Author Of 3 Presentations
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.
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.