Author Of 2 Presentations
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)
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).
To evaluate prespecified MRI-based endpoints and no evidence of disease activity (NEDA) status in patients with RMS.
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.
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.
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.
P0204 - Effect on disability measures and MSFC in patients with relapsing multiple sclerosis from the phase 3 ponesimod versus teriflunomide optimum study (ID 1667)
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.
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.
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).
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.
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.