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)

Helmut Butzkueven, Ludwig Kappos, Tim Spelman, Maria Trojano, Heinz Wiendl, Ray Su, Shirley Liao, Robert Hyde, Stephanie Licata, Pei-Ran Ho, Nolan Campbell, Helmut Butzkueven, Ludwig Kappos, Tim Spelman, Maria Trojano, Heinz Wiendl, Ray Su, Shirley Liao, Robert Hyde, Stephanie Licata, Pei-Ran Ho, Nolan Campbell

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.

Clinicaltrialsgov identifier: NCT00493298.

Keywords: clinical outcomes; extended interval dosing; multiple sclerosis; natalizumab; real-world evidence.

Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HB: institution (Monash University) has received compensation for consulting, talks, advisory/steering board activities from Alfred Health, Biogen, Genzyme, Merck, and Novartis and research support from Biogen, Merck, MS Research Australia, National Health and Medical Research (Australia), Novartis, the Oxford Health Policy Forum, the Pennycook Foundation, and Roche. LK: institution (University Hospital Basel) has received and used exclusively for research support steering committee, advisory board, consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; and grants from Bayer HealthCare, Biogen, F. Hoffmann-La Roche, Merck, Novartis, the European Union, Inno-Swiss, the Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. TS: has received honoraria for consultancy and funding for travel from Biogen and Novartis. MT: has received compensation for consulting from Biogen, Merck Serono, Novartis, and Roche; speaker honoraria from Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva; and research grants from Biogen, Merck Serono, Novartis, and Roche. HW: has received honoraria from AbbVie, Actelion, Alexion, Biogen, Cognomed, Evgen, F. Hoffmann-La Roche, MedDay, Merck Serono, Novartis, Roche Pharma AG, Sanofi Genzyme, and Teva and research support from Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi. RS, S Liao, S Licata, P-RH: former employees of and may hold stock and/or stock options in Biogen. RH, NC: employees of and may hold stock and/or stock options in Biogen.

© The Author(s), 2021.

Figures

Figure 1.
Figure 1.
Tysabri Observational Program (TOP) patients included in propensity score matching. EID, extended interval dosing; Q4W, every 4 weeks; Q6W, every 6 weeks. *Other includes infusion records with missing dates (n = 13), no Q4W infusion history (switch occurred prior to 2014; n = 5), and multiple switches between Q4W and Q6W (n = 22).
Figure 2.
Figure 2.
Annualized relapse rates (ARRs) in propensity score–matched Q6W and Q4W patients (all matched patients). ARRs in the matched population calculated with negative binomial regression. CIs derived using generalized estimating equation for robust standard errors. ARR, annualized relapse rate; CI, confidence interval; Q4W, every 4 weeks; Q6W, every 6 weeks.
Figure 3.
Figure 3.
Cumulative probability of remaining relapse free in propensity score–matched Q6W and Q4W patients (all matched patients). Cox p-value equivalent to log-rank test. Dashed lines indicate the 95% CIs. CI, confidence interval; Q4W, every 4 weeks; Q6W, every 6 weeks.
Figure 4.
Figure 4.
Cumulative probability of 24-week CDW in propensity score–matched Q6W and Q4W patients (all matched patients). CDW was defined as an increase of ⩾0.5 point from a baseline EDSS score of ⩾6.0, ⩾1.0 point from a baseline EDSS score of ⩾1.0 to  p-value equivalent to log-rank test. Dashed lines indicate the 95% CIs. CDW, confirmed disability worsening; CI, confidence interval; EDSS, Expanded Disability Status Scale; Q4W, every 4 weeks; Q6W, every 6 weeks.

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Source: PubMed

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