Barts-MS rose-tinted-odometer: ★★★★★
Lime green and purple Thursday, #32cd32 & #6a0dad
If you are on natalizumab and are JC virus seropositive, you are at increased risk of developing PML (progressive multifocal leukoencephalopathy). If you transfer from 4-weekly infusions or standard interval dosing (SID) to 6-weekly or extended interval dosing (EID) you reduce the risk of getting PML by close to 90%.
Does shifting from SID to EID affect the efficacy of natalizumab? In short NO.
The following data was presented at ECTRIMS 2021 and should reassure both patients and HCPs
The NOVA trial was designed to estimate the difference in efficacy between EID and
SID dosing in a population that was clinically stable on SID dosing.
Although a small difference in efficacy between EID and SID dosing was estimated for the primary endpoint (number of new or newly enlarging T2 lesions at week 72) this was driven by two subjects in the EID arm with very high lesion values. The one subject had 30 lesions that occurred 3 months after natalizumab discontinuation, which represents rebound disease activity. The other subject had 25 lesions at week 72 and was subsequently diagnosed with asymptomatic progressive multifocal leukoencephalopathy (PML). The latter could have been PML lesions and not MS lesions.
When you exclude these 2 patients or outliers there is no difference in the primary endpoint between EID and SID. This study shows that patients who are stable on natalizumab SID dosing can switch to EID dosing without a meaningful loss of efficacy.
I hope you now feel confident enough to switch from SID to EID without worrying about rebound or loss of efficacy.Foley_NOVA_ECTRIMS2021_P970_Final
Foley et al. Primary results of NOVA: a randomized controlled study of the efficacy of 6‑week dosing of natalizumab versus continued 4-week treatment for multiple sclerosis. ECTRIMS 2021, P970.
Background: Natalizumab 4-week dosing (Q4W) with 300 mg is approved for treatment of relapsingremitting multiple sclerosis. Dosing frequency of approximately 6 weeks (Q6W) is associated with lower progressive multifocal leukoencephalopathy (PML) risk in retrospective analyses. Real-world data suggest similar effectiveness, but NOVA is the first randomized trial to assess Q6W efficacy.
Objective: Evaluate the efficacy of natalizumab Q6W in patients previously treated with natalizumab Q4W for ≥12 months compared with continuation of Q4W over 72 weeks.
Methods: NOVA is a randomized, contro led, open-label, rater-blinded phase 3b trial. Included patients were treated with natalizumab Q4W without relapse for ≥12 months and had no enhancing lesions at screening. Patients were randomized 1:1 to Q6W or Q4W arms. The primary endpoint was number of new/newly enlarging T2 (N/NET2) hyperintense lesions analysed by negative binomial regression with baseline (BL) weight, prior natalizumab exposure, and region as covariates. Secondary endpoints included relapses and 24week confirmed disability worsening (CDW). Primary estimand used a l observed data; secondary estimand treated post-intercurrent event data as missing. Missing data were imputed by worst value on treatment or multiple imputation depending on discontinuation reason.
Results: 195/248 (79%) Q4W patients and 207/251 (82%) Q6W patients completed NOVA. BL characteristics were wel balanced. Proportions of patients with N/NET2 lesions among observed data were low in both arms (Q4W:4.1%; Q6W:4.3%). Mean N/NET2 lesions in the Q4W and Q6W arms with the primary estimand were 0.05 and 0.20 (P=0.0755) and 0.06 and 0.31 (P=0.0437) with the secondary estimand. The difference was mainly due to 2 Q6W patients with high values: (1) 30 lesions that occurred 3 months after natalizumab discontinuation and (2) 25 lesions that occurred with asymptomatic PML observed at week 72. The sum of a lother N/NET2 lesions in NOVA was 18 with no other patient having >2. Relapse occurred in 2.1% and 2.8% (P=0.64) and CDW occurred in 8% and 10% (P=0.40) of patients in the Q4W and Q6W arms, respectively. Safety data were consistent with the known drug profile and similar between groups.
Conclusions: Despite a sma l difference in efficacy between arms, NOVA data suggest the vast majority of patients stable on Q4W dosing can switch to Q6W dosing with no clinica ly meaningful loss of efficacy. No conclusions on PML risk can be drawn from NOVA.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.