Personalized Extended Interval Dosing of Natalizumab in Relapsing Remitting Multiple Sclerosis

Summary

Rationale: Natalizumab is an effective drug in the treatment for relapsing remitting multiple sclerosis (RRMS) and is approved by de FDA/EMA in a treatment regimen of 4-weekly 300mg natalizumab infusions. Natalizumab trough concentrations after a 4-weekly interval are high in the large majority of patients which implies a relative overdose in most patients. A recent randomized controlled trial (RCT) suggests natalizumab maintains a high level of effi-cacy in stable patients with RRMS switching to a 6 week interval. Our study group demon-strated that efficacy of natalizumab is maintained when the infusion interval is extended based on natalizumab trough concentrations (personalized extended interval dosing). This leads to fewer hospital visits, a decrease of healthcare costs and decrease of risk of compli-cations of natalizumab treatment. Objective: Our objective is to test feasibility and validate safety of personalized extended interval dosing of natalizumab starting from 6 weeks in a large real-life cohort across the Netherlands. Study design: Prospective national phase IV natalizumab cohort study. Study population: All patients, aged 18 years or older, who are currently treated with natalizumab in the Netherlands for RRMS, with a minimum of 6 consecutive infusions. Intervention: All patients currently included in the NEXT-MS trial will receive an adjusted personalized extended interval dosing treatment regimen of natalizumab based on natalizumab concentrations starting from an infusion interval of 6 weeks. Main study parameters/endpoints: Our main study endpoint is the safety (defined by radiological disease activity) of personalized natalizumab dosing in a large real-life cohort across the Netherlands. Data will be collected regarding disease activity and disability progression. A cost analysis will be performed to show the extent of cost reduction. Patients will be annually followed to assess the influence of personalized dosing on JC virus conversion, JC virus index, incidence of progressive multifocal leukoencephalopathy, treatment satisfaction and quality of life. The influence of personalized dosing on pharmacokinetics will be monitored.

Timeline

Start

2020-02-03

Primary completion

2025-03-01

Completion

2025-03-01

Publications

• Background Foley JF, Defer G, Ryerson LZ, Cohen JA, Arnold DL, Butzkueven H, Cutter G, Giovannoni G, Killestein J, Wiendl H, Smirnakis K, Xiao S, Kong G, Kuhelj R, Campbell N; NOVA study investigators. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 Jul;21(7):608-619. doi: 10.1016/S1474-4422(22)00143-0. Epub 2022 Apr 25.
• Toorop AA, van Lierop ZY, Gelissen LM, Hoitsma E, Zeinstra EM, van Rooij LC, van Munster CE, Vennegoor A, Mostert JP, Wokke BH, Kalkers NF, Hoogervorst EL, van Eijk JJ, Roosendaal CM, Kragt JJ, Eurelings M, van Genugten J, Nielsen J, Sinnige L, Kloosterziel ME, Arnoldus EP, van Dijk GW, Bouvy WH, Wessels MH, Boonkamp L, Strijbis EM, van Oosten BW, De Jong BA, Lissenberg-Witte BI, Barkhof F, Moraal B, Teunissen CE, Rispens T, Uitdehaag BM, Killestein J, van Kempen ZL. Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS). J Neurol Neurosurg Psychiatry. 2024 Apr 12;95(5):392-400. doi: 10.1136/jnnp-2023-332119.

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