{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:35:17Z","timestamp":1793198117311,"version":"4.5.0"},"reference-count":19,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"accepted":{"date-parts":[[2026,2,12]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This Tysabri Observational Program (TOP) final analysis evaluated the 15-year safety and effectiveness of natalizumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This multinational, real-world observational study assessed natalizumab-associated serious adverse events, annualised relapse rates (ARRs) and disability progression\/improvement in patients with RRMS. These outcomes were evaluated in subpopulations receiving short- (1\u20132 years) versus long-term (\u226510 years) natalizumab and in patients who switched from intravenous to subcutaneous (SC) natalizumab formulation. The probability of conversion to non-active secondary progressive multiple sclerosis (SPMS) was assessed in patients who remained on versus discontinued natalizumab after \u22651 year.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>As of November 2023, TOP enrolled 6319 patients. Median time on natalizumab was 4.13 years. There were no new safety signals after up to 15 years of treatment. Marked, sustained reductions in pretreatment ARR occurred with natalizumab independent of baseline disease indicators (eg, Expanded Disability Status Scale score). On natalizumab, the ARR decreased by 91.5% after 15 years, relative to the year before baseline. At 15.5 years, cumulative probabilities of 24-week confirmed disability progression and improvement were 48.5% and 38.8%, respectively. Long-term natalizumab treatment significantly decreased ARR compared with short-term treatment. Switching from intravenous to SC formulation did not affect ARR after 1 year post-switch. The cumulative probability of converting to non-active SPMS was significantly lower in patients remaining on natalizumab compared with those who discontinued (0.22 vs 0.29, respectively).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Follow-up of over 15 years did not reveal new safety concerns and confirmed sustained real-world effectiveness of natalizumab in patients with RRMS (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT00493298\">NCT00493298<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jnnp-2025-337367","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T17:20:27Z","timestamp":1776360027000},"page":"591-599","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Tysabri Observational Program (TOP): long-term safety and effectiveness of natalizumab treatment in relapsing-remitting multiple sclerosis over 15 years"],"prefix":"10.1136","volume":"97","clinical-trial-number":[{"clinical-trial-number":"nct00493298","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Helmut","family":"Butzkueven","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Central Clinical School, Monash University Central Clinical School, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4175-5509","authenticated-orcid":false,"given":"Ludwig","family":"Kappos","sequence":"additional","affiliation":[{"name":"Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz","family":"Wiendl","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurophysiology, Medical Center, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Trojano","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neurosciences, University of Bari Aldo Moro, Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Spelman","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Central Clinical School, The Alfred, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Greco","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaonan","family":"Sun","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7401-1463","authenticated-orcid":false,"given":"Tyler","family":"Lasky","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"2026102807301010000_97.7.591.1","unstructured":"Tysabri [package insert]. Cambridge, MA: Biogen, Inc, 2023."},{"key":"2026102807301010000_97.7.591.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa044397"},{"key":"2026102807301010000_97.7.591.3","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.clineuro.2016.07.001","article-title":"Effectiveness and safety of natalizumab in real-world clinical practice: review of observational studies","volume":"149","author":"van Pesch","year":"2016","journal-title":"Clin Neurol Neurosurg"},{"key":"2026102807301010000_97.7.591.4","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2019-322326"},{"key":"2026102807301010000_97.7.591.5","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2013-306936"},{"key":"2026102807301010000_97.7.591.6","unstructured":"Spelman T , Kappos L , Butzkueven H , et al . Comparably low disease activity during natalizumab treatment in patients who remained on or who later discontinued natalizumab suggests limited attrition bias in the Tysabri Observational Program. Presented at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); September 11\u201313, 2019, Stockholm, Sweden."},{"key":"2026102807301010000_97.7.591.7","doi-asserted-by":"crossref","unstructured":"Kappos L , Butzkueven H , Trojano M , et al . Conversion to non-active secondary progressive multiple sclerosis (SPMS) in Patients Who Discontinued or Remained on Natalizumab in the Real-World TYSABRI Observational Program (TOP) (2505). Neurology 2021;96. doi:10.1212\/WNL.96.15_supplement.2505","DOI":"10.1212\/WNL.96.15_supplement.2505"},{"key":"2026102807301010000_97.7.591.8","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1177\/1352458520926869","article-title":"Real-world disability improvement in patients with relapsing-remitting multiple sclerosis treated with natalizumab in the Tysabri Observational Program","volume":"27","author":"Wiendl","year":"2021","journal-title":"Mult Scler"},{"key":"2026102807301010000_97.7.591.9","unstructured":"Kobelt G , Trojano M , Spelman T , et al . Improved or maintained employment status in natalizumab-treated relapsing-remitting multiple sclerosis patients in the Tysabri Observational Program. 8th Joint ACTRIMS ECTRIMS Meeting Virtual; 2020"},{"key":"2026102807301010000_97.7.591.10","doi-asserted-by":"crossref","first-page":"17562864211042458","DOI":"10.1177\/17562864211042458","article-title":"No evidence for loss of natalizumab effectiveness with every-6-week dosing: a propensity score\u2013matched comparison with every-4-week dosing in patients enrolled in the Tysabri Observational Program (TOP)","volume":"14","author":"Butzkueven","year":"2021","journal-title":"Ther Adv Neurol Disord"},{"key":"2026102807301010000_97.7.591.11","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1177\/1352458520917925","article-title":"Clinical outcomes in patients who discontinue natalizumab therapy after 2 years in the Tysabri Observational Program (TOP)","volume":"27","author":"Butzkueven","year":"2021","journal-title":"Mult Scler"},{"key":"2026102807301010000_97.7.591.12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.msard.2018.04.020","article-title":"Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting","volume":"24","author":"Trojano","year":"2018","journal-title":"Mult Scler Relat Disord"},{"key":"2026102807301010000_97.7.591.13","unstructured":"Tysabri: EPAR \u2013 product information. Biogen Netherlands B.V, 2024."},{"key":"2026102807301010000_97.7.591.14","unstructured":"Kappos L , Trojano M , Butzkueven H , et al . Tysabri Observational Program: intravenous to subcutaneous natalizumab efficacy and safety switch analysis. Presented at the 10th Congress of the European Academy of Neurology; 2024, Helsinki, Finland."},{"key":"2026102807301010000_97.7.591.15","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww173"},{"key":"2026102807301010000_97.7.591.16","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1177\/13524585221125382","article-title":"Recurrent disability progression endpoints in multiple sclerosis clinical trials","volume":"29","author":"B\u00fchler","year":"2023","journal-title":"Mult Scler"},{"key":"2026102807301010000_97.7.591.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa044396"},{"key":"2026102807301010000_97.7.591.18","unstructured":"Ferlay J , Ervik M , Lam F , et al . Global Cancer Observatory: cancer today. Lyon, France: International Agency for Research on Cancer, Available: https:\/\/gco.iarc.who.int\/today"},{"key":"2026102807301010000_97.7.591.19","unstructured":"National Cancer Institute . Age and cancer risk. Available: https:\/\/www.cancer.gov\/about-cancer\/causes-prevention\/risk\/age [Accessed 16 Apr 2025]."}],"container-title":["Journal of Neurology, Neurosurgery &amp; Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jnnp-2025-337367","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:31:39Z","timestamp":1793197899000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnnp.bmj.com\/lookup\/doi\/10.1136\/jnnp-2025-337367"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":19,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,6,12]]},"published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1136\/jnnp-2025-337367"],"URL":"https:\/\/doi.org\/10.1136\/jnnp-2025-337367","relation":{},"ISSN":["0022-3050","1468-330X"],"issn-type":[{"value":"0022-3050","type":"print"},{"value":"1468-330X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]}}}