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2015-04-16

Actelion Pharmaceuticals Ltd: Actelion advances clinical development of its specialty immunology pipeline compounds

Actelion Pharmaceuticals Ltd / Actelion advances clinical development of its
specialty immunology pipelinecompounds . Processed and transmitted by NASDAQ
OMX Corporate Solutions.The issuer is solely responsible for the content of
this announcement.
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 S1P1receptor 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 S1P1receptor 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 S1P1receptor 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 S1P1receptor, 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 S1P1FOLLOW-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 S1P1receptor 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 S1P1receptor 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.

###

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 S1P1RECEPTOR MODULATOR

Actelion's second selective S1P1receptor 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<...

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