Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial

Abstract

ObjectiveThis 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).Methods464 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.ResultsThe 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.ConclusionsOnce-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 numberNCT01006265.

Biocomparison of THREE formulations of the S1P1 receptor modulator ponesimod in healthy subjects

“…Between Study 1 and Study 2, the increases in C max were dose proportional and the increases in AUC were slightly greater than dose proportional, which is in line with the findings of previous clinical studies performed with ponesimod [8][9][10][11]. Whereas similar exposure in male and female subjects has been seen previously [10], the findings of a recent study [11] are in good agreement with the greater exposure in female subjects that was observed in the present work.…”

“…In terms of safety and tolerability, a similar incidence and nature of adverse events was observed in Study 1 and Study 2. No new findings were observed, in comparison with previous studies [7][8][9][10][11][12][13]. The incidence of adverse events and the percentage of subjects displaying adverse events were dose dependent.…”

“…Ponesimod (ACT-128800) is a potent, orally active, selective, reversible S1P 1 receptor modulator [6] currently in clinical development for the treatment of autoimmune diseases and has successfully reached its study end points in recent phase II trials in patients with chronic plaque psoriasis [7] or relapsing-remitting multiple sclerosis [8]. Single-and multiple-dose administration of ponesimod results in a dose-dependent decrease in circulating lymphocytes in healthy subjects and is associated with heart rate reduction, a delay in atrioventricular conduction, and pulmonary effects [9][10][11][12][13].…”

Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases

“…A double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy, safety and tolerability of ponesimod in the treatment of relapsing remitting MS [ClinicalTrials.gov identifier: NCT01006265] (Table 1) [Olsson et al 2014]. A total of 464 patients were randomized across 94 centers in 23 countries (in Europe, Australia, Canada and USA) between October 2009 and November 2010 to receive ponesimod 10, 20 and 40 mg o.d.…”

Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator

“…Thus, S1P 1 receptor modulators as ponesimod may be a valuable therapeutic approach for various autoimmune diseases such as rheumatoid arthritis, type I diabetes, MS and psoriasis. In the last two mentioned diseases, the modulation of lymphocytes in peripheral blood by ponesimod was shown to have positive effects in Phase II trials [6,7].At single doses ranging from 1 to 75 mg and multiple doses of up to 100 mg once daily, in healthy individuals, ponesimod's pharmacokinetic (PK) profile was characterized by a rapid absorption, with time to maximum concentration (t max ) of 2-4 hr, a terminal half-life (t 1/2 ) of approximately 30 hr and an accumulation factor of 2-2.5 with generally low variability [8]. These PK properties were also confirmed in a thorough QT study in which 40 and 100 mg multiple doses of ponesimod were administered to healthy individuals [9].…”