Contributions
Abstract: P777
Type: Poster
Abstract Category: Therapy - disease modifying - 30 Tools for detecting therapeutic response
Background: Disability in MS has been evaluated using confirmed worsening/improvement on several measures (EDSS, MSFC), or multicomponent endpoints with established change thresholds (EDSS, T25FW, 9HPT). Worsening/improvement are rarely examined jointly; current multicomponent endpoints do not tend to reflect changes on >1 disability measure. The patient population is typically classified by these criteria into binary categories (changed or not); data are usually censored after reaching the endpoint with subsequent disability worsening/stabilisation/improvement information lost. An endpoint integrating clinically relevant worsening/improvement across domains could provide a more complete assessment of disability trajectory and a sensitive tool to evaluate new therapies.
Objectives: To describe the overall response score (ORS), a novel endpoint measuring disability improvement and worsening simultaneously, and to evaluate its sensitivity to changes over time and relationship to established disability progression endpoints.
Methods: The ORS has 4 components: EDSS, T25FW, 9HPT (dominant and non-dominant), and a range of +4 to -4. At each visit, each component is scored vs baseline: -1 (threshold for worsening met), 0 (no change met threshold), or +1 (threshold for improvement met). Component thresholds are based on commonly used definitions. Patients are scored against baseline repeatedly over time. ORS was evaluated with different therapies and types of MS using historical data in RRMS (natalizumab, AFFIRM; dimethyl fumarate, DEFINE, CONFIRM), SPMS (natalizumab, ASCEND), and PPMS (rituximab, OLYMPUS). Comparisons were quantified by overall disability status (area under curve), trajectory of decline (slope), and difference at 2 years. Sensitivity analyses explored different thresholds or weighting for components and the relationship with conventionally defined confirmed improvement/worsening.
Results: ORS over time for each therapy vs placebo captured the treatment efficacy observed with established disability progression endpoints (AFFIRM: N=942; DEFINE: N=818; CONFIRM: N=722; ASCEND: N=887; OLYMPUS: N=439) and displayed lower variability. Differences by type of MS were observed in the ORS slope over time. Sensitivity analyses further demonstrated the endpoint's utility.
Conclusions: This novel endpoint includes well-established components and was sensitive to change, allowing assessment of worsening/improvement over time without censoring.
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.
LK: institution has received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; license fees for Neurostatus products; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation.
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.
PAC: consulting fees from Biogen; research support to his institution from Annexon Biosciences, Biogen, MedImmune, Novartis, and Teva.
IC, AS, YC, BZ, CC-V, AD, and SS: employees of and hold stock/options in Biogen.
Abstract: P777
Type: Poster
Abstract Category: Therapy - disease modifying - 30 Tools for detecting therapeutic response
Background: Disability in MS has been evaluated using confirmed worsening/improvement on several measures (EDSS, MSFC), or multicomponent endpoints with established change thresholds (EDSS, T25FW, 9HPT). Worsening/improvement are rarely examined jointly; current multicomponent endpoints do not tend to reflect changes on >1 disability measure. The patient population is typically classified by these criteria into binary categories (changed or not); data are usually censored after reaching the endpoint with subsequent disability worsening/stabilisation/improvement information lost. An endpoint integrating clinically relevant worsening/improvement across domains could provide a more complete assessment of disability trajectory and a sensitive tool to evaluate new therapies.
Objectives: To describe the overall response score (ORS), a novel endpoint measuring disability improvement and worsening simultaneously, and to evaluate its sensitivity to changes over time and relationship to established disability progression endpoints.
Methods: The ORS has 4 components: EDSS, T25FW, 9HPT (dominant and non-dominant), and a range of +4 to -4. At each visit, each component is scored vs baseline: -1 (threshold for worsening met), 0 (no change met threshold), or +1 (threshold for improvement met). Component thresholds are based on commonly used definitions. Patients are scored against baseline repeatedly over time. ORS was evaluated with different therapies and types of MS using historical data in RRMS (natalizumab, AFFIRM; dimethyl fumarate, DEFINE, CONFIRM), SPMS (natalizumab, ASCEND), and PPMS (rituximab, OLYMPUS). Comparisons were quantified by overall disability status (area under curve), trajectory of decline (slope), and difference at 2 years. Sensitivity analyses explored different thresholds or weighting for components and the relationship with conventionally defined confirmed improvement/worsening.
Results: ORS over time for each therapy vs placebo captured the treatment efficacy observed with established disability progression endpoints (AFFIRM: N=942; DEFINE: N=818; CONFIRM: N=722; ASCEND: N=887; OLYMPUS: N=439) and displayed lower variability. Differences by type of MS were observed in the ORS slope over time. Sensitivity analyses further demonstrated the endpoint's utility.
Conclusions: This novel endpoint includes well-established components and was sensitive to change, allowing assessment of worsening/improvement over time without censoring.
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.
LK: institution has received in the last 3 years and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; license fees for Neurostatus products; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation.
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.
PAC: consulting fees from Biogen; research support to his institution from Annexon Biosciences, Biogen, MedImmune, Novartis, and Teva.
IC, AS, YC, BZ, CC-V, AD, and SS: employees of and hold stock/options in Biogen.