Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study

Abstract

Objectives: Report long-term safety and effectiveness of natalizumab over 240 weeks in the prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) Study.

Methods: Patients (N = 1,094) previously enrolled in natalizumab multiple sclerosis clinical trials received natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed.

Results: At data cutoff (February 9, 2012), natalizumab exposure was 3,460 patient-years; a median of 56 (range 1-70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with natalizumab's known profile. Upon natalizumab re-exposure, rates of anti-natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among patients with 1 to 2 prior natalizumab doses. Patients originally randomized to placebo/another disease-modifying therapy vs natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. Patients initially randomized to natalizumab had lower annualized relapse rates over 240 weeks.

Conclusions: Serious adverse events were consistent with natalizumab's known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of natalizumab treatment are consistent with its known efficacy profile.

Classification of evidence: This study provides Class III evidence that in patients with relapsing-remitting multiple sclerosis, natalizumab stabilizes EDSS scores, decreases relapse rates, and is associated with an increased risk of progressive multifocal leukoencephalopathy.

© 2014 American Academy of Neurology.

Figures

Figure 1. STRATA Study flow diagram

Eligible patients previously participated in a natalizumab multiple sclerosis clinical feeder study. (Some patients from these studies were enrolled in a safety extension study before STRATA started.) The safety extension and STARS studies were prematurely terminated when natalizumab dosing was voluntarily suspended. While the ROW patients entered the first 48 weeks of STRATA and subsequent extension period (still ongoing), US STRATA patients had the option to enroll in TOUCH once the STRATA Study was closed in the United States; some of these patients were also enrolled in TYGRIS (US STRATA/TYGRIS). Red dashed lines indicate that some patients did not participate in the safety EXT study, but went directly into STRATA from the feeder studies. Data are shown as of February 9, 2012. aAll US patients who continued on treatment beyond week 48 were enrolled in TOUCH (as per US requirements); TYGRIS patients remained part of TOUCH. Enrollment in these programs was simultaneous. bAt week 240 or have not reached week 240 yet. EXT = extension; FU = follow-up; GA = glatiramer acetate; IFNβ-1a = interferon β-1a; ROW = rest of world; SC = subcutaneous; STRATA = Safety of TYSABRI Re-dosing and Treatment; TOUCH = TYSABRI Outreach: Unified Commitment to Health; TYGRIS = TYSABRI Global Observation Program in Safety; US = United States.

Figure 2. EDSS scores over time

STRATA EDSS data, assessed every 24 weeks in the study, are plotted by 48-week intervals in the figure. (A) By original treatment assignment in feeder studies. Includes all available on-treatment EDSS score data during STRATA. ap < 0.0001 for comparison between scores pre- and postnatalizumab treatment gap (among patients who had at least one natalizumab dose prenatalizumab treatment gap). bp < 0.001 for comparison between original assignment to placebo vs original assignment to natalizumab. cIncludes data on patients dosed with natalizumab. dp < 0.05 for comparison between original assignment to placebo vs original assignment to natalizumab; ep < 0.01 for comparison between original assignment to placebo vs original assignment to natalizumab. (B) By continuation of treatment status in STRATA (completed 240 weeks vs discontinued treatment before week 240). Includes all available on-treatment EDSS score data for natalizumab and placebo groups combined. Patients who only completed the initial 24- to 48-week period (n = 217) are not included in panel B. cIncludes data on patients dosed with natalizumab. EDSS = Expanded Disability Status Scale; LOCF = last observation carried forward; STRATA = Safety of TYSABRI Re-dosing and Treatment.

Figure 3. Annualized relapse rates over time

(A) By original treatment assignment in feeder studies. Reflects all available on-treatment relapse data during the STRATA Study. ap < 0.0001 for comparison between original assignment to placebo vs original assignment to natalizumab. bIncludes data on patients dosed with natalizumab. cp < 0.01 for comparison between original assignment to placebo vs original assignment to natalizumab. dp < 0.001 for comparison between original assignment to placebo vs original assignment to natalizumab. (B) By continuation of treatment status in STRATA (at or have not yet reached week 240 vs discontinued treatment before week 240). Includes all available on-treatment relapse data for natalizumab and placebo groups in STRATA combined. bIncludes data on patients dosed with natalizumab. STRATA = Safety of TYSABRI Re-dosing and Treatment.