Actelion Ltd has announced that it is accelerating its clinical development efforts in the field of immunological disorders, following a broad scientific, medical and commercial evaluation of a series of its selective S1P1 receptor modulators, discovered in-house.

Actelion has initiated Phase III development with ponesimod, its lead compound, in patients suffering from relapsing multiple sclerosis, with patient enrollment expected imminently.

In parallel, Actelion will also initiate a Phase II study with ponesimod in patients suffering from chronic graft versus host disease. In addition, a second selective S1P1 receptor modulator will advance into Phase II clinical development in patients with systemic lupus erythematosus.

Jean-Paul Clozel, M.D. and Chief Executive Officer commented: "Our efforts in the field of immunology have reached the necessary maturity to warrant fully-fledged clinical investigation. We have a thorough understanding of what selective S1P1 receptor modulators can bring to the clinic and have matched our compounds with the appropriate indication. We have carried out extensive groundwork and benefited from Health Authority input to design the optimal clinical program, which balances clinical risk, investment, medical need and commercial opportunity."

Jean-Paul continued: "Our ongoing success in the field of PAH is enabling us to pursue the second element of our strategy and take action now to build an additional specialty franchise in the field of immunology. Our confidence in our portfolio means we can take this step while maintaining our commitment to optimize profitability."

About the Phase III Program of Ponesimod in Multiple Sclerosis

OPTIMUM, is a multicenter, randomized, double-blind, parallel-group, active-controlled superiority study to compare the efficacy and safety of ponesimod to teriflunomide in subjects with relapsing multiple sclerosis. The study aims to determine whether ponesimod is more efficacious than teriflunomide in reducing relapses. The study is expected to enroll approximately 1'100 subjects, randomized in 2 groups in a 1:1 ratio to receive ponesimod 20 mg/day or teriflunomide 14 mg/day, and is expected to last a little over 3 years.

Guy Braunstein, M.D. and Head of Global Clinical Development commented: "The ongoing extension of the Phase II study, has provided a substantial amount of long-term efficacy and safety data with ponesimod in patients with multiple sclerosis, including some who have been treated for more than 5 years. In addition, we have identified a gradual up-titration dosing regimen that could mitigate the known first-dose effects of this class of drug. This regimen has been tested in a dedicated trial and the results will be presented in June this year."

Guy Braunstein added: "Ponesimod brings a number of unique properties, which include selectivity for the S1P1 receptor, rapid onset of action, a clear dose-response, and rapid reversibility upon discontinuation, an important option for physicians in case restoration of the immune system is required. We are convinced that - following regulatory approval - all these features and the data collected can make ponesimod an important oral therapeutic option."

An additional study to further characterize the utility and differentiation of ponesimod in multiple sclerosis is being discussed with Health Authorities.

The decision to move into Phase III development was based on the Phase IIb dose-finding study with ponesimod in patients with relapsing-remitting multiple sclerosis. A total of 464 patients were randomized into this study and the efficacy, safety and tolerability of three ponesimod doses (10, 20 and 40 mg/day) versus placebo, administered once daily for 24 weeks, was evaluated.

The primary endpoint of this study was defined as the cumulative number of new gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) scans at weeks 12, 16, 20 and 24 after study drug initiation. A key secondary endpoint of this study was the annualized relapse rate over 24 weeks of treatment. The results of this study were published during 2014 in the Journal of Neurology, Neurosurgery and Psychiatry [1].

Patients who completed 24 weeks of treatment were offered the opportunity to enter into an extension study. This ongoing trial is investigating the long-term safety, tolerability, and efficacy of 10 and 20 mg/day of ponesimod in patients with relapsing-remitting multiple sclerosis, in a double-blind fashion. The study continues to provide extensive safety and efficacy information for ponesimod in this indication, with some patients treated for more than 5 years.

About the Phase II Study of Ponesimod in Graft vs. Host Disease

Actelion will initiate a Phase II, open-label, single-arm, intra-subject dose-escalation study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in subjects with symptomatic moderate or severe chronic graft vs. host disease inadequately responding to first or second line therapy. The study will also investigate the clinical response to ponesimod treatment in these patients. Approximately 30 subjects will be enrolled to receive ponesimod in escalating doses of 5, 10 and 20 mg/day over the course of 24 weeks. The study will be conducted at approximately 10 sites in the US and is expected to last approximately 18 months.

About the Phase II Study of Actelion's S1P1 Follow-up in Systemic Lupus Erythematosus

Actelion will initiate a Phase II, prospective, multicenter, multinational, randomized, double-blind, placebo-controlled, dose-response study to investigate the biological activity, safety, and tolerability of Actelion's second S1P1 receptor modulator in adult subjects with systemic lupus erythematosus. Approximately 64 subjects will be enrolled to receive either 0.5, 1, 2 or 4 mg/day of second S1P1 receptor modulator over a treatment period of 12 weeks. The study will be conducted at approximately 20 sites and is expected to last around 20 months.