This multiple‐ascending‐dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P₁ receptor modulator and a potential new treatment for autoimmune diseases. In part A, 10 healthy male and female subjects received once daily oral doses of ponesimod (5, 10, or 20 mg) or placebo for 7 days. Sinus bradycardia and, in some subjects, atrioventricular (AV) block occurred primarily on the first day of dosing, as desensitization developed to ponesimod‐induced heart rate (HR) reduction and PR‐prolongation. This elicited the design of an up‐titration schedule in 17 subjects to a dose of 40 mg in part B. The up‐titration regimen reduced HR and PQ/PR effects. Reported adverse events were mainly related to the cardiac and respiratory systems. Respiratory effects increased with higher doses. Ponesimod multiple‐dose pharmacokinetics were slightly more than dose‐proportional and characterized by a time to maximum concentration and an elimination half‐life varying from 2.5 to 4.0 hours and 30.9 to 33.5 hours, respectively, and an accumulation of about 2.3‐fold. Ponesimod caused a dose‐dependent sustained decrease in total lymphocyte count, reversible within 7 days of discontinuation. A pharmacokinetic–pharmacodynamic model enabled comparing day 1 and steady‐state conditions. These results warrant further investigation of ponesimod in patients.

The racemic mixture dimiracetam negatively modulates NMDA-induced glutamate release in rat spinal cord synaptosomal preparations and is orally effective in models of neuropathic pain. In this study, we compared the effects of dimiracetam, its R- or S-enantiomers, and the R:S 3:1 non-racemic mixture (MP-101). In vitro, dimiracetam was more potent than its R- or S-enantiomers in reducing the NMDA-induced [³H]D-aspartate release in rat spinal cord synaptosomes. Similarly, acute oral administration of dimiracetam was more effective than a single enantiomer in the sodium monoiodoacetate (MIA) paradigm of painful osteoarthritis. Then, we compared the in vitro effects of a broad range of non-racemic enantiomeric mixtures on the NMDA-induced [³H]D-aspartate release. Dimiracetam was a more potent blocker than each isolated enantiomer but the R:S 3:1 non-racemic mixture (MP-101) was even more potent than dimiracetam, with an IC₅₀ in the picomolar range. In the chronic oxaliplatin-induced neuropathic pain model, MP-101 showed a significantly improved anti-neuropathic profile, and its effect continued one week after treatment suspension. MP-101 also performed better than dimiracetam in animal models of cognition and depression. Based on the benign safety and tolerability profile previously observed with racemic dimiracetam, MP-101 appears to be a novel, promising clinical candidate for the prevention and treatment of several neuropathic and neurological disorders.