Immunogenicity with Peginterferon Beta-1a: 2-Year Data from the ADVANCE Study in Relapsing-Remitting Multiple Sclerosis

Background: Development of persistent neutralizing antibodies (NAbs) against interferon (IFN) beta has been associated with reduced levels of efficacy on clinical and magnetic resonance imaging variables; thus there is an unmet need for therapies with low levels of treatment-emergent NAbs. Drug modification by attachment of poly(ethyleneglycol) (PEG) molecules (pegylation) has been used to increase drug half-life and efficacy, and may also reduce immunogenicity. Subcutaneous (SC) peginterferon beta-1a (PEG-IFN), a pegylated IFN beta-1a, is under investigation in the randomized, Phase 3 ADVANCE study. During the placebo-controlled first year of this study the development of antibodies that bind to IFN beta-1a (BAbs), as well as NAbs and anti-PEG antibodies was low and similar for PEG-IFN 125 µg administered every 2 (Q2W) or 4 (Q4W) weeks.

Objectives: We assessed the immunogenicity of PEG-IFN in patients with relapsing-remitting multiple sclerosis (RRMS) during Year 2 and over 2 years of ADVANCE. 

Methods: At the end of the first year, patients on placebo were re-randomized to PEG-IFN Q2W or Q4W (during Year 2 all patients received dose-frequency-blinded PEG-IFN). Serum samples were collected pre-dose on Weeks 60, 72 and 96, and a tiered testing scheme was used to measure anti-IFN beta-1a BAbs (using a validated enzyme-linked immunosorbent assay [ELISA]), the titer of anti-IFN beta-1a NAbs (using a validated cell-based assay), and the titer of antibodies to PEG (using a validated ELISA). We present results for patients with 2 years of data at cut-off.

Results: During Year 2, persistent treatment-emergent antibodies were low in those switched to PEG-IFN from placebo and in patients on PEG-IFN Q2W and Q4W over 2 years: BAbs incidence, 1% across groups; NAbs incidence, <1% across groups; anti-PEG antibodies incidence, 3%, <1% and 2%, respectively; NAbs and anti-PEG antibody titers were low. Incidences over the 2-year observation period for Q2W and Q4W were reported as: BAb 4% and 2%; NAb: <1% and <1%; anti-PEG: 2% and 6%, respectively. No discernible impact on clinical efficacy or safety was observed in this study.

Conclusions: The overall incidence and titer levels of treatment-emergent antibodies were low and similar for PEG-IFN Q2W and Q4W over 2 years of treatment, with no discernible clinical impact. Low rates of immunogenicity support the potential benefits of SC PEG-IFN as a treatment for RRMS.