Late Breaking News IISaturday, October 13, 2012, 09:00 - 09:15
Positive proof of concept of AIN457, an antibody against interleukin-17A, in relapsing-remitting multiple sclerosisE. HavrdovŠ, A. Belova, A. Goloborodko, A. Tisserant, I. Jones, H. Garren, D. Johns , AIN457 for MS Study Group
Objective: To determine the effect of AIN457 on the number of brain magnetic resonance imaging (MRI) lesions in relapsing remitting multiple sclerosis (RRMS) patients.
Background: AIN457 is a recombinant fully human anti-human interleukin-17A (IL-17A) monoclonal antibody that binds to and neutralizes the bioactivity of human IL-17A. Proof of concept trials in psoriasis, rheumatoid arthritis and uveitis have indicated significant efficacy, with a favorable safety and tolerability profile. Preclinical and human evidence have implicated IL-17 in the pathogenesis of RRMS.
Design/methods: We performed a randomized, multi-center, double-blind, placebo-controlled trial in RRMS patients. Randomization was 1:1 to either 10 mg/kg of AIN457 or placebo by intravenous infusion. AIN457 or placebo was administered at weeks 0, 2, 4, 8, 12, 16, and 20 after randomization. The primary outcome measure was efficacy of AIN457 compared to placebo as determined by the cumulative number of combined unique active lesions (CUAL) observed on brain MRIs performed every 4th week from week 4 to 24 after randomization. Key secondary outcome measures included the cumulative number of new Gd-enhancing lesions on T1-weighted MRI scans, the derived annualized relapse rate, as well as safety and tolerability of AIN457.
Results: 73 patients were randomized with 38 to AIN457 and 35 to placebo. 61 patients completed the study.
The treatment was well tolerated with no serious adverse events (AEs). Two placebo patients discontinued due to AEs. All AEs were rated as mild to moderate in severity.
Comparing the effect of AIN457 to placebo by MRI, there was a 49% reduction in cumulative CUALs (p=0.087) and a 67% reduction in cumulative new Gd-enhancing lesions on the week 4-24 MRIs (p=0.003). Restricting the analysis to Week 8-24 MRIs (to allow for onset of action to be considered), the reduction in CUAL reaches 61% (p=0.014) while for Gd-enhancing lesions this reaches 69% reduction (p=0.001). Modeling based analysis using longitudinal nonlinear regression also demonstrated similar magnitudes and time course of lesion reduction.
Furthermore, the annualized relapse rate was 0.4 on AIN457 compared to 0.7 on placebo.
Conclusion: 10 mg/kg of AIN457 administered intravenously over 20 weeks appears to be safe, well-tolerated, and significantly reduced MRI lesion activity suggesting that the drug may be an effective treatment for RRMS. These data support the further clinical development of AIN457 in RRMS.
Eva Havrdova has received speakersí honoraria and research grant support from Bayer Schering Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva and has received compensation for Advisory Board activities from Biogen Idec, Genzyme, Merck Serono, Novartis, and TEVA
Anna Belova and Alla Goloborodkohave nothing to disclose.
Anne Tisserant, Ieuan Jones, Hideki Garren and Donald Johns, are employees of Novartis)