Nataliumab Benefits and Risks

Natalizumab (NTZ) is a highly efficacious treatment for relapsing multiple sclerosis (MS) that was first approved by the Food and Drug Administration (FDA) in 2004, but withdrawn from the market in 2005 after 2 people being treated with NTZ developed progressive multifocal leukoencephalopathy (PML).1-3 In 2006, NTZ was reintroduced to the market under a risk evaluation and mitigation program, the Tysabri Outreach: Unified Commitment to Health (TOUCH).4 The TOUCH program is designed to inform doctors and patients using NTZ about known risk factors for PML including JC virus (JCV) antibody status and concurrent use of antineoplastic, immunosuppressant, or immunomodulatory agents. The TOUCH program also monitors individuals for the development of PML and other serious opportunistic infections during treatment with NTZ. The TOUCH database captures all NTZ infusion records, patient demographic information, prior immunosuppressant therapy, and antiJCV antibody-status data.

Since reintroduction, NTZ has remained a highly efficacious and relevant medication option for patients with MS despite the expanded treatment algorithm.5,6

Approximately 202,300 people have been treated with NTZ for a total of 765,985 patient-years of exposure globally in the postapproval setting with overall PML incidence of 4.08 per 1,000 (95% CI, 3.80-4.36 per 1,000 patients) with 825 confirmed PML cases.7

Since the discovery of NTZ-related PML risk, significant research has been done to identify patients at high risk, with 3 factors identified: positive anti-JCV antibody status in enzyme-linked immunoassay (ELISA), prior immunosuppressive therapy, and duration of NTZ therapy for more than 24 months.8-10

Mechanism of Action

A humanized neutralizing monoclonal antibody (MAb), NTZ is directed against α4 integrin, which is expressed on T-cell surfaces and plays a crucial role in leukocyte transmigration across the endothelial barrier in the central nervous system (CNS).11 By binding to the α4 integrin subunit, NTZ inhibits T-cell association with endothelium receptors, preventing leukocyte transmigration from blood to brain. The reduced leukocyte transmigration reduces CNS inflammation in MS.

Extended Interval Dosing

Clinicians have investigated the role of altering NTZ infusion frequency to potentially reduce PML risk. This approach has become known as extended interval dosing (EID) in which NTZ infusions are given more than 4 weeks apart.12,13 The hypothesis for this approach stems from the fact that the approved treatment schedule (300 mg intravenous infusion every 4 weeks), known as standard interval dosing (SID) was selected to provide more than 80% saturation of mononuclear cell α4β1-integrin receptors for approximately 1 month after administration.14 Dosing of NTZ in the intermediate range—less frequently than every 4 weeks, but more frequently than every 10 weeks—may result in acceptable reduction of trough concentration and saturation of NTZ to maintain NTZ efficacy while reducing the risk of PML.15


Several retrospective studies have investigated the effect of EID.12,13 Although these studies are limited by nonrandomized designs, small participant populations, and variable definitions of EID, they nevertheless suggest that switching to EID after a period of SID may be efficacious.

The TOUCH database is the largest repository of information about NTZ and PML but does not capture efficacy data. The key outstanding question at this point is whether the efficacy of monthly NTZ could be maintained with less frequent dosing (eg, every 6 weeks). The NOVA triala is underway to evaluate the efficacy of NTZ EID, with results expected in 2021.

Possible Risk Reduction

Because PML is a rare event, the small studies on EID did not have sufficient statistical power to assess whether EID is associated with a PML risk reduction relative to SID.

The TOUCH program is the largest dataset of people treated with NTZ and provides sufficient power to evaluate safety information associated with alternative NTZ dosing intervals. A retrospective cohort study included data collected in the TOUCH program as of June 1, 2017, including all patients with a known positive anti-JCV antibody serostatus and a known status of prior immunosuppressant use (n=35,521). The data for PML occurrence up to June 1, 2017, from the Tysabri Global Safety Database, were used. Data from individuals who had intervals between infusions of more than 12 weeks (a dosing gap) or less than 3 weeks (overdose) were excluded.

A precise understanding of how NTZ increases PML risk or how dosing schedules might affect that risk is unknown. Thus, 3 planned analyses, each with different EID inclusion criteria, were used to evaluate the effect of EID on PML risk. The primary analysis examined PML risk in individuals who had EID vs SID in the last 18 months (n=1,988 vs n=13,132) The secondary analysis examined individuals with any EID any time during their treatment with NTZ vs those who had only SID (n=3,331 vs n=15,424). The tertiary analysis was of individuals with EID throughout treatment history vs those with SID (n=815 vs n=23,168). It is important to reiterate these definitions were designed to capture prolonged EID in a real-world database, where missed doses and infusion holidays are very common. The definitions were not aimed at identifying the best pattern of the EID schedule.

Results of all 3 analyses showed clinically meaningful and statistically significant risk reductions. Those who had EID in the last 18 months had a 94% risk reduction vs those who had SID in the last 18 months. In the secondary analysis, the risk reduction with EID was 88%. For the tertiary analysis—extended dosing throughout treatment history—there were no PML cases among 815 people who met the inclusion criteria for having had EID at some point vs 96 cases in the SID group (Table). The average dosing interval extension ranged from 35 to 42 days. Although a robust reduction in PML with statistically significant differences was observed, 13 PML cases occurred, which suggests that EID may lower but not eliminate the risk of PML.16

Analysis of the TOUCH database was repeated in 2018. Compared with the 2017 analysis, 4,888 participants were added with a relative increase in the number of those who had EID vs SID; the average dosing interval of 35 to 42 days was maintained. The updated analysis continued to show significant PML risk reduction in the primary and secondary analyses (hazard ratio [HR] 0.096 [95% CI, 0.034-0.292]; P<.0001 and HR 0.200 [95% CI, 0.099-0.407]; P<.0001, respectively). In the tertiary analysis, no PML cases were seen in those who had EID (Table). There were an additional 7 PML cases in the EID cohort, although a majority of those individuals had switched back to SID when PML occurred. Furthermore, the risk factors for PML in those treated with EID appear to be the same as previously identified for SID, with majority of people who developed PML on EID having a JCV index of 1.5 or more or immunosuppressant exposure. Overall the analysis was reassuring in that despite the addition of more patients, longer follow-up times, and slightly longer exposures, EID continued to be associated with significantly lower PML risk than SID.17

Pathophysiology of Natalizumab and Progressive Multifocal Leukoencephalopathy

The biological mechanisms underlying increased PML with NTZ and the risk reduction seen with EID require additional research. Partial reversal of the pharmacodynamic effects of NTZ, including decreased receptor saturation, increased soluble vascular cell adhesion molecule (VCAM) expression, and reduced NTZ-induced peripheral lymphocytosis have been reported to occur 4 to 8 weeks after a dose of NTZ. These effects may allow for some reestablishment of immune surveillance in the CNS.18-20 Other hypotheses for the observed EID risk reduction include roles of decreased forced cellular migration from the bone marrow and relative temporal downregulation of factors that favor JCV growth.21


Although the exact mechanism of action for PML risk reduction associated with EID is not known, it does seem that the EID approach of NTZ administration can improve the risk-benefit profile with significant PML risk reduction seen. The results of the NOVA trial may provide great understanding of whether the NTZ efficacy is maintained with EID and ongoing monitoring of the TOUCH database is indicated to assure that the PML risk is actually decreased and not simply delayed with ongoing EID.

1. 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.

2. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911-923.

3. 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.

4. Risk Evaluation and Mitigation Strategy (REMS): TYSABRI Outreach: Unified Commitment to Health (TOUCH®) Prescribing Program. Accessed February 11, 2020. and Providers/UCM288126.pdf

5. Prosperini L, Saccà F, Cordioli C, et al. Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naive patients with multiple sclerosis. J Neurol. 2017;264(2):284-294.

6. Butzkueven H, Kappos L, Pellegrini F, et al. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry. 2014;85:1190-1197.

7. TYSABRI. Package insert. Biogen; 2019.

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

9. Plavina T, Subramanyam M, Bloomgren G, et al. Anti–JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014;76(6):802-812.

10. 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;16(11):925-933.

11. Stüve O, Bennett JL. Pharmacological properties, toxicology and scientific rationale for the use of natalizumab in inflammatory diseases. CNS Drug Reviews. 2007;13(1):79-95.

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

13. 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.

14. Rudick R, Sandrock A. Natalizumab: α4-integrin antagonist selective adhesion molecule inhibitors for MS. Exp Rev Neurother. 2004;4(4): 571-558.

15. Foley J, Goelz S, Hoyt T, Christensen A, Metzger RR.. Evaluation of natalizumab pharmacokinetics and pharmacodynamics with standard and extended interval dosing. Mult Scler Rel Dis. 2019;31:65-71.

16. Zhovtis Ryerson L, Foley J, Chang I, et al. Risk of natalizumab-associated PML in MS patients is reduced with extended interval dosing. Neurology. 2019;93(15):e1452-e1462.

17. 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. Presented at: 71st AAN Annual Meeting; May 4-11, 2019; Philadelphia, PA.

18. Plavina T, Muralidharan KK, Kuesters G, et al. Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients. Neurology. 2017;89(15):1584-1593.

19. Kappos L, Radue EW, Comi G, et al. Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology. 2015;85:29-39.

20. Fox RJ, Cree BA, De Sèze J, et al. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study [published correction appears in Neurology. 2015 Feb 24;84(8):862. multiple investigator names added]. Neurology. 2014;82:1491-1498.

21. Major EO, Yousry TA, Clifford DB. Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned [published correction appears in Lancet Neurol. 2018 Jul;17(7):578]. Lancet Neurol. 2018;17(5):467-480.

LZR has received compensation for being on the speaker bureau from Biogen, Genentech, and Teva; being on the advisory board for Biogen and Celgene; and research support from Biogen and Genentech