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The purpose of this study is to evaluate the effect of steady-state carbamazepine (CBZ; a strong pregnane X receptor \[PXR\] agonist) on the pharmacokinetics (PK) of ponesimod following a gradual up-titration regimen in healthy adult participants.

International clinical trial to compare ponesimod and teriflunomide in relapsing multiple sclerosis

This is a Phase 1, single-center, double-blind, randomized, placebo and positive-controlled, double-dummy, parallel group, multiple-dose, up-titration study of the electrocardiographic effects of ponesimod in healthy male and female subjects with a nested cross-over comparison between moxifloxacin and placebo. Subjects will be randomly assigned to Group A (ponesimod treatment group) or Group B (placebo treatment group) in a 1:1 ratio. Subjects in Group B will be further randomized in a 1:1 ratio to one of the following sequences: 400 mg moxifloxacin followed by moxifloxacin-matching placebo or moxifloxacin matching placebo followed by 400 mg moxifloxacin.

BACKGROUND: Ponesimod is currently the only S1P receptor modulator studied in psoriasis. In a dose-finding study, the active doses showed similar efficacy. OBJECTIVE: Prediction of efficacy at lower doses to aid clinical phase 3 planning with respect to dose selection, duration of treatment, and patient inclusion criteria based on pharma-co-kinetic/pharmacodynamic (PK/PD) modeling and simulation. METHODS: The dose-finding study treated 326 patients (67 on placebo, 126 on 20mg, and 133 on 40mg) over 16 weeks. PK/PD modeling of steady-state trough concentrations and longitudinal PASI scores was employed to characterize data and simulate scenarios. RESULTS: PASI score continually decreased with time on ponesimod treatment, reaching a plateau at 16 weeks. Absolute and relative (percent) PASI score change was larger in patients with higher PASI score at baseline. Doses below 10mg were predicted to show lower efficacy than doses of 10mg and higher. CONCLUSION: Concentration-response modeling was able to predict the efficacy of doses that were not studied. In psoriasis patients, a dose of 10mg (not administered in the study) was predicted to show efficacy similar to 20mg. Disease status (PASI score at baseline) as study inclusion criterion has pronounced influence on study outcome.

OBJECTIVE: The aim of this study was to characterize the relationship between ponesimod plasma concentrations and the temporal evolution of lymphocyte counts in multiple sclerosis (MS) patients. METHODS: Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were developed using data from phase I, II, and III trials, and the impact of clinically relevant covariates on PK and PD parameters was assessed. Simulations were conducted to evaluate the maximal lymphocyte count reduction after ponesimod treatment, and the time required for total lymphocyte counts to return to normal values after treatment interruption. RESULTS: In MS patients, ponesimod PK were characterized by a low mean apparent plasma clearance (5.52 L/h) and a moderate mean apparent volume of distribution at steady state (239 L). The model developed indicated that none of the evaluated covariates (age, sex, formulation, food, body weight, clinical condition, and renal impairment) had a clinically relevant impact on the PK/PD parameters. In MS patients, total lymphocyte counts were characterized by a maximum reduction of 88.0% and a half maximal inhibitory concentration (IC50) of 54.9 ng/mL. Simulations indicated that in patients with normal hepatic function treated with ponesimod 20 mg daily, total lymphocyte counts were reduced to 41% of baseline at trough. After stopping treatment, lymphocyte counts were restored to normal levels within one week. CONCLUSIONS: The population PK/PD model well-characterized the PK of ponesimod and the time course of total lymphocyte counts in MS patients. Additionally, none of the evaluated covariates had a clinically relevant impact. This should be taken into consideration when assessing the risk of infection, administration of live-attenuated vaccines, and concomitant use of immunosuppressants.

Background Ponesimod is a potent selective sphingosine‐ 1‐phosphate receptor 1 (S1P1) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P1 receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis). Objectives The aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2). Methods Two open‐label, randomized, two‐way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed. Results Comparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC0‐inf), the area under the curve from time zero to the time of the last measurable concentration (AUC0‐t), the terminal half‐life (t1/2), and the maximum plasma concentration (Cmax) were all within the 0.80‐1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations. Conclusion The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability. Copyright © The Author(s) 2015.

AIMS: This study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine-1-phosphate (S1P1) receptor modulator in development for the treatment of auto-immune diseases. METHODS: This was a double-blind, placebo-controlled, ascending, single-dose study. Healthy male subjects received doses of 1-75 mg or placebo control. RESULTS: Ponesimod was well tolerated. Starting with a dose of 8 mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximal concentration ranged from 2.0 to 4.0 h, and ponesimod was eliminated with a mean half-life varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of ≥8 mg reduced total lymphocyte count in a dose-dependent manner. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts. CONCLUSIONS: Single doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single-dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once-a-day dosing.

OBJECTIVE: This double‐blind, placebo‐controlled, dose‐finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing‐remitting multiple sclerosis (RRMS). METHODS: 464 patients were randomised to receive once‐daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium‐enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated. RESULTS: The mean cumulative number of new T1 Gd+ lesions at weeks 12‐24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥ 1 treatment‐emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema. CONCLUSIONS: Once‐daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RRMS is under consideration. TRIAL REGISTRATION NUMBER: NCT01006265.

PURPOSE: To determine the effects of steady-state concentrations of the selective S1P1 receptor modulator ponesimod on the pharmacokinetics (PK) of a single dose of a combined oral contraceptive, containing 1 mg norethisterone (NET) and 35 μg ethinyl estradiol (EE) and to investigate the effects on heart rate at different ponesimod doses within an up-titration regimen prior to co-administration of the contraceptive. METHODS: Twenty-two healthy women (age: 29-60 years) received twice a single oral dose of the combined oral contraceptive, alone or in combination with multiple doses of 40 mg ponesimod attained by an up-titration regimen. Heart rate (HR) effects were assessed on the first day of each up-titration level. PK parameters of NET and EE were determined by non-compartmental analysis. RESULTS: Geometric mean ratios (ponesimod and contraceptive / contraceptive alone) of Cmax and AUC0-24 of NET were 0.87 (90 % CI: 0.80, 0.94) and 0.84 (90 % CI: 0.76, 0.93), respectively. Geometric mean ratios of Cmax and AUC0-24 of EE were 0.94 (90 % CI: 0.86, 1.03) and 0.95 (90 % CI: 0.89, 1.01), respectively. The maximum mean HR reduction after the first dose of 10 mg ponesimod was 12.4 bpm (SD ± 6.2) at 2.5 h post-dose. On Day 4 (first dose of 20 mg) and Day 7 (first dose of 40 mg) the maximum mean HR reduction was 4.3 bpm (SD ± 5.7) and 1.4 (SD ± 6.4), respectively, at 2.5 h post-dose compared to baseline. CONCLUSION: No clinically relevant PK interactions between ponesimod and the combined oral contraceptive were observed, therefore, efficacy of hormonal contraceptives is not expected to be affected by concomitant administration of ponesimod. The up-titration regimen showed that HR reductions are diminished upon repeated ponesimod administration.