Multicenter, randomized, double-blind, parallel-group extension to study AC 058B201 to investigate the long-term safety, tolerability, and efficacy of 10, 20, and 40 mg/day ponesimod, an oral S1P1 receptor agonist, in patients with relapsing-remitting multiple sclerosis

Multicenter, randomized, double-blind, parallel-group extension to study AC
058B201 to investigate the long-term safety, tolerability, and efficacy of 10,
20, and 40 mg/day ponesimod, an oral S1P1 receptor agonist, in patients with
relapsing-remitting multiple sclerosis.

In order to differentiate between the original treatment period of up to 96
weeks and the prolonged treatment period of 432 weeks, the study has been
subdivided into two periods:
* Treatment period 1: original up to 96 weeks (10, 20, and 40 mg ponesimod).
* Treatment period 2/3: up to 540 weeks (10 and 20 mg ponesimod).

* To investigate the long-term safety and tolerability of ponesimod
* To investigate the long-term efficacy of ponesimod
* To explore the dose response relationship of 10, 20 and 40 mg ponesimod on
lymphocyte count, MRI endpoints and annualized relapse rate (ARR).

Prospective, multicenter, multinational, randomized, double-blind,
multiple-dose, uncontrolled, parallel group extension to Phase 2b study
AC-058B201.

Treatment period 1 (up to 96 weeks)
One capsule of ponesimod, administered orally in the morning with or without
breakfast (preferably always in the same way and at approximately the same
time).
* Group I: Patients who received 10 mg during the core study, will also
receive 10 mg until the end of treatment in the extension study.
* Group II: Patients who received 20 mg during the core study, will also
receive 20 mg until the end of treatment in the extension study.
* Group III: Patients who received 40 mg during the core study, will also
receive 40 mg for up to 96 weeks.
Patients who received placebo during the core study will continue on placebo
during the transition period and then be randomised 1:1:1 to:
* Group IV: 10 mg from Day 1 until the end of treatment in the extension study.
* Group V: 10 mg from Day 1 to Day 7. 20 mg from Day 8 until the end of
treatment in the extensions study.
* Group VI: 10 mg from Day 1 to Day 7. 20 mg from Day 8 to Day 14. 40 mg from
Day 15 for up to 96 weeks

Treatment period 2/3 (up to 540 weeks)
Patients who have received 40 mg ponesimod in treatment period 1, will be
re-assigned randomly to receive either 10 or 20 mg ponesimod during period 2.
These patients should at least have completd visit E9 of treatment period 1.
If patients have received 10 or 20 mg ponesimod in treatment period 1, they
will continue with the same dose throughout period 2.
From the first visit of treatment period 2 onwards, the capsules will be
replaced by tablets of ponesimod. Patients will continue taking the tablets in
exactly the same way as they took the capsules before.

Treatment period 1 (up to 96 weeks + follow up period)
Hospital visits x 15
Blood sample x 14
Physical examination x14
MRI x4
Chest X-ray x1
ECG x 33
Pulmonary function test x 11
Ophthalmological Assessment x 7
Echocardiography x5

Treatment period 2 and 3 (up to 540 weeks + follow up period)
Hospital visits x 40
Blood sample x 40
Physical examination x 40
MRI x 11
Chest X-ray x 2
ECG x 39
Pulmonary function test x 22
Ophthalmological Assessment x 20
Echocardiography x 19

Headache, dizziness, fatigue, a transient drop in heart rate after
administration of the first dose of ponesimod, asymptomatic, intermittent
AV-block second degree Mobitz type I/Wenckebach after administration of first
dose of 10 mg ponesimod, QT prolongation after administration of first dose of
10 mg ponesimod. A reduction in FEV1 (mainly observed with the 40 mg dose) has
been reported in previous clinical trials with ponesimod. Due to
immunosuppression in general there may be an increased risk of opportunistic
infections and skin cancers. However, this has not been seen in previous
clinical trials with ponesimod.