Contributions
Abstract: P718
Type: Poster
Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair
Background: SYNERGY (NCT01864148) assessed the efficacy and safety of opicinumab in participants with relapsing forms of MS when used concurrently with IM IFN beta-1a. The primary endpoint was 12-week confirmed improvement in ≥1 test of a multicomponent endpoint (EDSS, T25FW, 9HPT [D, ND], PASAT-3) over 72 weeks. A non-monotonic, inverted U-shaped dose response to opicinumab was observed, with favourable outcomes in the 10 and 30 mg/kg groups. Identification of participants who experienced larger and more durable effects would enable a more targeted treatment approach.
Objectives: To identify demographic and baseline predictors of opicinumab treatment response, and identify a subpopulation with a greater treatment response.
Methods: A multivariate modelling approach anchored on the overall response score (ORS), a pre-specified endpoint based on EDSS, T25FW, 9HPT-D and 9HPT-ND, was used. At each visit, each component was scored relative to baseline (worsening threshold met: -1; no change met threshold: 0; improvement threshold met: +1). Multivariate repeated measure mixed models with stepwise model selection were used to identify treatment response predictors. Baseline candidate covariates included nine demographic/clinical and 13 MRI characteristics. The likelihood ratio test was used to select significant predictors; a numerical search identified optimal cutoff values. Cross validation and tree-based classification algorithms evaluated the robustness of identified subpopulations.
Results: Three predictive characteristics of greater and more durable efficacy were identified by the ORS: shorter disease duration (≤20 y), lower baseline magnetisation transfer ratio (MTR) values in T2 lesions (may be consistent with lower myelin content), and lower baseline diffusion tensor imaging-radial diffusivity (DTI-RD) values in T2 lesions (may be consistent with higher structural integrity). For the subpopulation with these characteristics, the proportions of participants with 12-week confirmed improvement over 72 weeks were 36% for placebo (IM IFN beta-1a only) and 81% for the 10 mg/kg opicinumab group, vs 49% and 63%, respectively, in the ITT population.
Conclusions: This post hoc analysis identified three predictive characteristics (disease duration, MTR and DTI-RD in T2 lesions) associated with a greater and more durable treatment effect. The subpopulation identified may allow a more targeted (personalised) approach for future opicinumab studies.
Supported by: Biogen.
Disclosure: This study was supported by Biogen (Cambridge, MA, USA). Editorial support was provided by Excel Scientific Solutions (Horsham, UK): funding was provided by Biogen.
PAC: consulting fees from Biogen; research support to his institution from Annexon Biosciences, Biogen, MedImmune, Novartis, and Teva.
GG: advisory boards for AbbVie Biotherapeutics Inc., Almirall, Atara Biotherapeutics, Biogen, Novartis, Merck, Merck Serono, Roche, Sanofi-Genzyme, and Teva; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Genzyme, Merck, Merck Serono, Sanofi-Genzyme, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, and Novartis.
RK: personal fees and/or travel support from Biogen, Genzyme, KaroBio and Roche; clinical trial steering committees for Biogen; grants from Novartis, Teva, US National Multiple Sclerosis Society and Multiple Sclerosis Society of Great Britain and Northern Ireland.
DLA: personal fees for consulting from Acorda, Biogen, Hoffman La Roche, MedImmune, Mitsubishi, Novartis, Receptos, and Sanofi-Aventis; grants from Biogen and Novartis; an equity interest in NeuroRx Research, which was the image analysis center for the trial.
SS, YC, BZ, CC-V, AD, IC: employees of and hold stock/options in Biogen.
Abstract: P718
Type: Poster
Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair
Background: SYNERGY (NCT01864148) assessed the efficacy and safety of opicinumab in participants with relapsing forms of MS when used concurrently with IM IFN beta-1a. The primary endpoint was 12-week confirmed improvement in ≥1 test of a multicomponent endpoint (EDSS, T25FW, 9HPT [D, ND], PASAT-3) over 72 weeks. A non-monotonic, inverted U-shaped dose response to opicinumab was observed, with favourable outcomes in the 10 and 30 mg/kg groups. Identification of participants who experienced larger and more durable effects would enable a more targeted treatment approach.
Objectives: To identify demographic and baseline predictors of opicinumab treatment response, and identify a subpopulation with a greater treatment response.
Methods: A multivariate modelling approach anchored on the overall response score (ORS), a pre-specified endpoint based on EDSS, T25FW, 9HPT-D and 9HPT-ND, was used. At each visit, each component was scored relative to baseline (worsening threshold met: -1; no change met threshold: 0; improvement threshold met: +1). Multivariate repeated measure mixed models with stepwise model selection were used to identify treatment response predictors. Baseline candidate covariates included nine demographic/clinical and 13 MRI characteristics. The likelihood ratio test was used to select significant predictors; a numerical search identified optimal cutoff values. Cross validation and tree-based classification algorithms evaluated the robustness of identified subpopulations.
Results: Three predictive characteristics of greater and more durable efficacy were identified by the ORS: shorter disease duration (≤20 y), lower baseline magnetisation transfer ratio (MTR) values in T2 lesions (may be consistent with lower myelin content), and lower baseline diffusion tensor imaging-radial diffusivity (DTI-RD) values in T2 lesions (may be consistent with higher structural integrity). For the subpopulation with these characteristics, the proportions of participants with 12-week confirmed improvement over 72 weeks were 36% for placebo (IM IFN beta-1a only) and 81% for the 10 mg/kg opicinumab group, vs 49% and 63%, respectively, in the ITT population.
Conclusions: This post hoc analysis identified three predictive characteristics (disease duration, MTR and DTI-RD in T2 lesions) associated with a greater and more durable treatment effect. The subpopulation identified may allow a more targeted (personalised) approach for future opicinumab studies.
Supported by: Biogen.
Disclosure: This study was supported by Biogen (Cambridge, MA, USA). Editorial support was provided by Excel Scientific Solutions (Horsham, UK): funding was provided by Biogen.
PAC: consulting fees from Biogen; research support to his institution from Annexon Biosciences, Biogen, MedImmune, Novartis, and Teva.
GG: advisory boards for AbbVie Biotherapeutics Inc., Almirall, Atara Biotherapeutics, Biogen, Novartis, Merck, Merck Serono, Roche, Sanofi-Genzyme, and Teva; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Genzyme, Merck, Merck Serono, Sanofi-Genzyme, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, and Novartis.
RK: personal fees and/or travel support from Biogen, Genzyme, KaroBio and Roche; clinical trial steering committees for Biogen; grants from Novartis, Teva, US National Multiple Sclerosis Society and Multiple Sclerosis Society of Great Britain and Northern Ireland.
DLA: personal fees for consulting from Acorda, Biogen, Hoffman La Roche, MedImmune, Mitsubishi, Novartis, Receptos, and Sanofi-Aventis; grants from Biogen and Novartis; an equity interest in NeuroRx Research, which was the image analysis center for the trial.
SS, YC, BZ, CC-V, AD, IC: employees of and hold stock/options in Biogen.