Author Of 3 Presentations
P0048 - Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: A Longitudinal Model-Based Meta-Analysis for Confirmed Disability Accumulation (ID 1257)
Abstract
Background
Multiple sclerosis (MS) is an inflammatory autoimmune disorder and causes progressive neurological disability in young adults. Ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator, is under development for treatment of relapsing multiple sclerosis (RMS).
Objectives
To assess the effect of ponesimod on confirmed disability accumulation (CDA) relative to placebo and other disease-modifying therapies (DMTs) in treating RMS.
Methods
A literature review was performed and a database of 154 unique trials with 58 MS treatments was developed. The database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Results for CDA were reported with Kaplan-Meier plots; thus, extensive data were available to develop a longitudinal model for probability of a 12-week CDA event. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time. Arm-level variables explored as effect modifiers included: percent of patients with remitting RMS, trial start year, mean duration of disease, percent of patients who received DMT within past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.
Results
This model utilized longitudinal data from 26 RCTs in RMS (18 unique treatments [including placebo], 69 treatment arms, and 417 timepoints in 31,160 patients). HRs were estimated for 12-week CDA for 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (6 treatments). Relative treatment effect was found to be significantly smaller in trials with higher pDMT. Results favored ponesimod in comparison to placebo (HR: 0.61; 95% CI: 0.44–0.83), glatiramer acetate (0.65; 0.44–0.94), and interferon β-1b (0.51; 0.33–0.77) in delaying 12-week CDA. Ponesimod was estimated to have numerical improvement to S1P receptor modulators fingolimod, ozanimod, laquinimod, as well as teriflunomide, interferon β-1a (intramuscular and subcutaneous), peginterferon β-1a, cladribine, daclizumab, and dimethyl fumarate (HR range: 0.77–0.94).
Conclusions
Ponesimod was statistically superior compared to placebo and a range of other DMTs suggesting robust efficacy in the treatment of MS.
P0049 - Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: A Model-Based Meta-Analysis for Annual Relapse Rate (ID 1256)
Abstract
Background
Multiple sclerosis (MS), an inflammatory autoimmune disorder, is responsible for progressive neurological disability among young adults. Ponesimod is a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator under development for relapsing multiple sclerosis (RMS).
Objectives
To assess the effect of ponesimod on the annual relapse rate (ARR) relative to other disease-modifying therapies (DMTs) for treatment of RMS.
Methods
A literature review was performed and a database with 154 unique clinical trials with 58 MS treatments was created. This database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Mean ARR for each treatment arm was modeled and rate ratios (RRs) between treatments were assumed constant from 48 to 156 weeks. Multiple arm-level variables were explored as modifiers of relative treatment effect: percent of patients with remitting RMS, trial start year, mean disease duration, percent of patients with history of DMT use in past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.
Results
The model utilized mean ARR data from 41 RCTs in RMS (18 unique treatments [including placebo], 106 treatment arms, 33,904 patients). Rate ratios were estimated for all 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (8 treatments). Relative treatment effect was smaller in trials with higher pDMT. In addition to superiority of ponesimod vs. teriflunomide, results suggested that ponesimod reduced ARR significantly compared to placebo (RR: 0.47; 95% CI: 0.32–0.68), interferon β-1a (intramuscular, 0.57; 0.39–0.85), laquinimod (0.58; 0.38–0.88), and interferon β-1b (0.65; 0.44–0.97). Results suggested that ponesimod had numerically superior ARR benefits compared to interferon β-1a (subcutaneous), peginterferon β-1a, glatiramer acetate, and dimethyl fumarate (RR range: 0.68–0.94). Ponesimod had similar ARR benefits to S1P receptor modulators ozanimod, fingolimod, cladribine, and daclizumab (RR range: 1.00–1.04).
Conclusions
Ponesimod reduced ARR in patients with RMS, and was statistically superior as compared with placebo and a range of other DMTs.
P1027 - Establishing Meaningful Change Threshold in Multiple Sclerosis related Fatigue on Fatigue Symptoms & Impacts Questionnaire-Relapsing MS (FSIQ-RMS) (ID 1249)
Abstract
Background
Fatigue, one of the most common symptoms in patients with multiple sclerosis (MS), impairs activity and limits physicial functioning in patients. A new patient reported outcome (PRO) instrument, the Fatigue Symptoms and Impact Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS) has been developed with input from MS patients, to capture patient experience of MS related fatigue and addresses the limitations of existing fatigue instruments. The FSIQ-RMS is an MS specific, content-valid, concise instrument to assess symptoms relevant to MS and the impact of these symptoms on patients' lives.
Objectives
The aim of this research was to establish a meaningful change threshold (MCT) for patients with MS associated fatigue on the FSIQ-RMS symptoms domain. Within-subject change of fatigue is critical for interpreting the individual effect of treatment on patients in terms of treatment response.
Methods
Data from the OPTIMUM study (NCT02425644) were obtained to derive MCT on the FSIQ-RMS symptoms domain score. The symptoms domain comprises seven items scored on an 11-point scale (0–10); with standardized domain score range from 0 to 100 with a higher score indicating greater fatigue. The Patient Global Impression of Severity of fatigue (PGI-S) assessed the patient’s fatigue severity on a 11-point Numeric Rating Scale from 0-10, anchored at 0 = “not severe at all” and 10 =”very severe”. The PGI-S was used as an anchor to establish and assess potential range of MCTs based on the magnitude of correlation between FSIQ-RMS symptoms domain score and PGI-S, and variability of change. Cumulative distribution function and kernel density plots (probability density functions [PDFs]) were also generated.
Results
Correlation between the scales measuring change from baseline to end of treatment (Week 108) was above the acceptable threshold (0.35 [r=0.471]). Final analyses of the blinded OPTIMUM study data showed that an MCTof -6.3 points on the FSIQ-RMS symptom scale was equivalent to a 3-point improvement on the PGI-S, and captured all patients reporting improvement on the PGI-S without overlapping with patients reporting no change. The MCT of ‑6.3 points also exhibited a moderate effect size consistent with established guidelines.
Conclusions
Development of the MCT for the FSIQ-RMS provides an important metric to understand within patient improvement in fatigue symptoms using a PRO developed to specifically measure symptoms of MS fatigue.
Presenter Of 3 Presentations
P0048 - Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: A Longitudinal Model-Based Meta-Analysis for Confirmed Disability Accumulation (ID 1257)
Abstract
Background
Multiple sclerosis (MS) is an inflammatory autoimmune disorder and causes progressive neurological disability in young adults. Ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator, is under development for treatment of relapsing multiple sclerosis (RMS).
Objectives
To assess the effect of ponesimod on confirmed disability accumulation (CDA) relative to placebo and other disease-modifying therapies (DMTs) in treating RMS.
Methods
A literature review was performed and a database of 154 unique trials with 58 MS treatments was developed. The database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Results for CDA were reported with Kaplan-Meier plots; thus, extensive data were available to develop a longitudinal model for probability of a 12-week CDA event. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time. Arm-level variables explored as effect modifiers included: percent of patients with remitting RMS, trial start year, mean duration of disease, percent of patients who received DMT within past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.
Results
This model utilized longitudinal data from 26 RCTs in RMS (18 unique treatments [including placebo], 69 treatment arms, and 417 timepoints in 31,160 patients). HRs were estimated for 12-week CDA for 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (6 treatments). Relative treatment effect was found to be significantly smaller in trials with higher pDMT. Results favored ponesimod in comparison to placebo (HR: 0.61; 95% CI: 0.44–0.83), glatiramer acetate (0.65; 0.44–0.94), and interferon β-1b (0.51; 0.33–0.77) in delaying 12-week CDA. Ponesimod was estimated to have numerical improvement to S1P receptor modulators fingolimod, ozanimod, laquinimod, as well as teriflunomide, interferon β-1a (intramuscular and subcutaneous), peginterferon β-1a, cladribine, daclizumab, and dimethyl fumarate (HR range: 0.77–0.94).
Conclusions
Ponesimod was statistically superior compared to placebo and a range of other DMTs suggesting robust efficacy in the treatment of MS.
P0049 - Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: A Model-Based Meta-Analysis for Annual Relapse Rate (ID 1256)
Abstract
Background
Multiple sclerosis (MS), an inflammatory autoimmune disorder, is responsible for progressive neurological disability among young adults. Ponesimod is a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator under development for relapsing multiple sclerosis (RMS).
Objectives
To assess the effect of ponesimod on the annual relapse rate (ARR) relative to other disease-modifying therapies (DMTs) for treatment of RMS.
Methods
A literature review was performed and a database with 154 unique clinical trials with 58 MS treatments was created. This database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Mean ARR for each treatment arm was modeled and rate ratios (RRs) between treatments were assumed constant from 48 to 156 weeks. Multiple arm-level variables were explored as modifiers of relative treatment effect: percent of patients with remitting RMS, trial start year, mean disease duration, percent of patients with history of DMT use in past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.
Results
The model utilized mean ARR data from 41 RCTs in RMS (18 unique treatments [including placebo], 106 treatment arms, 33,904 patients). Rate ratios were estimated for all 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (8 treatments). Relative treatment effect was smaller in trials with higher pDMT. In addition to superiority of ponesimod vs. teriflunomide, results suggested that ponesimod reduced ARR significantly compared to placebo (RR: 0.47; 95% CI: 0.32–0.68), interferon β-1a (intramuscular, 0.57; 0.39–0.85), laquinimod (0.58; 0.38–0.88), and interferon β-1b (0.65; 0.44–0.97). Results suggested that ponesimod had numerically superior ARR benefits compared to interferon β-1a (subcutaneous), peginterferon β-1a, glatiramer acetate, and dimethyl fumarate (RR range: 0.68–0.94). Ponesimod had similar ARR benefits to S1P receptor modulators ozanimod, fingolimod, cladribine, and daclizumab (RR range: 1.00–1.04).
Conclusions
Ponesimod reduced ARR in patients with RMS, and was statistically superior as compared with placebo and a range of other DMTs.
P1027 - Establishing Meaningful Change Threshold in Multiple Sclerosis related Fatigue on Fatigue Symptoms & Impacts Questionnaire-Relapsing MS (FSIQ-RMS) (ID 1249)
Abstract
Background
Fatigue, one of the most common symptoms in patients with multiple sclerosis (MS), impairs activity and limits physicial functioning in patients. A new patient reported outcome (PRO) instrument, the Fatigue Symptoms and Impact Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS) has been developed with input from MS patients, to capture patient experience of MS related fatigue and addresses the limitations of existing fatigue instruments. The FSIQ-RMS is an MS specific, content-valid, concise instrument to assess symptoms relevant to MS and the impact of these symptoms on patients' lives.
Objectives
The aim of this research was to establish a meaningful change threshold (MCT) for patients with MS associated fatigue on the FSIQ-RMS symptoms domain. Within-subject change of fatigue is critical for interpreting the individual effect of treatment on patients in terms of treatment response.
Methods
Data from the OPTIMUM study (NCT02425644) were obtained to derive MCT on the FSIQ-RMS symptoms domain score. The symptoms domain comprises seven items scored on an 11-point scale (0–10); with standardized domain score range from 0 to 100 with a higher score indicating greater fatigue. The Patient Global Impression of Severity of fatigue (PGI-S) assessed the patient’s fatigue severity on a 11-point Numeric Rating Scale from 0-10, anchored at 0 = “not severe at all” and 10 =”very severe”. The PGI-S was used as an anchor to establish and assess potential range of MCTs based on the magnitude of correlation between FSIQ-RMS symptoms domain score and PGI-S, and variability of change. Cumulative distribution function and kernel density plots (probability density functions [PDFs]) were also generated.
Results
Correlation between the scales measuring change from baseline to end of treatment (Week 108) was above the acceptable threshold (0.35 [r=0.471]). Final analyses of the blinded OPTIMUM study data showed that an MCTof -6.3 points on the FSIQ-RMS symptom scale was equivalent to a 3-point improvement on the PGI-S, and captured all patients reporting improvement on the PGI-S without overlapping with patients reporting no change. The MCT of ‑6.3 points also exhibited a moderate effect size consistent with established guidelines.
Conclusions
Development of the MCT for the FSIQ-RMS provides an important metric to understand within patient improvement in fatigue symptoms using a PRO developed to specifically measure symptoms of MS fatigue.