Authors' objectives: Multiple sclerosis is an immune-mediated inflammatory disease, causing long-term disability in young adults. Most cases begin as relapsing–remitting multiple sclerosis. Some people have a form of relapsing–remitting multiple sclerosis known as highly active relapsing–remitting multiple sclerosis, defined as multiple sclerosis with unchanged or increased disease activity despite prior treatment with at least one disease-modifying therapy. To appraise the clinical and cost-effectiveness of natalizumab [Tysabri® (Biogen, Cambridge, MA, USA)] and natalizumab biosimilar [Tyruko® (Sandoz)] for treating highly active relapsing–remitting multiple sclerosis compared to other disease-modifying therapy. Multiple sclerosis (MS) is a chronic autoimmune condition that affects the central nervous system, usually starting in early adulthood and often causing long-term disability in young adults. Symptoms can vary but commonly include fatigue, muscle weakness, vision problems and cognitive issues. In the UK, around 130 in every 100,000 people are affected. Most cases (85–90%) begin as relapsing–remitting multiple sclerosis (RRMS), with periods of relapses and remissions, which can later progress to secondary progressive multiple sclerosis (SPMS). A smaller group have primary progressive multiple sclerosis from the start. RRMS can be further categorised based on disease activity. Highly active relapsing–remitting multiple sclerosis (HARRMS), the focus of this appraisal, is broadly defined as MS with unchanged or increased disease activity – clinically or radiologically – despite prior treatment with at least one disease-modifying therapy (DMT). Management typically includes multidisciplinary care and DMTs to reduce relapses and slow progression. The overall aim was to appraise the clinical and cost-effectiveness of natalizumab (Tysabri) and natalizumab biosimilar (Tyruko) within their marketing authorisations for treating HARRMS after at least one DMT.

Authors' results and conclusions: We included 42 studies (22,409 participants): 40 in people with relapsing–remitting multiple sclerosis and 2 in highly active relapsing–remitting multiple sclerosis. Six studies also reported data separately for highly active relapsing–remitting multiple sclerosis. Only four studies evaluated natalizumab or natalizumab biosimilar; none provided data on those with highly active relapsing–remitting multiple sclerosis. Follow-up ranged from 4 to 36 (median 24) months. 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)]. Data in highly active relapsing–remitting 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–remitting multiple sclerosis. All interventions except interferon beta-1a were associated with reduced relapse risk compared to placebo (six studies; seven interventions). Compared with natalizumab-intravenous, natalizumab biosimilar-intravenous and natalizumab subcutaneous, all treatments had greater net benefit at £20,000–30,000/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. There is no direct evidence on the effectiveness of natalizumab or its biosimilar in patients with highly active relapsing–remitting multiple sclerosis. Limited data suggest similar effectiveness in patients with relapsing–remitting 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–remitting multiple sclerosis, with similar quality-adjusted life-years but higher costs, with the only exception being ocrelizumab. We included 42 studies (22,409 participants): 40 reported data for a general RRMS population and 2 were conducted in HARRMS. Six studies reported data separately for those with HARRMS. Only four studies evaluated natalizumab or natalizumab biosimilar, the technologies of interest for this appraisal; none provided data on those with HARRMS. AHSCT was only evaluated in people with HARRMS. General relapsing–remitting multiple sclerosis population All studies were considered to be sufficiently similar for inclusion in the NMAs. The fixed-effects model gave the best fit to the data with little evidence of heterogeneity for all outcomes. There is no direct evidence on the effectiveness of natalizumab or its biosimilar in patients with highly active disease. Limited data indicate that both treatments show similar effectiveness in patients with RRMS. Comparisons of DMT effectiveness in people with highly active disease and general RRMS suggest that DMTs are at least as effective in the highly active population, although this is based on sparse data. Assuming natalizumab and its biosimilar follow this trend, they may also be effective in this group. However, trials specifically targeting this population are needed to confirm these assumptions. The economic model used evidence on treatment effects in the general RRMS population and baseline rates in HARRMS. Natalizumab i.v., natalizumab biosimilar i.v. and natalizumab s.c. were not cost-effective compared to any of the included comparators in HARRMS, with similar QALYs but higher costs, with the only exception being ocrelizumab. The greatest decision uncertainty was found in the treatment effects, again supporting the need for trials targeting this population.

Authors' methods: Systematic review with network meta-analysis and economic model. Searches last updated in April 2024. Clinical effectiveness review We conducted a systematic literature review (SLR) with network meta-analysis (NMA). As we did not expect to find many randomised controlled trials (RCTs) in people with HARRMS, we broadened inclusion to people with RRMS. We included RCTs that compared one of the interventions (natalizumab or natalizumab biosimilar) or comparators of interest [glatiramer acetate, interferon beta (IFNB)-1a, IFNB-1b, peginterferon beta-1a, alemtuzumab, cladribine tablets, fingolimod, ocrelizumab, ofatumumab, ponesimod and autologous haematopoietic stem cell treatment (AHSCT)] to each other or to placebo. We searched MEDical Literature Analysis and Retrieval System (MEDLINE), Excerpta Medica dataBASE (EMBASE) and trial registries from inception to April 2024. We screened existing relevant technology appraisals (TAs), SLRs and submissions from manufacturers of natalizumab and natalizumab biosimilar. Title and abstract screening and assessment of full-text papers were conducted by two reviewers independently. Data extraction and risk-of-bias (ROB) assessment were performed by one reviewer and checked by a second. ROB was assessed with the RoB-2 tool at the outcome level. We extracted and synthesised data on the following outcomes: annualised relapse rate (ARR) disability progression confirmed at 3 and 6 months (CDP3 and CDP6) MRI measurements (proportion of participants with gadolinium enhancing (Gd+) or new or enlarging T2 lesions) adverse effects (AEs) of treatment (any AEs, treatment-related AEs, serious adverse events (SAEs), AEs leading to treatment discontinuation) health-related quality of life assessed using the EuroQol-5 Dimensions (EQ-5D) or Short Form questionnaire-36 items (SF-36) scales. For each outcome, we provided a narrative summary of study details, ROB, and results. Bayesian random- and fixed-effects NMA was performed to compare the efficacy and safety of treatment options using the available trial information. Most treatments were not compared in head-to-head RCTs, and NMA allowed for the use of indirect information to make that comparison. We selected the model (random vs. fixed-effects) that provided the best fit to the data. We presented results as comparisons of each intervention in the network with placebo, mean ranking of each intervention, probability that each intervention would rank first or in specific positions, and a pairwise comparison of each intervention included in the network. Bayesian 95% credible intervals (CrI) were used to represent uncertainty. We used the R (The R Foundation for Statistical Computing, Vienna, Austria) package ‘multinma’ for all analyses.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR165943

Year Published: 2026

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/GJHT1811

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/GJHT1811

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk