{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T17:37:50Z","timestamp":1786469870046,"version":"build-2736575974"},"reference-count":336,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["NIHR165943"],"award-info":[{"award-number":["NIHR165943"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"\n Background<\/jats:title>\n Multiple sclerosis is an immune-mediated inflammatory disease, causing long-term disability in young adults. Most cases begin as relapsing\u2013remitting multiple sclerosis. Some people have a form of relapsing\u2013remitting multiple sclerosis known as highly active relapsing\u2013remitting multiple sclerosis, defined as multiple sclerosis with unchanged or increased disease activity despite prior treatment with at least one disease-modifying therapy.<\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n \n To appraise the clinical and cost-effectiveness of natalizumab [Tysabri\n \u00ae<\/jats:sup>\n (Biogen, Cambridge, MA, USA)] and natalizumab biosimilar [Tyruko\n \u00ae<\/jats:sup>\n (Sandoz)] for treating highly active relapsing\u2013remitting multiple sclerosis compared to other disease-modifying therapy.\n <\/jats:p>\n <\/jats:sec>\n \n Design<\/jats:title>\n Systematic review with network meta-analysis and economic model. Searches last updated in April 2024.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n We included 42 studies (22,409 participants): 40 in people with relapsing\u2013remitting multiple sclerosis and 2 in highly active relapsing\u2013remitting multiple sclerosis. Six studies also reported data separately for highly active relapsing\u2013remitting multiple sclerosis. Only four studies evaluated natalizumab or natalizumab biosimilar; none provided data on those with highly active relapsing\u2013remitting multiple sclerosis. Follow-up ranged from 4 to 36 (median 24) months.<\/jats:p>\n Most interventions reduced relapses (39 studies, 17 interventions) and magnetic resonance imaging lesions (19 studies, 11 interventions for gadolinium enhancing lesions and 17 studies, 12 interventions for T2-weighted lesions) compared to placebo. Alemtuzumab, ocrelizumab, cladribine, natalizumab, fingolimod and peginterferon beta-1a reduced disease progression compared to placebo (15 studies, 12 interventions). There were no differences in any adverse events (24 studies, 16 interventions), serious adverse events (31 studies, 15 interventions) or treatment-related adverse events (8 studies, no network meta-analysis) for any intervention compared to placebo. Fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b and peginterferon beta-1a were associated with an increased treatment discontinuation (29 studies, 13 interventions). There was little evidence for a difference in quality of life. There was no evidence of a difference between natalizumab and natalizumab biosimilar for relapse rates [rate ratio 0.65 (95% credible interval 0.33 to 1.23], gadolinium enhancing lesions [hazard ratio 1.29 (0.69 to 2.37)], T2-weighted lesions [hazard ratio 1.07 (0.73 to 1.57)], any adverse events [hazard ratio 1.06 (0.77 to 1.46)] or treatment discontinuation [hazard ratio 0.48 (0.13 to 1.76)].<\/jats:p>\n Data in highly active relapsing\u2013remitting multiple sclerosis were available for fingolimod, ocrelizumab, alemtuzumab, cladribine, interferon beta, autologous haematopoietic stem cell treatment and placebo. We also included one study on natalizumab conducted in a population that was close to our definition of highly active relapsing\u2013remitting multiple sclerosis. All interventions except interferon beta-1a were associated with reduced relapse risk compared to placebo (six studies; seven interventions).<\/jats:p>\n Compared with natalizumab-intravenous, natalizumab biosimilar-intravenous and natalizumab subcutaneous, all treatments had greater net benefit at \u00a320,000\u201330,000\/quality-adjusted life-year, with the only exception being ocrelizumab, which had lower net benefits. Costs were generally higher on natalizumab than other treatments, though there was no difference in quality-adjusted life-years with 95% credible interval completely overlapping. The results and conclusions were unchanged under all sensitivities. VOI analysis found that the greatest contributor to decision uncertainty was the effectiveness of treatments.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n There is no direct evidence on the effectiveness of natalizumab or its biosimilar in patients with highly active relapsing\u2013remitting multiple sclerosis. Limited data suggest similar effectiveness in patients with relapsing\u2013remitting multiple sclerosis. The economic model found that natalizumab and natalizumab biosimilar were not cost-effective compared to any of the included comparators in highly active relapsing\u2013remitting multiple sclerosis, with similar quality-adjusted life-years but higher costs, with the only exception being ocrelizumab.<\/jats:p>\n <\/jats:sec>\n \n Future work<\/jats:title>\n There is need for studies of natalizumab and natalizumab biosimilar in people with highly active relapsing\u2013remitting multiple sclerosis.<\/jats:p>\n <\/jats:sec>\n \n Study registration<\/jats:title>\n The study is registered as PROSPERO CRD42024556838.<\/jats:p>\n <\/jats:sec>\n \n Funding<\/jats:title>\n \n This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR165943) and is published in full in\n Health Technology Assessment<\/jats:italic>\n ; Vol. 30, No. 60. See the NIHR Funding and Awards website for further award information.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3310\/gjht1811","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T11:45:27Z","timestamp":1754912727000},"page":"1-290","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Natalizumab and Tyruko (natalizumab biosimilar) for treating highly active relapsing-remitting multiple sclerosis after at least one disease-modifying therapy: a systematic review and economic model"],"prefix":"10.3310","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8883-0167","authenticated-orcid":true,"given":"Catalina Lopez","family":"Manzano","sequence":"first","affiliation":[{"name":"Bristol Technology Assessment Group, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, 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