ACTELION ADVANCES CLINICAL DEVELOPMENT OF ITS SPECIALTY IMMUNOLOGY PIPELINE COMPOUNDS

ALLSCHWIL/BASEL, SWITZERLAND - 16 April 2015 - Actelion Ltd (SIX: ATLN) announced today 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.

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ABOUT PONESIMOD
Ponesimod is an orally active, selective sphingosine-1-phosphate receptor 1 (S1P1) immunomodulator. Ponesimod prevents lymphocytes from leaving lymph nodes, thereby reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. The lymphocyte count reduction is rapid, dose-responsive, is sustained with continued dosing and quickly reversed upon discontinuation. Initial results suggest that ponesimod does not cause lymphotoxicity by destroying lymphocytes or interfering with their cellular function. Other blood cells e.g. cells of the innate immune system are largely unaffected. Ponesimod is therefore considered a promising new oral agent for the treatment of a variety of autoimmune disorders.
ABOUT MULTIPLE SCLEROSIS [2,3]
Multiple sclerosis is an autoimmune disorder of the central nervous system and is the most common cause of progressive neurological disability in young adults. It is a disease caused by a cascade of events involving an activation of the immune system, acute focal inflammatory demyelinating lesions with limited remyelination and axonal loss, culminating in chronic multifocal sclerotic plaques in the brain and spinal cord.
Patients suffering from multiple sclerosis experience a heterogeneous collection of clinical symptoms, an unpredictable course and a variable prognosis. A large variety of symptoms and signs of multiple sclerosis result from axonal demyelination and axonal loss, with a corresponding slowing or blockade of axonal conduction at affected sites of the brain and spinal cord. Repeated episodes of disease activity may lead to a progressive loss of neurological function.
The incidence of multiple sclerosis is about 7 cases per 100,000 persons per year and, although the etiology of multiple sclerosis is still unknown, the prevalence rate varies between ethnic origins and geographical latitudes, ranging from 50 to 120 per 100,000. It is widely accepted that it is an immune-mediated, demyelinating disease precipitated by unknown environmental factors in genetically susceptible people.
ABOUT CHRONIC GRAFT VS. HOST DISEASE
Chronic graft vs. host disease is a pleomorphic syndrome with autoimmune-like features. Chronic graft vs. host disease is the most serious and common long-term complication of allogeneic hematopoietic stem cell transplantation representing a leading cause of late death in these patients [4].
The disease which has a median time to onset of 4 to 6 months after transplantation [5], can affect multiple sites, including the skin and subcutaneous connective tissues, lacrimal and salivary glands, oral mucosa, lungs, esophagus, joints, gastrointestinal tract and liver [6].
Chronic graft vs. host disease has distinctive signs and symptoms, which include sicca syndrome, obstructive bronchiolitis, and lichenoid or sclerotic skin changes, among others. Chronic graft vs. host disease also has signs and symptoms that are shared with acute graft vs. host disease, and these include erythematosus skin rash, nausea, vomiting, diarrhea, and cholestatic liver disease [7]. Risk factors for chronic graft vs. host disease include use of a mobilized blood cell graft, a human leukocyte antigen (HLA)-mismatched or unrelated donor, older patient age, and especially a history of acute graft vs. host disease. The risk of this disease can be decreased by T-cell depletion from the graft or treatment of the recipient with anti-T-cell antibodies as part of the conditioning regimen prior to transplant [6]. Treatment of chronic graft vs. host disease is based on the use of anti-inflammatory and immunosuppressive drugs.
ABOUT ACTELION'S SECOND SELECTIVE S1P1 RECEPTOR MODULATOR
Actelion's second selective S1P1 receptor modulator is potent, orally active, and blocks the egress of lymphocytes from lymphoid organs and thus reduces the availability of circulating effector T and B cells that can invade target organs. This pharmacodynamic effect is sustained with continued daily oral dosing and is reversible upon drug discontinuation.
ABOUT SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus is a complex and heterogeneous autoimmune disease of unknown etiology, characterized by the production of pathogenic autoantibodies, tissue deposition of immune complexes, and tissue damage across multiple organ systems. The adaptive T and B cells and the innate immune system are considered to play a major pathophysiological role in this disease.
Systemic lupus erythematosus is primarily a disease of young women with a peak incidence between the ages of 15 and 40 years [8, 9] and an estimated male to female ratio of 1:7 to 1:10 [10]. The natural history of systemic lupus erythematosus is characterized by relapses or flares, alternated with periods of remission. The outcome is highly variable, ranging from prolonged remission to high morbidity with progression of organ damage and death.
Clinical manifestations of systemic lupus erythematosus include rash, arthritis, anemia, thrombocytopenia, serositis, nephritis, seizures, and psychosis among others [11]. Current treatment of systemic lupus erythematosus is based on the use of anti-inflammatory and immunosuppressive therapies. With improved diagnosis and treatment, the life expectancy of systemic lupus erythematosus patients has improved from an approximate 4-year survival rate of 50% in the 1950s to a 15-year survival rate of 80% [12] nowadays.
ABOUT S1P RECEPTORS
Sphingosine-1-phosphate (S1P) is a sphingolipid released by erythrocytes, platelets, mast cells and other cell types. It is currently established that S1P stimulates at least five different cell surface resident G-protein coupled receptors (GPCRs) - S1P1,2,3,4, and 5. Activation of these GPCRs mediates a complex variety of biological responses such as lymphocyte migration, endothelial cell proliferation, blood vessel constriction and heart rate modulation.
REFERENCES
Olsson T et al. Oral ponesimod in relapsing-remitting multiple sclerosis: A randomized trial. J Neurol Neurosurg Psychiatr. 2014 Nov;85(11):1198-208. doi: 10.1136/jnnp-2013-307282. Epub 2014 Mar 21.
Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221-31.
Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502-18.
Garnett C, Pavlu J. Treament and management of graft-versus-host disease: improving response and survival. Ther Adv Hematol 2013. 4:366-378.
Lee SJ, Flowers MED. Recognizing and managing chronic graft-versus-host-disease. Hematology Am Soc Hematol Educ Program 2008; 134-140
Martin PJ, et al. Treatment of chronic graft-versus-host disease: past, present and future. Korean J Hematol 2011.46:153-163.
Weisdorf D. GVHD - the nuts and bolts. Hematology Am Soc Hematol Educ Program 2007;62-67.
Borchers AT, et al. The geoepidemiology of systemic lupus erythematosus. Autoimmun Rev. 2010 Mar;9(5):A277-87.
Pons-Estel GJ, et al. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum. 2010 Feb;39(4):257-68.
Govoni M, et al. Incidence and prevalence of systemic lupus erythematosus in a district of north Italy. Lupus. 2006;15:110-113.
Rahman A, Isenberg DA. Systemic lupus erythematosus. The New England journal of medicine 2008; 358:929-39.
Abu-Shakra M, et al. Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol 1995;22(7):1259-64.

Actelion Ltd.
Actelion Ltd. is a leading biopharmaceutical company focused on the discovery, development and commercialization of innovative drugs for diseases with significant unmet medical needs.
Actelion is a leader in the field of pulmonary arterial hypertension (PAH). Our portfolio of PAH treatments covers the spectrum of disease, from WHO Functional Class (FC) II through to FC IV, with oral, inhaled and intravenous medications. Although not available in all countries, Actelion has treatments approved by health authorities for a number of specialist diseases including Type 1 Gaucher disease, Niemann-Pick type C disease, Digital Ulcers in patients suffering from systemic sclerosis, and mycosis fungoides type cutaneous T-cell lymphoma.
Founded in late 1997, with now over 2,400 dedicated professionals covering all key markets around the world including Europe, the US, Japan, China, Russia and Mexico, Actelion has its corporate headquarters in Allschwil / Basel, Switzerland.
Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®). All trademarks are legally protected.

For further information please contact:
Andrew Weiss
Senior Vice President, Head of Investor Relations & Corporate Communications
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
www.actelion.com

The above information contains certain "forward-looking statements", relating to the company's business, which can be identified by the use of forward-looking terminology such as "estimates", "believes", "expects", "may", "are expected to", "will", "will continue", "should", "would be", "seeks", "pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company's investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected.

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