Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing

Abstract

Objective: To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS).

Methods: This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions.

Results: This study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01-0.22, p < 0.001) and 0.12 (0.05-0.29, p < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID.

Conclusion: Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID.

Classification of evidence: This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

Figure 1. Descriptions of the 3 planned analyses of PML risk and the definitions of EID and SID used in this study

Each hypothetical patient dosing diagram depicts 2 years of infusion history. EID = extended interval dosing; PML = progressive multifocal leukoencephalopathy; SID = standard interval dosing.

Figure 2. Patient flow diagram for primary, secondary, and tertiary PML risk analyses

For inclusion in any analysis, patients must have had no dosing gaps (defined as an interval >12 weeks between 2 consecutive infusions) or overdoses (defined as an interval <3 weeks between 2 consecutive infusions). EID = extended interval dosing; JCV = JC virus; PML = progressive multifocal leukoencephalopathy; SID = standard interval dosing; TOUCH = Tysabri Outreach: Unified Commitment to Health. ^aEnrolled number as of June 1, 2017. ^bAt least 1 occurrence of dosing gap (interval >12 weeks between 2 consecutive infusions) or overdose (interval <3 weeks between 2 consecutive infusions). ^cPatients switched between SID and EID more than once.

Figure 3. Kaplan-Meier estimates of the cumulative probability of PML in EID vs SID groups in the (A) primary, (B) secondary, and (C) tertiary analyses

CI = confidence interval; EID = extended interval dosing; HR = hazard ratio; PML = progressive multifocal leukoencephalopathy; SID = standard interval dosing. ^aEID vs SID. Model includes age, sex, prior use of immunosuppressants, EID/SID group, and calendar year at the start of natalizumab treatment as covariates. The Cox regression analysis could not be performed for the tertiary analysis because no cases of PML occurred in the EID-3° group. ^bNumber of patients who were still in the study and did not have PML at the end of the specified time. ^cCumulative number of cases of PML at the end of the specified time.