New data from the NOVA trial showed differences in the number of T2 lesions in patients with relapsing-remitting multiple sclerosis at 72 weeks of treatment with natalizumab (Tysabri; Biogen), though seemingly driven by data from only 2 participants with extreme new or newly enlarging T2 hyperintense lesion numbers.
John F. Foley, MD
Recent data from the NOVA trial (NCT03689972), a randomized controlled, open-label, phase 3b study, showed a numerical difference in the estimated number of new or newly enlarging T2 hyperintense lesions in patients with relapsing-remitting multiple sclerosis (RRMS) treated with stable natalizumab (Tysabri; Biogen) dosing once every 6 weeks vs once every 4 weeks. The efficacy of switching to extended-interval dosing of natalizumab was previously unclear as it was associated with lower progressive multifocal leukoencephalopathy risk.
The mean number of new or newly enlarging T2 hyperintense lesions at week 72, after adjusting for missing data, was 0.20 (95% CI, 0.07-0.63) in the once every 6 weeks group and 0.05 (95% CI, 0.01-0.22) in the once every 4 weeks group (mean lesion ratio, 4.24; 95% CI, 0.86-20.85; P = .076) under the primary estimand.1 Notably, under the secondary estimand, these numbers were 0.31 (95% CI, 0.12-0.82) in the longer interval group and 0.06 (95% CI, 0.01-0.31) in the shorter interval group, which was significant (mean lesion ratio 4.93 [95% CI, 1.05-23.20]; P =.044).
Lead investigator John F. Foley, MD, neurologist, Rocky Mountain MS Clinic, and colleagues wrote, “Most participants had no new or newly enlarging T2 lesions at 72 weeks (82% in the once every 6 weeks group and 78% in the once every 4 weeks group). The extreme T2 lesion numbers in 1 of the 2 participants might have been related to factors other than the efficacy of 6-week dosing, such as the prolonged period without disease-modifying therapy after discontinuation of study drug at week 55, and confounding from asymptomatic progressive multifocal leukoencephalopathy in the other participant.”
Patients (n = 605) from MS centers (n = 89) across 11 countries were assessed for eligibility between Dec 26, 2018, and Aug 30, 2019. The eligible patients (n = 499) enrolled were assigned to receive natalizumab 300 mg once every 6 weeks (n = 251) or once every 4 weeks (n = 248). These participants, aged 18 to 60 years, had no relapses for at least 12 months before randomization. Then, participants were randomly assigned 1:1 to switch to natalizumab once every 6 weeks or continue with the dosage of once every 4 weeks.
Two participants treated in the once every 6 weeks group contributed most of the excess lesions. Between the 2 groups, 78% (n = 194) of those in the longer interval group and 77% (n = 190) of those in the shorter interval group experienced adverse events (AEs). In total, serious AEs were found in 7% of both groups, respectively.
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“Analysis of the distribution of participants with new or newly enlarging T2 hyperintense lesions indicated that the estimated difference between the groups were strongly influenced by 3factors,” Foley and colleagues noted. The two participants who were both in the once every 6 weeks dosing group had extreme T2 lesion numbersand that there was an imbalance in the amount of participants who received optional rescue therapy.1 In addition, the numerical difference could have been exaggerated because of the imputation rules which were used in the prespecified estimands.1
Limitations of the trial included assumptions on the sample size calculations and prespecified inferences, based on prior trials,2 and no assumption of equivalence for 6-week and 4-week dosing. Also, the duration and size of the trial were not sufficient to be informative on rare AEs.1
Foley et al noted that their findings, “suggest that most patients who are stable on natalizumab 4-week dosing can switch to 6-week dosing without clinically meaningful loss of efficacy. These results could provide important information for physicians who are making natalizumab treatment decisions, and reinforce the need to balance these decisions with consideration of individual patient benefit and risk.”
Their recommendations for future research included continuing to monitor the patient population in a follow-up, open-label extension study which could provide more findings on the efficacy and safety of natalizumab in patients who received 4-week dosage and switched to 6-week dosage.1
