Most patients with relapsing-remitting multiple sclerosis (RRMS) who are stable on natalizumab (Tysabri, Biogen) administered once every 4 weeks (Q4W) may be able to safely switch to a once every 6 weeks (Q6W) dosing interval with no clinically meaningful loss of efficacy, new research shows.
The hope is that Q6W dosing may lower the risk of progressive multifocal leukoencephalopathy (PML), although the NOVA trial was not powered to assess differences in risk of PML, investigators led by John Foley, MD, Rocky Mountain MS Clinic, Salt Lake City, Utah, note.
The study was published online April 25 in Lancet Neurology.
Comparable Disease Control
Natalizumab is approved for Q4W dosing as a 300-mg intravenous infusion.
The open-label, phase 3b NOVA study tested the safety and efficacy of natalizumab Q6W and Q4W dosing in 499 patients with RRMS at 89 MS centers across 11 countries.
All patients had been treated with the approved Q4W dosing regimen of natalizumab with no relapses for at least 12 months; 251 switched to Q6W dosing and 248 remained on Q4W dosing.
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 MRI, relapse, or neurological examination or efficacy assessment after baseline.
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.
In the primary estimand analysis, there were numerically more new or newly enlarging T2 hyperintense lesions at week 72 in the Q6W versus Q4W group (adjusted mean number of lesions, 0.20 vs 0.05; ratio of adjusted mean lesion numbers, 4.24; 95% CI, 0.86 – 20.85; P = .076).
This difference only reached significance in the secondary estimand analysis (adjusted mean number of lesions, 0.31 vs 0.06; ratio of adjusted mean lesion number, 4.93 (95% CI, 1.05 – 23.20; P = .044).
Importantly, this difference was primarily due to two patients in the Q6W group who had “atypically” large numbers of lesions (25 or more).
One of them had stopped treatment due to becoming JC-virus seropositive during the study. The other was diagnosed with asymptomatic PML after completing the trial.
These two patients aside, “distributions of participants with none, one, or two new or newly enlarging T2 hyperintense lesions were similar in the two groups, as were secondary clinical and MRI outcomes over 72 weeks,” the investigators report.
They add that interpretation of statistical differences (or absence thereof) is limited because disease activity in the Q4W group was lower than expected and that overall disease activity was “well controlled in both groups.”
Safety findings were consistent with the known profile of natalizumab, with no between-group differences in the incidence of adverse events and serious adverse events.
A spokesperson for Biogen told Medscape Medical News that the NOVA results build upon the retrospective safety analyses of the TOUCH (Tysabri Outreach: Unified Commitment to Health) prescribing program, which found that extended-interval dosing of approximately Q6W with IV natalizumab is associated with significantly lower risk of PML than the Q4W dosing schedule.
In March 2022, the natalizumab Summary of Product Characteristics was updated by the European Medicines Agency to include data on the efficacy of Q6W IV dosing from NOVA while maintaining Q4W as the only approved dosing regimen, according to Biogen.
In an accompanying commentary, Kerstin Hellwig, MD, PhD, Department of Neurology, Catholic Clinic Bochum, Germany, says a thorough radiological investigation of the patient who developed PML in the study would be helpful.
Because extended-interval dosing “might be the preferred strategy” for use of natalizumab in the future, it will be “important to learn whether the PML pattern of MRI changes is different with standard dosing versus extended-interval dosing, Hellwig writes.
“The most important message from NOVA is that neurologists and neuroradiologists must remain vigilant, even with extended-interval dosing, so as to not miss cases of progressive multifocal leukoencephalopathy,” Hellwig concludes.
The study was funded by Biogen. Several authors have disclosed financial relationships with the company. Hellwig has received speaker honoraria and research support from Almirall, Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, Roche, and Teva, and support for congress participation from Bayer, Biogen, Merck, Roche, Sanofi Genzyme, and Teva; and has served on scientific advisory boards for Bayer, Biogen, Sanofi, Teva, Roche, Novartis, and Merck.
Lancet Neurol. Published online April 25, 2022. Abstract, Comment
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