Guest Post: Extending natalizumab dosing interval may reduce the risk of PML

Natalizumab extended interval dosing (EID) is associated with a significant reduction in PML risk compared with standard interval dosing (SID) in the TOUCH® Prescribing Program.

Natalizumab, a highly efficacious medication approved for relapsing forms of MS, is used to prevent relapses, slow worsening disability, and may improve the quality of life for some patients. The medication is indicated to be prescribed as 300-milligram infusion dosed every four weeks.

However, taking the medication longer than two years may increase risk of PML, which is caused by JCV. There have been 756 PML cases reported worldwide as of December 2017, with a global incidence rate of 4.19 per 1,000 PML cases in people treated with natalizumab. Patients who test JCV antibody-positive and therefore are presumed to have been infected with the virus, which comprises roughly half of the world population, are typically either told to not to start natalizumab, or have had treatment stopped after two years, when risk is deemed to be too high.

Our new study, carried out in collaboration with Biogen and academic partners presented at ACTRIMS in San Diego, CA last month, adds an important caveat to known PML risk in natalizumab users. According to the comprehensive analysis of TOUCH database, which includes all natalizumab users in the Unites States, the risk of PML is very significantly lower in JCV Antibody positive patients whose natalizumab infusions have been extended from 4 weeks to 5-12 weeks.

Since the potential mechanisms, whereby extended interval dose schedule may lead to PML reduction is not known, we chose to look at the data in multiple ways. The primary analysis examined PML risk in patients with an extended dose history in the last 18 months, the secondary analysis at extended dose occurring at any time in the dosing history, and tertiary analysis looked at extended dosing during entire treatment history.

The results showed clinically meaningful and statistically significant risk reductions with all definitions with a very robust risk reduction of 94% in the primary analysis and 88% risk reduction in the secondary analysis. For the tertiary analysis – extended dosing throughout treatment history – there were no PML cases among 815 patients who met the inclusion criteria as compared to 96 cases noted in standard interval group (comprised of 23,168 patients). The average dosing interval extension ranged from 35 to 42 days. It is important to note that patients with dosing gaps over 12 weeks were excluded since numerous studies have demonstrated loss of drug efficacy after 3 months period. However, further sensitivity analysis is needed to assure this exclusion and other potential selection biases do not alter the results.

The TOUCH database does not capture efficacy data. Key outstanding question at this point is whether the efficacy of monthly natalizumab could be maintained with less frequent dosing (e.g. q 6 weeks). Our prior retrospective work found that extending the dose up to 8 weeks did not negatively affect the medication’s efficacy in a retrospective review of 2,000 patients in 6 MS Centers across the US. The level of evidence that could be obtained from retrospective studies is relatively weak, and we hope that a prospective randomized study of q6 week v q4 week natalizumab would be initiated to definitively answer the question of efficacy of extended dosing.

In the meantime, our recent findings could influence how neurologists prescribe the medication. Neurologists have been looking for safer ways to administer natalizumab infusions to their patients, but there hasn’t been clear data on whether decreasing dosing frequency improves safety. The large risk reduction seen with extending natalizumab infusions by just 2 weeks is potentially practice-changing since it could give neurologists an opportunity to prescribe a highly efficacious medication in a safer way.

Our research team includes I. Kister, J.D. Goldberg, X. Li from New York University Langone Medical Center, J. Foley and R. Metzger from Rocky Mountain Multiple Sclerosis Clinic, G Cutter from University of Alabama at Birmingham School of Medicine, and I. Chang, B. Yu, Z. Ren, C. Hotermans, P.R. Ho, and N. Campbell from Biogen.

Post by Lana Zhovtis

Dr Lana Zhovtis Ryerson is a magna cum laude graduate of the University of Rochester with a degree in biology and member of the Phi Beta Kappa National Honor Society. She earned her medical degree from the University of Rochester School of Medicine and Dentistry. She received her neurology training at Mount Sinai Medical Center where she was honored with House Staff Physician of the Year Award in 2011. She completed her fellowship in Multiple Sclerosis at NYU Langone Medical Center where she is currently an Assistant Professor of Neurology.

Dr Zhovtis Ryerson has devoted her career to developing and providing rigorous, comprehensive, and compassionate care to pwMS, as well as other immune-mediated disease affecting the central nervous system. 

She has been spearheading the Extended Interval Natalizumab (EID – NTZ) Project development resulting in a successful manuscript for the retrospective chart review of patients treated with EID NTZ published in 2016. 

About the author

Rebecca Aldam


  • 756 cases of pml since 2017 is huge! How is this still being prescribed while Daclizumab was taken off the market so quickly over much less? I'm on Tysabri but this just seems odd to me. Also, if EID became standard prescribing in the future, would it only be recommended to those who are jcv positive or everyone on Tysabri?

  • It's not 756 cases since 2017, but 756 overall. Still huge, I agree.

    My guess is that Tysabri can be prescribed safely to JCV- PwMS. And its high efficiency makes it hard to quit, even if you become positive.

  • I think over dose is a bit strong. The more appropriate question would be with all of the DMT should all be assessed on a more personal level? I am slight of stature and my whole life I have been asking this. The conversation is starting with Ocrevus. These are medications that have a profound effect on our immune system. Far beyond just our MS. And we are on many of these DMTS for years. It is time to think about decades and population diversity.

  • I think it is important to remember that efficacy has not been proven with EID schedule of Tysabri with the same scientific rigor as the standard dose schedule. More studies need to be done to accurately understand the pros and cons of using less frequent infusions.



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