Peginterferon β-1a every 2 weeks increased achievement of no evidence of disease activity over 4 years in the ADVANCE and ATTAIN studies in patients with relapsing-remitting multiple sclerosis

Douglas L Arnold, Shulian Shang, Qunming Dong, Matthias Meergans, Maria L Naylor, Douglas L Arnold, Shulian Shang, Qunming Dong, Matthias Meergans, Maria L Naylor

Abstract

Background: No evidence of disease activity (NEDA) is a composite measurement, incorporating clinical and magnetic resonance imaging (MRI) elements of disease activity to sensitively evaluate the therapeutic efficacy of treatments for relapsing-remitting multiple sclerosis (RRMS).

Objective: To assess the NEDA status of patients treated with peginterferon β-1a in the ADVANCE and ATTAIN studies and explore its predictive value on longer-term clinical outcomes.

Methods: ATTAIN was a 2-year extension of the pivotal 2-year ADVANCE study of peginterferon β-1a for RRMS. Achievement of clinical NEDA, MRI NEDA, or overall NEDA was calculated cumulatively and by year over 4 years. Clinical outcomes during ATTAIN were analyzed based on NEDA status at the end of ADVANCE.

Results: Significantly more patients treated with peginterferon β-1a every 2 weeks than every 4 weeks achieved clinical NEDA (60.6% versus 50.6%, p = 0.0063) and MRI NEDA (28.3% versus 15.8%, p = 0.0005) through year 4 and overall NEDA through year 3 (20.9% versus 13.9%, p = 0.0160). Over 4 years, 15.8% of patients in the every 2 weeks group and 10.7% of patients in the every 4 weeks group maintained overall NEDA (p = 0.0584). Achievement of clinical NEDA, MRI NEDA, or overall NEDA in ADVANCE was predictive of annualized relapse rate in ATTAIN; achievement of clinical NEDA in ADVANCE was also predictive of NEDA achievement and confirmed disability worsening in ATTAIN.

Conclusions: Peginterferon β-1a every 2 weeks is associated with higher levels of NEDA compared with placebo in year 1 or peginterferon β-1a every 4 weeks in years 2-4. Overall NEDA within the first 2 years of treatment may be prognostic of long-term clinical outcomes.Clinicaltrials.gov: NCT01332019.

Keywords: multiple sclerosis; peginterferon β-1a; pegylated interferon; relapse; relapsing–remitting multiple sclerosis.

Conflict of interest statement

Conflict of interest statement: DA: had an equity interest in NeuroRx during the conduct of the study and has received personal fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Hoffman–La Roche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi, and Teva, and grants from Biogen and Novartis. SS, QD: full-time employees and stockholders of Biogen at the time of the analysis. MM, MLN: full-time employees and stockholders of Biogen.

Figures

Figure 1.
Figure 1.
Patients who achieved (a) clinical NEDA, (b) MRI NEDA, and (c) overall NEDA over 4 years (cumulative). **p < 0.01; ****p < 0.0001 for peginterferon β-1a every 2 weeks versus placebo. †p < 0.05; ††p < 0.01; †††p < 0.001; ††††p < 0.0001 for peginterferon β-1a every 2 weeks versus peginterferon β-1a every 4 weeks. MRI, magnetic resonance imaging; NEDA, no evidence of disease activity.
Figure 2.
Figure 2.
Patients who achieved (a) clinical NEDA, (b) MRI NEDA, and (c) overall NEDA over 4 years (cumulative, baseline at 6 months). †p < 0.05; ††p < 0.01; †††p < 0.001; ††††p < 0.0001 for peginterferon β-1a every 2 weeks versus peginterferon β-1a every 4 weeks. MRI, magnetic resonance imaging; NEDA, no evidence of disease activity.
Figure 3.
Figure 3.
ARR in years 3 and 4 by clinical NEDA, MRI NEDA, and overall NEDA in the 2-year ADVANCE study. Mean ARRs during years 3 and 4 are shown for subgroups of patients who did (NEDA+) or did not (NEDA−) achieve clinical NEDA, MRI NEDA, or overall NEDA at year 2 in ADVANCE. ***p < 0.001; ****p < 0.0001 for NEDA+ versus NEDA−. ARR, annualized relapse rate; MRI, magnetic resonance imaging; NEDA, no evidence of disease activity.
Figure 4.
Figure 4.
Twenty-four-week CDW in years 3 and 4 in patients by achievement of clinical NEDA in the 2-year ADVANCE study. Kaplan–Meier estimate; CDW is defined as ⩾1.0-point increase from an ATTAIN baseline EDSS score of ⩾1.0 or a ⩾1.5-point increase from an ATTAIN baseline EDSS score of ⩾0.0, confirmed ⩾24 weeks later; p value is based on a Cox proportional hazards model, with adjustment for baseline EDSS score and age (<40 or ⩾40). CDW, confirmed disability worsening; EDSS, Expanded Disability Status Scale; NEDA, no evidence of disease activity; NEDA+, achieved NEDA during ADVANCE; NEDA–, did not achieve NEDA during ADVANCE.
Figure 5.
Figure 5.
NEDA achievement in years 3 and 4 by NEDA achievement in the 2-year ADVANCE study. Proportion of patients achieving clinical NEDA, MRI NEDA, or overall NEDA during years 3 and 4 are shown for subgroups of patients who did (NEDA+) or did not (NEDA−) achieve clinical NEDA, MRI NEDA, or overall NEDA, respectively, at year 2. Only patients for whom NEDA data were available were included in the analysis. ****p < 0.0001 for NEDA+ versus NEDA−. MRI, magnetic resonance imaging; NEDA, no evidence of disease activity.

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