Extending dosing to reduce PML Risk


I suspect you will get a piece on this from ProfG in a few weeks . As you know natalizumab is a very good drug for stopping disease activity of the brain. However it is also good at stopping immune surveillence of the brain and if you are one of the 50% of people who are infected with the John Cunningham (JC) virus you are at risk from a brain disease called Progressive multifocal leukoencephalopathy. Natalizumab is normally dosed at 4 weekly intervals. This gives you a risk of developing infection that makes people switch to other drugs after 2 years if you are JC positive. This study looks at a dosing interval of 6 weeks, maybe enough time to allow abit of anti-viral surveillence of the brain but too short to allow MS to start.

Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Ryerson LZ, Foley J, Chang I, Kister I, Cutter G, Metzger RR, Goldberg JD, Li X, Riddle E, Smirnakis K, Kasliwal R, Ren Z, Hotermans C, Ho PR, Campbell N. Neurology. 2019 Sep 12. pii: 10.1212/WNL.0000000000008243

OBJECTIVE: To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS).

METHODS: This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions.

RESULTS: This study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01-0.22, p < 0.001) and 0.12 (0.05-0.29, p < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID.

CONCLUSION:Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID.

CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

If you are a regular blog reader you will know this info already. However until we are advised otherwise the approved dosing regime is every 4 weeks. As you can see it dose not elliminate risk completely but it does reduce this alot. The European Regulators are mulling this over and are expected to pass judgement in a few months. ProfG will give you the news as it happens

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