Media Release English

Page 1 of 6
Media Release
16 April 2015
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
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
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.”
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.
page 2 of 6
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 uptitration 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 dosefinding 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.
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
- Actelion advances clinical development of its specialty immunology pipeline compounds -
page 3 of 6
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.
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.
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.
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.
- Actelion advances clinical development of its specialty immunology pipeline compounds -
page 4 of 6
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.
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.
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.
- Actelion advances clinical development of its specialty immunology pipeline compounds -
page 5 of 6
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.
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
2. Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221-31.
3. Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502-18.
4. Garnett C, Pavlů J. Treament and management of graft-versus-host disease: improving response
and survival. Ther Adv Hematol 2013. 4:366-378.
5. Lee SJ, Flowers MED. Recognizing and managing chronic graft-versus-host-disease. Hematology
Am Soc Hematol Educ Program 2008; 134-140
6. Martin PJ, et al. Treatment of chronic graft-versus-host disease: past, present and future. Korean J
Hematol 2011.46:153-163.
7. Weisdorf D. GVHD - the nuts and bolts. Hematology Am Soc Hematol Educ Program 2007;62-67.
8. Borchers AT, et al. The geoepidemiology of systemic lupus erythematosus. Autoimmun Rev. 2010
9. Pons-Estel GJ, et al. Understanding the epidemiology and progression of systemic lupus
erythematosus. Semin Arthritis Rheum. 2010 Feb;39(4):257-68.
10. Govoni M, et al. Incidence and prevalence of systemic lupus erythematosus in a district of north Italy.
Lupus. 2006;15:110-113.
11. Rahman A, Isenberg DA. Systemic lupus erythematosus. The New England journal of medicine
2008; 358:929-39.
12. 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 Tcell 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.
- Actelion advances clinical development of its specialty immunology pipeline compounds -
page 6 of 6
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
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.
- Actelion advances clinical development of its specialty immunology pipeline compounds -