Author Of 9 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.
P0071 - Effect of oral ponesimod on clinical disease activity and MRI-based outcomes in patients with relapsing multiple sclerosis: Phase 3 OPTIMUM study (ID 1570)
Abstract
Background
Ponesimod (PON), an orally active, highly selective and reversible modulator of sphingosine-1-phosphate receptor 1, reduces circulating lymphocytes by sequestration in lymphoid organs. In the phase-3 OPTIMUM study (NCT02425644), PON showed superior efficacy vs teriflunomide (TER) in patients with relapsing multiple sclerosis (RMS).
Objectives
To evaluate prespecified MRI-based endpoints and no evidence of disease activity (NEDA) status in patients with RMS.
Methods
Patients (18-55 years) with RMS (expanded disability status scale scores: 0-5.5) were randomized (1:1) to receive PON 20 mg or TER 14 mg for 108 weeks. MRI endpoints included: percentage change from baseline to week 108 in brain volume (SIENA, Structural Image Evaluation, using Normalization of Atrophy), mean number of new gadolinium-enhancing (Gd+) T1 lesions and volume/count of new/enlarging T2-weighted (T2) lesions. NEDA-3 (absence of confirmed relapse, 12-week confirmed disability accumulation, Gd+T1 and new/enlarging T2 lesions on annual MRIs) and NEDA-4 status (NEDA-3 and no average annual brain volume decrease ≥0.4%) were evaluated from baseline to week 108.
Results
985/1133 (86.9%) randomized patients completed the study. MRI findings for PON vs TER from baseline to week 108, respectively, were: least square (LS) mean percent change from baseline in brain volume: −0.91% vs −1.25% (difference: 0.34%, 95% CLs: 0.17;0.50, p<0.0001); LS mean difference (PON−TER) in change from baseline in total T2 lesion load: −399.2 mm3 (95% CLs: −651.5;−146.8, p=0.002); mean number of new/enlarging T2 lesions per year: 1.40 vs 3.16 (rate ratio [RR]: 0.44, 95% CLs: 0.36;0.54, p<0.0001); PON vs TER odds ratio (OR [95% CL]) for absence of new/enlarging T2 lesions: 1.71 (1.30;2.25, p=0.0001); mean number of new Gd+T1 lesions per scan: 0.18 vs 0.43 (RR: 0.42, 95% CLs: 0.31;0.56, p<0.0001); PON vs TER (OR [95% CL]) for absence of new Gd+T1 lesions: 2.18 (1.61;2.95, p<0.0001). At week 108, 28.2% (159/564) PON vs 18.3% (102/558) TER patients (OR: 1.70, 95% CLs: 1.27;2.28, p=0.0004) achieved NEDA-3; 15.0% (79/526) PON vs 8.5% (45/532) TER patients (OR: 1.85, 95% CLs: 1.24;2.76, p=0.0026) achieved NEDA-4. The most common reason for not achieving NEDA-3 or NEDA-4 status was presence of new/enlarging T2 lesions.
Conclusions
PON showed benefit vs TER for all MRI outcomes including brain volume loss and a significantly higher proportion of patients achieved NEDA-3 and NEDA-4 status, supporting the effects observed on clinical endpoints.
P0177 - Treatment Persistency for Patients in a Phase 2 Long-Term Extension Study of Ponesimod (ID 1700)
Abstract
Background
Multiple Sclerosis (MS) is a disorder of the central nervous system characterized by inflammation, demyelination, and degenerative changes. For chronic conditions requiring a potential lifetime of treatment, treatment discontinuation may result in significant clinical issues, including relapse risk and disease progression. There can be a number of factors contributing to treatment discontinuation, but several studies have demonstrated that adverse events and the lack of efficacy represented by continued disease progression are the leading causes. In MS, patient satisfaction with treatment is essential for sustained persistency and positive long-term health outcomes.
Objectives
Understanding the long-term safety and efficacy considerations of a potential treatment in a chronic disease such as MS is critical to both patients and providers. The aim of this analysis is to understand the frequency and reason leading to premature treatment discontinuation from the long-term extension for patients on the 20mg of ponesimod.
Methods
In the main phase 2 study (B201), a total of 464 subjects were randomized in a 1:1:1:1 ratio to receive ponesimod 10 mg (N=108), ponesimod 20 mg (N=116), ponesimod 40 mg (N=119), or placebo (N=121), resulting in a total of 462/464 (99.6%) treated subjects, of whom 393 completed the 24-week double-blind treatment period. Of the 393 subjects who completed treatment in the core study, subjects were eligible to be enrolled into of the extension study (B202) of three treatment phases (TP1, TP2, and TP3) maintaining the either the same dose or for placebo patients rerandomized to 10, 20 or 40mg (although the 40mg was discontinued after TP1).
Results
As of the 31 March 2019 (8.3 years after initiation), a total of 60.7% of subjects in the 20mg arm had maintained therapy on ponesimod over the course of the study and subsequent extensions. For those patients with premature discontinuations, reasons for discontinuation: 40.4% unknown subject decision, 28.1% tolerability/AE related, 17.5% efficacy related, and 14% other reasons.
Conclusions
Patient satisfaction with treatment is key to ensure adherence in a long-term chronic disease. The retention of over 60% of patients during an 8 year, phase 2 long term extension study suggests a high degree of patient satisfaction with the tolerability, safety and efficacy of ponesimod.
P0194 - Cardiac Safety of Ponesimod in Relapsing Multiple Sclerosis in the Randomized, Active-Controlled, Double-Blind, Parallel-Group Phase 3 OPTIMUM Study (ID 565)
Abstract
Background
Ponesimod (PON) is a sphingosine-1-phosphate receptor 1 modulator. Activation of these receptors on cardiomyocytes during treatment initiation cause transient effects on heart rate (HR) and antrioventicular (AV) conduction. The OPTIMUM phase 3 study assessed efficacy, safety, and tolerability of PON and teriflunomide (TER) in relapsing multiple sclerosis.
Objectives
We report on the cardiac safety profile of ponesimod versus teriflunomide in the phase 3 OPTIMUM study (NCT02425644).
Methods
Patients (18-55 years) were randomized 1:1 to PON (20 mg) or TER (14 mg) for 108 weeks. For PON, a gradual 14-day up-titration starting with 2 mg was implemented to address 1st-dose cardiac effects. Cardiac safety was assessed by blood pressure (BP) and 12-lead ECG measurements. Cardiac treatment-emergent adverse events (TEAEs), major adverse cardiovascular (CV) events (MACE; defined as CV death, non-fatal myocardial infarction [MI], and non-fatal stroke), and TEAEs of special interest (AESIs) are reported.
Results
Of 1131 patients who received treatment (PON: n=565, TER: n=566), baseline mean HR was 70.6 bpm (PON), 70.3 bpm (TER), range 45-126 bmp. Cardiac TEAEs leading to treatment discontinuation occurred in 1 (0.2%) patient on PON (cardiomyopathy) and 2 (0.4%) patients on TER (1 atrial fibrillation, 1 coronary artery insufficiency). No MACE were reported on PON; 3 MACE occurred on TER. HR and rhythm AESIs were reported in 29 (5.1%) PON patients vs. 24 (4.2%) TER patients. Incidence of HR and rhythm AESIs on Day 1 in the PON group (2 mg) was 2.1%, and included bradycardia (HR<50bpm) in 0.7% and 1st degree AV block in 0.5%; vs. 0.4% in TER. Max mean reduction in HR from pre- to post-dose on Day 1 was observed at 2h post-dose for PON at -8.7bpm compared with -1.7bpm for TER. On Day 1, 3 patients on PON had post-dose asymptomatic HR≤40bpm, all had pre-treatment HR<55bpm. On Day 1, new ECG findings of sinus bradycardia was 20.0% in patients at risk for symptomatic bradyarrhythmia, compared to 3.0% (all asymptomatic) in patients who were not at-risk. The up-titration was not associated with clinically significant bradyarrhythmia events; none were serious or leading to discontinuation of treatment, no 2nd degree or higher AV blocks were reported.
Conclusions
In the 2-year OPTIMUM study, PON treatment was not associated with an increased risk for major CV events such as MI, stroke, or CV death compared to TER. The up-titration regimen successfully mitigates 1st-dose effects and supports removing the requirement for 1st-dose cardiac monitoring in patients without risk factors of symptomatic bradycardia.
P0204 - Effect on disability measures and MSFC in patients with relapsing multiple sclerosis from the phase 3 ponesimod versus teriflunomide optimum study (ID 1667)
Abstract
Background
OPTIMUM was a multicenter, double-blind, active-comparator phase 3 superiority trial that assessed efficacy, safety, and tolerability of ponesimod 20 mg (PON) vs teriflunomide 14 mg (TER) in patients with relapsing multiple sclerosis (RMS). The primary endpoint of annualized relapse rate was met demonstrating PON’s superiority vs TER.
Objectives
To assess treatment effect on disability progression using time to worsening of timed 25-foot walk (T25FW), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test [PASAT-3] , Expanded Disability Status Scale (EDSS) and composites of these endpoints.
Methods
OPTIMUM enrolled patients with RMS (EDSS:0-5.5), randomized (1:1) to daily PON or TER for 108 weeks. Change in MS functional composite (MSFC) Z-score (mean of T25FW, 9HPT, PASAT-3 Z-scores), and SDMT from baseline to Week 108 was assessed using Mixed-Effect Model Repeated Measures. Analyses of time to first confirmed (12-week) disability event were conducted post-hoc; disability was defined as 4-point worsening in SDMT, 20% worsening in T25FW or 9HPT, in addition to EDSS (as defined for the secondary endpoint).
Results
Of 1133 patients (PON=567, TER=566), 86.9% completed study. Changes from baseline in overall MSFC Z‑score: 0.02 PON vs −0.039 TER (mean difference, 0.059; p=0.047); for the 3 individual components of MSFC Z-score, mean differences (p-values) were: T25FW, 0.20 sec (p=0.37); 9HPT, –0.93 sec (p<0.0001); PASAT-3, 0.55 number correct (p=0.16). The PON vs TER worsening events up to EOS were, respectively: confirmed 20% worsening in T25FW, 9.2% vs 13.1% (hazard ratio [HR]:0.70; p=0.045); 4-point worsening in SDMT, 22.1% vs 26.4% (HR:0.82; p=0.12)], composite EDSS/SDMT, 26.3% vs 32.7% (HR:0.80; p=0.045)]; composite EDSS/9HPT/T25FW, 18.2% vs 24.0% (HR:0.76; p=0.035); numerical differences in favour of PON in time to confirmed worsening in 9HPT and SDMT assessed individually were not statistically significant.
Conclusions
Measures of worsening of impairment and disability in this exploratory analysis indicated benefits for PON vs TER. Composite endpoints provide more power to statistical assessments owing to greater number of events analyzed, making them particularly useful in RMS trials.
P0215 - Long-term efficacy and safety of ponesimod: Results from randomized phase II core and extension studies in relapsing‑remitting multiple sclerosis (ID 470)
Abstract
Background
Ponesimod, an orally active, selective sphingosine 1-phosphate receptor-1 (S1P) modulator, showed benefits in clinical and MRI outcomes in a double-blind, placebo controlled, phase 2b Core Study (NCT01006265). Patients rolled-over into an ongoing Extension Study (NCT01093326).
Objectives
Evaluate the long-term efficacy and safety of ponesimod in patients with relapsing-remitting multiple sclerosis (RRMS).
Methods
A total of 435 patients with RRMS received ≥1 dose of ponesimod (10, 20, or 40-mg/day) during the Core and/or Extension Study. The 40 and 10-mg doses were subsequently discontinued during Treatment Period 1 (TP1) and TP2 of the Extension Study. All patients received 10 or 20-mg during TP2, followed by open-label 20-mg in TP3. Key efficacy parameters: annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), and MRI outcomes. Safety parameters: frequencies of adverse events (AEs) and serious AEs (SAEs). Results of combined analyses of Core and Extension studies are presented.
Results
As of 31 March 2019, 214 patients were still on ponesimod treatment; median exposure in 20-mg group was 8.02 years; Cumulative exposure across all doses was 2372.47 patients-years. In 20-mg group, ARR (95% CI) for confirmed relapses was 0.154 (0.111‒0.214); 64.1% patients remained free of confirmed relapse; Kaplan-Meier estimate of 6- month CDA at Week 432 was 20.4% (13.7‒29.7); Mean number of T1 gadolinium enhancing lesions per patient per scan was 0.448 (0.305‒0.657); Mean number of new or enlarging T2 lesions per year was 0.718 (0.523‒0.985). In ponesimod-treated patients, the most common treatment-emergent AEs were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%). Most SAEs were reported in a single patient, no SAE was reported at an incidence of >1%.
Conclusions
Long-term treatment with ponesimod 20 mg showed consistently low levels of disease activity across relevant clinical and MRI outcomes in patients with RRMS. No new safety signals were identified.
P0224 - Pharmacokinetic-Pharmacodynamic Models of Lymphocyte Count and Heart Rate Following Ponesimod Dosing in a Phase 2 Study in Multiple Sclerosis Patients (ID 582)
Abstract
Background
Ponesimod (PON) is a sphingosine-1-phosphate receptor 1 modulator in development for the treatment of relapsing multiple sclerosis. A population PK (PopPK) model was previously developed from data of healthy volunteers (HV) and MS patients. Pharmacokinetic-pharmacodynamic (PK-PD) models describing the effect of PON on lymphocyte count (LC) and heart rate (HR) were also available based on data from HV.
Objectives
To evaluate previously developed PopPK and PK-PD models to characterize the effect of PON on LC and HR in patients with MS from a phase 2 study.
Methods
Patients randomized (1:1:1:1) in the multicenter, double-blind, B201 study (NCT01006265) received PON 10, 20, and 40 mg QD (up-titrated every 7 days from 10 mg) or placebo for 24 weeks. PON plasma concentrations, LC, and HR measurements (2508, 3938, and 10336 measurements, respectively) were obtained from 461 patients (107, 114, 119, 121 patients in 10, 20, 40 mg PON, or placebo, respectively). Models were fit to the observations using nonlinear mixed-effects models, using NONMEM 7.3.0 (ICON plc).
Results
PON PK were well described by the available open 2-compartment linear PopPK model. The PK-LC model was characterized by parameters (maximal effect and concentration inhibiting 50% LC of 0.86∙109 L-1 and 43.4 ng/mL, respectively) in agreement with those previously obtained in HV. The model estimated a mean reduction of LC at steady state (CV%) of 50.20% (19.2%), 66.61% (12.2%), and 72.36% (12.6%) for 10, 20, and 40 mg doses, respectively. LC are predicted to return to baseline by 1 week after the end of dosing. No clinically relevant covariates were identified for this model, indicating that covariate-based dose adjustments are not warranted. The maximal effect parameter of the PK-HR model was found to be lower in MS patients (24.7% decrease) compared to HV (44.9%) to accommodate a lower incidence of bradycardia (HR<50bpm). After 2 weeks of treatment with 10 mg, the model indicated full tolerance development. Further increasing the PON dose did not have additional effects on HR. Baseline HR was identified as a significant covariate indicating increased bradycardia in case of low baseline HR. The PK-HR model supported first-dose HR monitoring in patients with baseline HR<55 bpm given PON.
Conclusions
The previously developed PopPK, PK-LC, and PK-HR PON models were able to describe the observed data and corresponding variability in patients with MS, consistently with previous knowledge from HV.
P1064 - Treatment Preferences of Patients with Relapsing Multiple Sclerosis: A Discrete Choice Experiment (ID 935)
Abstract
Background
A variety of treatments are available to slow the progression of multiple sclerosis (MS). Understanding patient preferences for efficacy and safety attributes of MS treatment can help clinicians and other decision-makers ascertain which treatments are acceptable to patients based on their overall benefit-risk profiles.
Objectives
To quantify the relative importance of treatment attributes to patients with relapsing MS and to measure how large a change in disease progression or relapse rate patients are willing to tolerate for improvements in other attributes.
Methods
A cross-sectional online Discrete Choice Experiment (DCE) in adults with relapsing MS was conducted in Poland, Russia, the United States, and the United Kingdom. Participants were considered relapsing if they had ≥1 MS attack within the last year or ≥2 MS attacks within the past 2 years prior to start of treatment. Preferences were elicited for 7 MS treatment attributes: drug interactions, cognitive fatigue, physical fatigue, immune system recovery time, monitoring visits, time to disease progression, and number of relapses. Multinomial logit models were used to estimate maximum decrease in time to disease progression and increase in relapses within 2 years that is acceptable in exchange for improvements in other attributes. P<0.05 was considered statistically significant.
Results
The DCE was completed by 201 participants. The mean age was 39 ± 10 years. All attributes included in the DCE significantly affected participant choices, although cognitive fatigue, physical fatigue, and time to disease progression were the most valued. Participants were willing to accept up to 4.4 years (95% CI, 2.3–6.4) decrease in time to disease progression or up to 4.6 additional relapses (95% CI, 2.0–7.2) within 2 years in exchange for an improvement in physical fatigue from ‘quite a bit difficulty’ to ‘moderate difficulty’. Further, participants were willing to accept up to 2.8 years (95% CI, 1.1–4.4) decrease in time to disease progression or up to 2.9 additional relapses (95% CI, 1.1–4.6) within 2 years in exchange for a similar improvement in cognitive fatigue.
Conclusions
Of the attributes tested, patients with relapsing MS most valued improvements in physical and cognitive fatigue and they were willing to accept significant increase in number of relapses and decrease in time to disease progression to obtain improvements in fatigue.