4 or 6 week natalizumab dosing

4

In a attempt to reduce the risk of PML dosing was extended and it was sugggested that you get reduced PML without an influence of disease activity. This study by the manufacturers of a natalizumab variant did a study and concluded that there was not PML risk difference by there were more lesions in the extended dosing group, with the acknowledgment that a few people (n=2), skewed the data alot. Maybe one of the neuros want to given their view of the implications of this. Maybe ProfG will do a guest post

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial.Foley JF, Defer G, Ryerson LZ, Cohen JA, Arnold DL, Butzkueven H, Cutter G, Giovannoni G, Killestein J, Wiendl H, Smirnakis K, Xiao S, Kong G, Kuhelj R, Campbell N; NOVA study investigators.Lancet Neurol. 2022 Apr 25:S1474-4422(22)00143-0. doi: 10.1016/S1474-4422(22)00143-0. Online ahead of print.

Background: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis.

Methods: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18-60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972.

Findings: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07-0·63) in the once every 6 weeks group and 0·05 (0·01-0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86-20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12-0·82) and 0·06 (0·01-0·31; mean lesion ratio 4·93 [95% CI 1·05-23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic.

Interpretation: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab.

COI: Non relevant

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9 comments

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  • I when’t from 4 to 6 weeks infusion they had to put me back to 4 because had new lesions in my brain.

  • This is interesting because when I was on Natalizumab it worked well for two weeks and then I struggled for two weeks. This became a recurring pattern. When Ocrelizumab became available I switched and it works much better for me. I would like to see an investigation of the difference between 2 and 4 weekly Natalizumab dosing.

  • I’m on Facebook groups for tysabri (UK and worldwide) and I have noticed people stating they were stable now having problems when moved to 6 weekly, not all are confirmed relapses but some just new symptoms.

    There are also a number of patients who have been initiated on 6 weekly dosing and are are not getting their very active MS under control (including in the UK). I wouldn’t have expected this would be possible as the study participants had been stable for a year. Just wondering what the view is on initiating on a 6 weekly dosing schedule is in treatment-naive patients and who is responsible for providing guidance on this, the ABN or NICE?

  • I dont know how people on tysabri handle 6 weekly, when i was om it 4 weekly was tough and when i had a 5 week month it was dreadful. Infact im certain it was only the amount of months that were 5 week that helped me qualify for hsct

  • I went from 4 to 6 weekly at the start of the pandemic. When I first started Tysabri I felt great for 2 weeks, so-so for week 3 and like a junkie craving the next hit in the 4th week. I don’t know how much of that was psychosomatic, but it subsided after several months of treatment.
    As I was led to believe that 6 weekly instead of 4 weekly dosing made little to no difference to the effeacy of the treatment, but substantially reduced the risk of PML for long term usage I wasn’t too bothered, I’m currently JC negative so could probably stay on Tysabri for several more years.
    I’m now wanting to see a comparison of my MRI scans and consider the risk/reward of possibly going back to 4 weekly dosing, but until The RLH reintroduce face to face neurology appointments that’s unlikely.

  • When I was on Tysabri, it was every 4wks. Within the 1st few months, my negative jcv level became positive, following month levels doubled and third month tripled. I decided NOPE, no more. Was offered every 6 weeks. My train of thought on that was… It’ll just be a slower process to PML than going every 4 weeks and so I came off of it. I did not feel comfortable chancing it.

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