Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and sixty patients were enrolled. Median dose interval (MDI) following 24th infusion was 4.7 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Two hundred and sixteen patients were in the SID group (MDI = 4.3 weeks) and 144 in the EID group (MDI 6.2 weeks). Annualized relapse rate was 0.060 (95% CI = 0.033–0.087) in the SID group and 0.039 (95% CI = 0.017–0.063) in the EID group. The non-inferiority of EID versus SID was satisfied. In conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting. This observation confirms previous results and together with the emerging evidence of a reduced risk of PML associated to an EID, supports the need of a randomized study to assess the need to change the standard of the natalizumab dosing schedule.
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Stüve O, Bennett JL. Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri®) in inflammatory diseases. CNS Drug Rev. 2007 Spring;13(1):79–95.
Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16510744. Accessed 27 May 2019
Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue E-W, et al. Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis. N Engl J Med. 2006;354(9):911–23.
Sehr T, Proschmann U, Thomas K, Marggraf M, Straube E, Reichmann H, et al. New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies. J Neuroinflammation. 2016;13(1):164. https://doi.org/10.1186/s12974-016-0635-2
Kleinschmidt-DeMasters BK, Tyler KL. Progressive Multifocal Leukoencephalopathy Complicating Treatment with Natalizumab and Interferon Beta-1a for Multiple Sclerosis. N Engl J Med 2005;353(4):369–74.
Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353(4):375–81.
Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010;9:425–37.
Rudick RA, Sandrock A. Natalizumab: α4-integrin antagonist selective adhesion molecule inhibitors for MS. Vol. 4, Expert Review of Neurotherapeutics. 2004. p. 571–80.
Khatri BO, Man S, Giovannoni G, Koo AP, Lee JC, Tucky B, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402–9.
Cofield SS, Salter A, Tyry T, Crowe C, Cutter GR, Fox RJ, et al. Perspectives on marijuana use and effectiveness: A survey of NARCOMS participants. Neurol Clin Pract. 2017;7(4):333–343. https://doi.org/10.1212/CPJ.0000000000000383
Rispens T, Vennegoor A, Wolbink GJ, Polman CH, Killestein J. Natalizumab remains detectable in patients with multiple sclerosis long after treatment is stopped. Mult Scler. 2012;18(16):899–901. https://doi.org/10.1177/1352458511431073
Wipfler P, Harrer A, Pilz G, Oppermann K, Afazel S, Haschke-Becher E, et al. Natalizumab saturation: Biomarker for individual treatment holiday after natalizumab withdrawal? Acta Neurol Scand. 2014;129(3):e12–5. https://doi.org/10.1111/ane.12182
van Kempen ZLE, Leurs CE, Witte BI, de Vries A, Wattjes MP, Rispens T, et al. The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing. Mult Scler. 2018;24(6):805–810. https://doi.org/10.1177/1352458517708464
Tan IL, McArthur JC, Clifford DB, Major EO, Nath A. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology. 2011;77(11):1061–7.
Zhovtis Ryerson L, Frohman TC, Foley J, Kister I, Weinstock-Guttman B, Tornatore C, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016;1–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26917698. Accessed 27 May 2019
Fox RJ, Cree BAC, De Sèze J, Gold R, Hartung HP, Jeffery D, et al. MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study. Neurology. 2014;82(17):1491–8.
Harrer A, Pilz G, Einhaeupl M, Oppermann K, Hitzl W, Wipfler P, et al. Lymphocyte subsets show different response patterns to in vivo bound natalizumab-a flow cytometric study on patients with multiple sclerosis. PLoS One. 2012;7(2):e31784. https://doi.org/10.1371/journal.pone.0031784
European Medicines Agency. European Medicines Agency recommends additional measures to better manage risk of progressive multifocal leukoencephalopathy (PML) with Tysabri [Internet]. [cited 2018 Jun 16]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/01/news_detail_000987.jsp&mid=WC0b01ac058004d5c1
Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, et al. Natalizumab treatment for multiple sclerosis: Updated recommendations for patient selection and monitoring. Lancet Neurol 2011;10(8):745–58. https://doi.org/10.1016/S1474-4422(11)70149-1
Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. N Engl J Med. 2012;366(20):1870–80. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMoa1107829. Accessed 27 May 2019
Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: A two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227–31. https://doi.org/10.1177/1756285614540224
Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018;17(2):162–73.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52.
Lucchetta RC, Tonin FS, Borba HHL, Leonart LP, Ferreira VL, Bonetti AF, et al. Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: A Network Meta-Analysis. CNS Drugs. 2018. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30014314. Accessed 27 May 2019
Sørensen PS, Bertolotto A, Edan G, Giovannoni G, Gold R, Havrdova E, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 2012;18(2):143–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22312009. Accessed 27 May 2019
EMA confirms recommendations to minimise risk of brain infection PML with Tysabri - EMA/137488/2016.
O’Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011;76(22):1858–65.
Berger JR, Centonze D, Comi G, Confavreux C, Cutter G, Giovannoni G, et al. Considerations on discontinuing natalizumab for the treatment of multiple sclerosis. Ann Neurol 2010;68(3):409–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20818795
Papeix C, Vukusic S, Casey R, Debard N, Stankoff B, Mrejen S, et al. Risk of relapse after natalizumab withdrawal: Results from the French TYSEDMUS cohort. Neurol Neuroimmunol Neuroinflammation 2016;3(6):e297. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27844037
González-Suarez I, Rodríguez de Antonio L, Orviz A, Moreno-García S, Valle-Arcos MD, Matias-Guiu JA, et al. Catastrophic outcome of patients with a rebound after Natalizumab treatment discontinuation. Brain Behav 2017;7(4):1–6.
Clerico M, Schiavetti I, De Mercanti SF, Piazza F, Gned D, Brescia Morra V, et al. Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab: Evidence From an Italian Spontaneous, Prospective, and Observational Study (the TY-STOP Study). JAMA Neurol 2014;71(8):954–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24977406
Van Kempen ZLE, Leurs CE, Vennegoor A, Wattjes MP, Rispens T, Uitdehaag BMJ, et al. Natalizumab-associated progressive multifocal leukoencephalopathy is not preceded by elevated drug concentrations. Mult Scler J. 2017;23(7):995–999. https://doi.org/10.1177/1352458516684023
Zhovtis, Ryerson L, Foley J CIKICGMRGJLXREYBRZHCHP-RCN. Natalizumab Extended Interval Dosing (EID) Is Associated with a Significant Reduction in Progressive Multifocal Leukoencephalopathy (PML) Risk Compared with Standard Interval Dosing (SID): Analyses of TOUCH® Prescribing Program Data. In: American Academy of Neurology. 2018.
Sorensen PS, Koch-Henriksen N, Petersen T, Ravnborg M, Oturai A, Sellebjerg F. Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients. J Neurol . 2014;261(6):1170–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24728334
A Study to Evaluate Efficacy, Safety, and Tolerability of 6-Week Extended Interval Dosing of Natalizumab (BG00002) in Participants With Relapsing-Remitting Multiple Sclerosis (RRMS) Switching From Treatment With 4-Week Natalizumab Standard Interval Dosing [Internet]. [cited 2019 Jul 30]. Available from: https://clinicaltrials.gov/ct2/show/NCT03689972?term=NCT03689972&rank=1
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Clerico, M., De Mercanti, S.F., Signori, A. et al. Extending the Interval of Natalizumab Dosing: Is Efficacy Preserved?. Neurotherapeutics 17, 200–207 (2020). https://doi.org/10.1007/s13311-019-00776-7
- Multiple sclerosis
- extended dose
- progressive multifocal leukoencephalopathy