A Pilot Study to Characterize the Biological Effect of a Pre-planned 12 Week Dose Interruption of Natalizumab

Summary

This is an open-label study of patients with relapsing forms of MS is designed to assess the biochemical, immunological, and kinetic profiles of natalizumab being used with specific brief dosing interruption. The study will be conducted at one site in the US. Ten subjects currently treated with natalizumab will be enrolled and will be evaluated for both PK/PD and cell trafficking in blood and/or CSF during standard dosing of natalizumab and at the end of a planned 12-week dosing interruption. MS disease activity will be carefully monitored clinically and by MRI and NfL.

Timeline

Start

2019-07-03

Primary completion

2021-11-01

Completion

2021-12-01

Publications

• Background Berkovich R, Togasaki DM, Cen SY, Steinman L. CD4 cell response to interval therapy with natalizumab. Ann Clin Transl Neurol. 2015 May;2(5):570-4. doi: 10.1002/acn3.190. Epub 2015 Mar 6.
• Background Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870-80. doi: 10.1056/NEJMoa1107829.
• Background Disanto G, Barro C, Benkert P, Naegelin Y, Schadelin S, Giardiello A, Zecca C, Blennow K, Zetterberg H, Leppert D, Kappos L, Gobbi C, Kuhle J; Swiss Multiple Sclerosis Cohort Study Group. Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017 Jun;81(6):857-870. doi: 10.1002/ana.24954.
• Background Foley J, Zhovtis Ryerson L, Chang I, Kister I, Cutter G, Metzger R, Goldberg JD, Li X, Riddle E, Kasliwal R, Ren Z, Hotermans C, Ho PR, Campbell N. Progressive multifocal leukoencephalopathy occurring with extended interval dosing of natalizumab: Analysis of cases in the TOUCH database. CMSC 2018; 5698.
• Background Foley J, Metzger R, Hoyt T, Christensen A. Optimizing the natalizumab dose interval to reduce PML risk - lessons from the pharmacokinetics of therapy discontinuation. AAN 2015; P4.032.
• Background Ho PR, Koendgen H, Campbell N, Haddock B, Richman S, Chang I. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017 Nov;16(11):925-933. doi: 10.1016/S1474-4422(17)30282-X. Epub 2017 Sep 29.
• Background Khatri BO, Man S, Giovannoni G, Koo AP, Lee JC, Tucky B, Lynn F, Jurgensen S, Woodworth J, Goelz S, Duda PW, Panzara MA, Ransohoff RM, Fox RJ. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009 Feb 3;72(5):402-9. doi: 10.1212/01.wnl.0000341766.59028.9d.
• Background Kuhle J, Kropshofer H, Haering DA, Kundu U, Meinert R, Barro C, Dahlke F, Tomic D, Leppert D, Kappos L. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology. 2019 Mar 5;92(10):e1007-e1015. doi: 10.1212/WNL.0000000000007032. Epub 2019 Feb 8.
• Background Novakova L, Zetterberg H, Sundstrom P, Axelsson M, Khademi M, Gunnarsson M, Malmestrom C, Svenningsson A, Olsson T, Piehl F, Blennow K, Lycke J. Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology. 2017 Nov 28;89(22):2230-2237. doi: 10.1212/WNL.0000000000004683. Epub 2017 Oct 27.
• Background Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain B, Campagnolo D, Belachew S, Ticho B. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014 Dec;76(6):802-12. doi: 10.1002/ana.24286. Epub 2014 Oct 24.
• Background Plavina T, Muralidharan KK, Kuesters G, Mikol D, Evans K, Subramanyam M, Nestorov I, Chen Y, Dong Q, Ho PR, Amarante D, Adams A, De Seze J, Fox R, Gold R, Jeffery D, Kappos L, Montalban X, Weinstock-Guttman B, Hartung HP, Cree BAC. Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients. Neurology. 2017 Oct 10;89(15):1584-1593. doi: 10.1212/WNL.0000000000004485. Epub 2017 Sep 15.
• Background Zhovtis Ryerson L, Foley J, Chang I, Kister I, Cutter G, Metzger R, Goldberg JD, Li X, Riddle E, Yu B, Ren Z, Hotermans C, Ho PR, Campbell N. Natalizumab extended interval dosing is associated with a reduction in progressive multifocal leukoencephalopathy risk in the TOUCH registry. ACTRIMS 2018; LB250.
• Background Zhovtis Ryerson L, Frohman TC, Foley J, Kister I, Weinstock-Guttman B, Tornatore C, Pandey K, Donnelly S, Pawate S, Bomprezzi R, Smith D, Kolb C, Qureshi S, Okuda D, Kalina J, Rimler Z, Green R, Monson N, Hoyt T, Bradshaw M, Fallon J, Chamot E, Bucello M, Beh S, Cutter G, Major E, Herbert J, Frohman EM. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):885-9. doi: 10.1136/jnnp-2015-312940. Epub 2016 Feb 25.
• Berkovich R, Schneider-Hohendorf T, Baetscher E, Riddle EL, Deffner M, Katsnelson E, Ferrant-Orgettas J, Czerkowicz J, Anderson J, Goelz SE, Schwab N. Annual 12-Week Dosing Gap of Natalizumab: Clinical Efficacy, Blood Biomarkers, and CSF Cell Composition. Ann Clin Transl Neurol. 2026 Jan;13(1):85-96. doi: 10.1002/acn3.70207. Epub 2025 Sep 23.

Drugs

Indications