Effectiveness of natalizumab extended interval dosing in multiple sclerosis patients

Czech version

Authors: M. Petržalka; E. Meluzínová; H. Mojžíšová; J. Libertínová; P. Ročková; E. Němá; M. Elišák; P. Marusič
Authors‘ workplace: Neurologická klinika 2. LF UK a FN Motol, Praha
Published in: Cesk Slov Neurol N 2020; 83(1): 79-83
Category: Original Paper
doi: https://doi.org/10.14735/amcsnn202079

Overview

Aim: Natalizumab is a highly effective drug used in the treatment of multiple sclerosis, but it is also often associated with a risk of inducing progressive multifocal leukoencephalopathy. In order to minimalize this risk, extended interval dosing has been proposed. The aim of this study was to assess possible consequences of extended interval dosing on the effectivity of the treatment.

Patients and methods: We conducted a retrospective analysis of all patients treated with natalizumab using a 6-week interval dosing schedule at the Centre for Diagnostics and Treatment of Demyelinating Disorders at Motol University Hospital. Only patients pre-treated for at least 1 year with a standard 4-week interval schedule, and then treated for at least 1 year with 6-week interval schedule were enrolled. The reasons to switch to an extended interval dosing were either a high risk of progressive multifocal leukoencephalopathy or long-term clinical stabilization on natalizumab.

Results: Overall, 25 patients were enrolled in this study. Data were collected for the periods before and after switching to 6-week interval dosing. The average analyzed period was 3.8 ± 1.9 years (for both dosing regimens altogether). The average annualized relapse rate in 4-week and 6-week interval periods was 0.073 ± 0.209 and 0.074 ± 0.178, resp. (P = 1.0000). The average new yearly MRI activity in 4-week and 6-week interval periods was 0.29 ± 0.40 and 0.16 ± 0.33, resp. (P = 0.1250). The average Expanded Disability Status Scale score in 4-week and 6-week interval periods was 2.29 ± 0.90 and 2.16 ± 0.88, resp. (P = 0.0127). There was one case of progressive multifocal leukoencephalopathy recorded in the 6-week interval group; none occurred in the 4-week interval group.

Conclusions: In the population of patients treated with natalizumab at our centre, we did not prove that 6-week interval dosing was less effective compared to the standard 4-week interval dosing.

Keywords:

Multiple sclerosis – natalizumab – extended dosing interval

Sources

1. Rice GP, Hartung HP, Calabresi PA. Anti-α4 integrin therapy for multiple sclerosis – mechanisms and rationale. Neurology 2005; 64(8): 1336–1342. doi: 10.1212/ 01.wnl.0000158329.30470.d0.

2. Yousry TA, Major EO, Ryschkewitsch C et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354(9): 924–933. doi: 10.1056/ NEJMoa054693.

3. Engelhardt B. α4-integrins: structure, function and secrets. In: Ley K (ed). Adhesion molecules: function and inhibition. Basel: Birkhäuser 2007: 117–139.

4. Carlos T, Schwartz B, Kovach N et al. Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood 1990; 76(5): 965–970.

5. Erle DJ, Briskin MJ, Butcher EC et al. Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. J Immunol 1994; 153(2): 517–528.

6. Bayless KJ, Meininger GA, Scholtz JM et al. Osteopontin is a ligand for the alpha4beta1 integrin. J Cell Sci 1998; 111(9): 1165–1174.

7. Guan JL, Hynes RO. Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha 4 beta 1. Cell 1990; 60(1): 53–61. doi: 10.1016/ 0092-8674(90)90715-Q.

8. Polman CH, O‘Connor PW, Havrdova E et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354(9): 899–910. doi: 10.1056/ NEJMoa044397.

9. Yednock TA, Cannon C, Fritz LC et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin. Nature 1992; 356(6364): 63–66. doi: 10.1038/ 356063a0.

10. van Pesch V, Sindic CJ, Fernández O. Effectiveness and safety of natalizumab in real-world clinical practice: review of observational studies. Clin Neurol Neurosurg 2016; 149: 55–63. doi: 10.1016/ j.clineuro.2016.07.001.

11. Major EO, Yousry TA, Clifford DB. Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned. Lancet Neurol 2018; 17(5): 467–480. doi: 10.1016/ S1474-4422(18)30040-1.

12. Frohman EM, Monaco MC, Remington G et al. JC Virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. JAMA Neurol 2014; 71(5): 596–602. doi: 10.1001/ jamaneurol.2014.63.

13. Bellizzi A, Anzivino E, Rodio DM et al. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013; 2013: 839719-19. doi: 10.1155/ 2013/ 839719.

14. Bloomgren G, Richman S, Hotermans C et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366(20): 1870–1880. doi: 10.1056/ NEJMoa1107829.

15. Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord 2014; 7(5): 227–231. doi: 10.1177/ 1756285614540224.

16. Yamout BI, Sahraian MA, Ayoubi NE et al. Efficacy and safety of natalizumab extended interval dosing. Mult Scler Relat Disord 2018; 24: 113–116. doi: 10.1016/ j.msard.2018.06.015.

17. Puñet-Ortiz J, Hervás-García JV, Teniente-Serra A et al. Monitoring CD49d receptor occupancy: a method to optimize and personalize natalizumab therapy in multiple sclerosis patients. Cytometry B Clin Cytom 2018; 94(2): 327–333. doi: 10.1002/ cyto.b.21527.

18. Zhovtis Ryerson L, Frohman TC, Foley J et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016; 87(8): 885–889. doi: 10.1136/ jnnp-2015-312940.

19. Brainin M, Barnes M, Baron JC et al. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2004. Eur J Neurol 2004; 11(9): 577–581. doi: 10.1111/ j.1468-1331.2004.00867.x.

20. Miller DH, Khan OA, Sheremata WA et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003(348): 15–23. doi: 10.1056/ NEJMoa020696.

21. Khatri BO, Man S, Giovannoni G et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009; 72(5): 402–409. doi: 10.1212/ 01.wnl.0000341766.59028.9d.

22. Rispens T, Vennegoor A, Wolbink GJ et al. Natalizumab remains detectable in patients with multiple sclerosis long after treatment is stopped. Mult Scler 2011; 18(6): 899–901. doi: 10.1177/ 1352458511431073.

23. Stüve O, Marra CM, Jerome KR et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006; 59(5): 743–747. doi: 10.1002/ ana.20858.

24. Foley JF, Goelz S, Hoyt T et al. Evaluation of natalizumab pharmacokinetics and pharmacodynamics with standard and extended interval dosing. Mult Scler Relat Disord 2019; 31: 65–71. doi: 10.1016/ j.msard.2019.03.017.

25. Niino M, Bodner C, Simard ML et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 2006; 59(5): 748–754. doi: 10.1002/ ana.20859.

26. Zhovtis Ryerson L, Foley J, Chang I et al. Reduced risk of progressive multifocal leukoencephalopathy (PML) associated with natalizumab extended interval dosing (EID): updated analysis of the TOUCH Prescribing Program database (S26.006) [abstract]. Neurology 2019; 92 (15 Suppl): S26.006.

27. Kubala Havrdová E. Osobní sdělění: 19. Jedličkovy neuroimunologické a likvorologické dny. Praha 24. 5. 2019.

28. Wipfler P, Harrer A, Pilz G et al. Natalizumab saturation: biomarker for individual treatment holiday after natalizumab withdrawal? Acta Neurol Scand 2014; 129(3): e12–e15. doi: 10.1111/ ane.12182.