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

Abstract

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.

Keywords: Multiple Sclerosis.

Figure 1

Study design. All patients randomised to ponesimod initially received ponesimod 10 mg (days 1–7). On day 8, patients randomised to receive ponesimod 20 or 40 mg were up-titrated to the 20 mg dose and patients randomised to the 10 mg dose were mock up-titrated. On day 15, patients randomised to receive ponesimod 40 mg were up-titrated to the 40 mg dose; patients randomised to ponesimod 10 or 20 mg were mock up-titrated. Patients randomised to placebo were mock up-titrated on days 8 and 15. Patient numbers are for the all-treated population. FU, follow-up.

Figure 2

Patient flow. ^†Two patients randomised to the ponesimod 20 mg group did not start treatment due to safety findings that were noted after randomisation (low heart rate and abnormal Holter ECG readings). ^‡Respiratory system criteria. ^§One patient discontinued treatment due to pregnancy, one patient discontinued treatment due to respiratory system criteria.

Figure 3

(A) Cumulative number of new T1 Gd+ lesions detected by magnetic resonance image scanning at weeks 12–24 (per-protocol analysis set). Graph shows mean+SE. The percentage reduction (95%CI) versus placebo is shown for each ponesimod treatment group. (B) Dose–response analysis for the cumulative number of new T1 Gd+ lesions from week 12 to 24 (per-protocol analysis set). Black dots represent the mean value for each dose and grey dots represent the fitted models obtained in the bootstrap process. *p<0.05; **p<0.0001. T1 Gd+, T1-weighted gadolinium-enhanced.

Figure 4

Kaplan–Meier estimate of the time to first confirmed relapse up to week 24 (all-treated analysis set).

Figure 5

(A) Percentage change from baseline in lymphocyte counts up to week 24 (all-treated analysis set). (B) The group of patients who underwent safety follow-up (discontinued treatment prematurely or did not enter the extension study). FU1, follow-up visit 1 (end of treatment + 7 days); FU2, follow-up visit 2 (end of treatment+30 days).

Figure 6

Mean change from baseline in heart rate (bpm) on day 1 (A), day 8 (B) and day 15 (C) (all-treated analysis set).