<h3>Objective:</h3> This second interim analysis of the ongoing PEARL study aims to provide real-world data on effectiveness, acute medication use, and disability in patients starting fremanezumab treatment. <h3>Background:</h3> Fremanezumab, a humanized monoclonal antibody selectively targeting calcitonin gene-related peptide, is approved in Europe for migraine prevention in adults with ≥4 monthly migraine days (MMD). <h3>Design/Methods:</h3> PEARL is a 24-month, pan-European, prospective, observational study in adults diagnosed with episodic or chronic migraine (EM, CM), initiating fremanezumab. Primary endpoint: proportion of patients with ≥50% reduction from baseline in average MMD (≥50% response) during the 6 months post-fremanezumab initiation. Secondary endpoints include mean change from baseline in: MMD, average monthly days of acute migraine medication use, and disability scores (Migraine Disability Assessment [MIDAS]; 6-item Headache Impact Test [HIT-6]) at different timepoints from Months 1–24. <h3>Results:</h3> 574 patients (EM, 26%; CM, 74%) were included in the interim full analysis set; 65% had used prior anticonvulsants, 61% beta-blockers, 51% tricyclic antidepressants, 23% angiotensin II receptor antagonists for preventive treatment. For patients with data for the primary endpoint (N=313), 56% (EM, 69%; CM, 52%) achieved ≥50% MMD response during the 6 months following fremanezumab initiation. For secondary endpoints, the mean±SD change from baseline at Month 6 for MMD was −8.0±7.1, for average monthly days of acute migraine medication use was −6.7±6.2, for MIDAS was −52.7±58.5, and for HIT-6 was −9.5±8.8. Of 897 patients in the safety analysis set, only 1 experienced a drug-related serious adverse event of dysphonia. <h3>Conclusions:</h3> This interim analysis supports the real-world effectiveness of fremanezumab, with more than half of patients reporting a ≥50% reduction in MMD during the 6 months after first fremanezumab dose, and improvements in other secondary outcome measures along with a favorable side effect profile. Previously submitted as: Ashina M, et al. Cephalalgia 2022;42(1_suppl):93–94. doi: 10.1177/03331024221117728. <b>Disclosure:</b> Dr. Ashina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AbbVie. Dr. Ashina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Ashina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Ashina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Ashina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Ashina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Dr. Ashina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. The institution of Dr. Mitsikostas has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. The institution of Dr. Mitsikostas has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. The institution of Dr. Mitsikostas has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for TEVA. The institution of Dr. Mitsikostas has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Leli Lilly. The institution of Dr. Mitsikostas has received research support from Eli Lilly. Dr. Mitsikostas has a non-compensated relationship as a Co-Chair of Headache Panel with EAN that is relevant to AAN interests or activities. Dr. Mitsikostas has a non-compensated relationship as a President with Hellenic Headache Society that is relevant to AAN interests or activities. Dr. Mitsikostas has a non-compensated relationship as a Associate Editor with J Headache Pain that is relevant to AAN interests or activities. Dr. Mitsikostas has a non-compensated relationship as a Associate Editor with Frontier Neurology that is relevant to AAN interests or activities. Dr. Amin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Amin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Amin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Dr. Amin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Pfizer. Dr. Amin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Dr. Amin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck. Dr. Amin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. The institution of Dr. Amin has received research support from Rigshospitalet. Dr. KOKTURK has received personal compensation for serving as an employee of Teva. The institution of Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. The institution of Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. The institution of Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. The institution of Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Sahin has received research support from Vinnova Sweden. The institution of Dr. Sahin has received research support from Swedish Neurological Association. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Grünenthal. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lilly. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. The institution of Dr. Schankin has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Teva. The institution of Dr. Schankin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck. Dr. Schankin has stock in Zynnon. The institution of Dr. Dorman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Dorman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Dorman has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Dr. Pozo-Rosich has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AbbVie. Dr. Pozo-Rosich has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Pozo-Rosich has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Eli Lilly. Dr. Pozo-Rosich has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Pharmaceuticals. Dr. Pozo-Rosich has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chiesi. Dr. Pozo-Rosich has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Pozo-Rosich has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medscape. Dr. Pozo-Rosich has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly Foundation Spain. Dr. Pozo-Rosich has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sociedad Española Neurologia. Dr. Lyras has received personal compensation for serving as an employee of Teva Pharmaceuticals. Mrs. Myers has nothing to disclose. Dr. Ahn has received personal compensation for serving as an employee of Teva Pharmaceuticals. Cristina Tassorelli has nothing to disclose.