No evidence for loss of natalizumab effectiveness with every-6-week dosing: a propensity score–matched comparison with every-4-week dosing in patients enrolled in the Tysabri Observational Program (TOP)

Abstract

Background: Extended interval dosing of natalizumab is associated with significantly lower progressive multifocal leukoencephalopathy risk compared with every-4-week (Q4W) dosing in patients with relapsing-remitting multiple sclerosis. Previous studies have suggested that natalizumab effectiveness is maintained in patients who switch from Q4W to extended interval dosing but have been limited by a lack of well-matched patient cohorts. Methods: Tysabri Observational Program (TOP) data as of November 2019 were used to identify patients with relapsing-remitting multiple sclerosis treated with natalizumab Q4W and those with a single physician-indicated dosing change from Q4W to every-6-week (Q6W) dosing after ⩾1 year of Q4W treatment. Patients were propensity score matched at the time of the switch from Q4W to Q6W dosing. Clinical outcomes (annualized relapse rate and probability of remaining relapse free or free of 24-week confirmed disability worsening) and safety outcomes were assessed for the two cohorts. Results: This study included 219 pairs of propensity score–matched Q6W and Q4W patients. Annualized relapse rates were similar for Q6W (0.150) and Q4W (0.157) patients. The probability of remaining relapse free [hazard ratio = 1.243 (95% confidence interval = 0.819–1.888); p = 0.307] and of remaining free of 24-week confirmed disability worsening [hazard ratio = 0.786 (95% confidence interval = 0.284–2.176); p = 0.644] did not differ significantly between Q6W and Q4W patients. Summarized safety results for the matched Q6W and Q4W patients are also presented. Conclusion: These real-world findings in well-matched patient cohorts from TOP demonstrate that natalizumab effectiveness is maintained in patients who switch to Q6W dosing after ⩾1 year of Q4W dosing. ClinicalTrials.gov identifier: NCT00493298

Use of natalizumab in persons with multiple sclerosis: 2022 update

“…TOP participants on EID and SID dosing had similar incidence of all serious adverse events (SAEs) as well as SAEs related to treatment based on a qualitative assessment. Two cases of PML were observed in this study, both in the EID dosing group; notably, both PML cases were characterized by the presence of known risk factors for PML and were, therefore, in the highest PML risk category (Butzkueven et al, 2021a). The study showed that natalizumab effectiveness is maintained in those PwMS who switch to EID after ≥1 year on SID treatment regimen (Butzkueven et al, 2021a).…”

“…The first step in exploring the utility of EID with natalizumab to reduce the risk of PML is establishing that there is no loss of clinical effectiveness. As described earlier, long-term data from the TOP registry indicate that the effectiveness of natalizumab is maintained with an EID schedule in comparison with SID, with no change to the safety profile (Butzkueven et al, 2021a). A number of real-world studies further support the findings that EID maintains the efficacy of natalizumab in cohorts that include anti-JCV antibody-positive and antibody-negative PwMS (Butzkueven et al, 2020a;Chisari et al, 2020;De Mercanti et al, 2021;Riancho et al, 2021).…”

“…The Tysabri Observational Programme (TOP) is a real-world, open-label, multinational, prospective, observational study that aims to evaluate the long-term safety and effectiveness of natalizumab in persons with relapsing-remitting MS (RRMS). A 10-year interim analysis (N = 6148) (Butzkueven et al, 2020a), with a median time on natalizumab of 3.3 (range 0-11.6) years and a median follow-up time of 5.2 (range: 0-10.8) years confirmed the long-term safety of natalizumab, including the comparable safety of EID with standard interval dosing (SID) (Butzkueven et al, 2021a). A subset of TOP data of propensity score-matched EID and SID PwMS (n = 219 pairs) was used to compare clinical outcomes between the two dosing regimens for natalizumab.…”

Infectious issues of therapeutic monoclonal antibodies in multiple sclerosis and neuromyelitis optica spectrum disorders

“…Today, emerging evidence suggests that extended interval dosing (EID) NTZ (infusion every 6 wk) might decrease the risk of PML among patients who were positive for JCV antibodies and had received prior immunosuppressants compared to standard interval dosing (SID) (every 4 wk) 43 . NTZ effectiveness was maintained when switched to EID from SID after more than 1‐y treatment 44 . However, it should be noted that the risk of PML cannot be completely eliminated with EID, and vigilance is required even under this regimen 45 …”

“…43 NTZ effectiveness was maintained when switched to EID from SID after more than 1-y treatment. 44 However, it should be noted that the risk of PML cannot be completely eliminated with EID, and vigilance is required even under this regimen. 45 Compared to NTZ, the risk of PML was lower with other mAbs.…”