discontinuing this study and the number of participants that had not yet reached the relevant observation timepoint, as well as delays in data being entered into the electronic data capture system, contributed to a drop in participant numbers over time. CM chronic migraine, EM episodic migraine, HIT-6 6-item Headache Impact Test, MIDAS Migraine Disability Assessment
Fig. 8
Fig. 8
Adherence to and persistence with the fremanezumab treatment schedule at Months 1, 3, 6, 9, and 12. Participants were classified as non-adherent either (a) from the time of the first dose occurring outside the ± 5 days of their dosing regimen, despite adherence at subsequent timepoints, or (b) per injection. At data cut-off, not all data for this endpoint were available and missing data have been excluded. The number of participants prematurely discontinuing this study and the number of participants that had not yet reached the relevant observation timepoint, as well as delays in data being entered into the electronic data capture system, contributed to a drop in participant numbers over time
Fig. 9
Fig. 9
Mean change from baseline at Months 1, 3, 6, 9, and 12 in headache severity (a) and duration (b). At data cut-off, not all data for this endpoint were available and missing data have been excluded. The number of participants prematurely discontinuing this study and the number of participants that had not yet reached the relevant observation timepoint, as well as delays in data being entered into the electronic data capture system, contributed to a drop in participant numbers over time. CM chronic migraine, EM episodic migraine, NRS Numeric Rating Scale
Fig. 10
Fig. 10
Proportion of all participants (non-switching and switching) who reached ≥ 50% reduction from baseline in MMD during the 6 months after fremanezumab initiation. Switch participants were defined as those participants switching from another CGRP pathway mAb treatment to fremanezumab. The number of participants prematurely discontinuing this study and the number of participants that had not yet reached the relevant observation timepoint, as well as delays in data being entered into the electronic data capture system, contributed to a drop in participant numbers over time. CGRP calcitonin gene-related peptide, CM chronic migraine, EM episodic migraine, mAb monoclonal antibody, MMD monthly migraine days
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