Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE

Bernd C Kieseier, Douglas L Arnold, Laura J Balcer, Alexey A Boyko, Jean Pelletier, Shifang Liu, Ying Zhu, Ali Seddighzadeh, Serena Hung, Aaron Deykin, Sarah I Sheikh, Peter A Calabresi, Bernd C Kieseier, Douglas L Arnold, Laura J Balcer, Alexey A Boyko, Jean Pelletier, Shifang Liu, Ying Zhu, Ali Seddighzadeh, Serena Hung, Aaron Deykin, Sarah I Sheikh, Peter A Calabresi

Abstract

Objective: To evaluate the efficacy and safety of subcutaneous peginterferon beta-1a over 2 years in patients with relapsing-remitting multiple sclerosis in the ADVANCE study.

Methods: Patients were randomized to placebo or 125 µg peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2.

Results: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183-0.291], Y2: 0.178 [0.136-0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231-0.355], Y2: 0.291 [0.231-0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, p<0.0001; every 4 weeks: 17%, p=0.0906), risk of relapse (every 2 weeks: 39%, p<0.0001; every 4 weeks: 19%, p=0.0465), 12-week disability progression (every 2 weeks: 33%, p=0.0257; every 4 weeks: 25%, p=0.0960), and 24-week disability progression (every 2 weeks: 41%, p=0.0137; every 4 weeks: 9%, p=0.6243). Over 2 years, greater reductions were observed with every 2 week versus every 4 week dosing for all endpoints and peginterferon beta-1a was well tolerated.

Conclusions: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1.Clinicaltrials.gov

Registration number: NCT00906399.

Keywords: Interferon; MRI; multiple sclerosis; peginterferon beta-1a; pegylated; phase 3; relapse; relapse-remitting multiple sclerosis.

Conflict of interest statement

Conflict of interest: Bernd C. Kieseier has received personal compensation for activities with Bayer Schering, Biogen Idec Inc, Merck Serono, Novartis, Roche, Sanofi-Aventis, and Teva Neurosciences as a lecturer. Research support from Bayer Schering, Biogen Idec Inc., Merck Serono, Teva Neurosciences

Douglas L. Arnold has received honoraria from Acorda Therapeutics, Bayer HealthCare, Biogen Idec Inc, Coronado Biosciences, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, NeuroRx Research, Novartis, Opexa Therapeutics, Roche, Merck Serono, Teva, Mitsubishi, StemCells, Inc, Teva, XenoPort and salary from NeuroRx Research, and owns stock in NeuroRx Research and research support from Bayer HealthCare.

Laura Balcer has received consulting fees from Biogen Idec Inc., Questcor and Novartis.

Alexey Boyko has received consulting fees from Schering, Merck Serono, Teva, Novartis, Biogen Idec Inc., Nycomed, and Genzyme.

Jean Pelletier has received consulting fees from Allergan, Bayer Schering Pharma, Biogen Idec Inc., Genzyme, Merck Serono, Novartis, Sanofi, and Teva, non-profit foundation support from ARSEP, academic research support from PHRC, and unconditional research support from Bayer Schering Pharma, Biogen Idec Inc., BMS, GSK, Merck Serono, Novartis, Peptimmune, Roche, Sanofi, Teva, and Wyeth.

Aaron Deykin, Serena Hung, Sarah I Sheikh, Ali Seddighzadeh, Ying Zhu, Shifang Liu are employees of Biogen Idec Inc.

Peter A Calabresi has received grants/research support from Biogen Idec Inc., Abbott, Novartis and MedImmune, and consulting fees from Abbott, Vaccinex, Prothena, and Vertex.

© The Author(s), 2015.

Figures

Figure 1.
Figure 1.
Patient disposition – over 2 years. N, n = number of subjects.
Figure 2.
Figure 2.
Annualized relapse rate by study year. aBased on negative binomial regression, with adjustment for baseline EDSS (<4 vs. ≥4), baseline relapse rate and age (<40 vs. ≥40). CI: confidence interval.
Figure 3.
Figure 3.
New or newly enlarging T2 lesions by study year. Observed data after subjects switched to alternative MS medications are excluded. Missing data prior to alternative MS medications and visits after subjects switched to alternative MS medications up to week 48 are imputed based on previous visit data assuming the constant rate of lesion development or group mean at same visit. SE: standard error.
Figure 4.
Figure 4.
Proportion of patients relapsed over 2 years (time to first relapse over 2 years). aBased on Cox proportional hazards model, adjustment for baseline EDSS (<4 vs. ≥4), age (<40 vs. ≥40), baseline relapse rate, and baseline Gd+ lesions (presence vs. absence). Analyses were conducted by combining patients who received placebo in Year 1 and either peginterferon beta-1a every 2 or 4 weeks in Year 2 as one group (delayed treatment).
Figure 5.
Figure 5.
Proportion of patients with 12-week confirmed disability progression over 2 years (time to disability progression). aBased on a Cox proportional hazards model, adjustment for baseline EDSS and age (<40 vs. ≥40). Disability progression is defined as ≥1.0 point increase on the EDSS from a baseline EDSS ≥1.0 sustained for 12 weeks or ≥1.5 point increase on the EDSS from a baseline EDSS of 0 sustained for 12 weeks. Analyses were conducted by combining patients who received placebo in Year 1 and either peginterferon beta-1a every 2 or 4 weeks in Year 2 as one group (delayed treatment group).
Figure 6.
Figure 6.
Proportion of patients with 24-week confirmed disability progression over 2 years (time to disability progression). Disability progression is defined as ≥1.0 point increase on the EDSS from a baseline EDSS ≥1.0 sustained for 24 weeks or ≥1.5 point increase on the EDSS from a baseline EDSS of 0 sustained for 24 weeks. Analyses were conducted by combining patients who received placebo in Year 1 and either peginterferon beta-1a every 2 or 4 weeks in Year 2 as one group (delayed treatment). aBased on a Cox proportional hazards model, adjustment for baseline EDSS and age (<40 vs. ≥40).

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