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2016-01-29

Actelion Pharmaceuticals Ltd: Actelion receives positive CHMP opinion for Uptravi (selexipag) for the long-term treatment of pulmonary arterial hypertension

Actelion Pharmaceuticals Ltd / Actelion receives positive CHMP opinion for
Uptravi (selexipag) for thelong-term treatment of pulmonary arterial
hypertension . Processed and transmitted by NASDAQ OMX Corporate
Solutions.The issuer is solely responsible for the content of this
announcement.
* The European Commission is expected to make a final decision within 67
days.

ALLSCHWIL, SWITZERLAND - 29 January 2016 -
Actelion (SIX: ATLN) announced today that the Committee for Medicinal Products
for Human Use (CHMP), the scientific committee of the European Medicines
Agency (EMA), issued a positive opinion for the use of the orally active,
selective IP prostacyclin receptor agonist Uptravi (selexipag), originally
discovered and synthesized by Nippon Shinyaku, for the treatment of pulmonary
arterial hypertension.

The CHMP recommended that the European Commission approves Uptravi for the
long-term treatment of pulmonary arterial hypertension (PAH) in adult
patients with WHO functional class (FC) II-III, either as combination therapy
in patients insufficiently controlled with an endothelin receptor antagonist
(ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor, or as monotherapy
in patients who are not candidates for these therapies. Efficacy has been
shown in a PAH population including idiopathic and heritable PAH, PAH
associated with connective tissue disorders, and PAH associated with
corrected simple congenital heart disease.

The CHMP's positive opinion is in part based on the review of efficacy and
safety data generated in GRIPHON, a long-term Phase III study in PAH patients
with WHO Functional Class I-IV symptoms. Patients were treated with Uptravi
in combination with an ERA, a PDE-5 inhibitor, an ERA together with a PDE-5
inhibitor or as monotherapy. Patients had idiopathic and heritable PAH (58%),
PAH associated with connective tissue disease (29%) or PAH associated with
congenital heart disease with repaired shunts (10%).

Marius Hoeper, a GRIPHON Steering Committee member, commented: "The
prostacyclin pathway is one of the fundamental pathways to be targeted in
PAH. However, it has been underutilized, mainly because of the significant
burden that the route of administration of existing treatments places on
patients and their caregivers. This positive opinion moves us a step closer
to the EMA-approval of Uptravi (selexipag), with the promise of efficacious
oral treatment, supported by excellent long-term outcome results, within
reach."

The safety of selexipag has been evaluated in a long-term, Phase III placebo
controlled study enrolling 1,156 patients with symptomatic PAH. The mean
treatment duration was 76.4 weeks (median 70.7 weeks) for patients receiving
selexipag versus 71.2 weeks (median 63.7 weeks) for patients on placebo. The
exposure to selexipag was up to 4.2 years.

The most commonly reported adverse reactions related to the pharmacological
effects of Uptravi are headache, diarrhoea, nausea and vomiting, jaw pain,
myalgia, pain in extremity, arthralgia, and flushing. These reactions are
more frequent during the up-titration phase. The majority of these reactions
are of mild to moderate intensity.

Jean-Paul Clozel, MD and Chief Executive Officer of Actelion, commented: "We
are delighted by today's announcement of a positive CHMP opinion. Coming hot
on the heels of both the US and Canadian approvals, we believe that Uptravi
can significantly improve long-term outcomes for PAH patients. Once market
authorization is granted by the EU Commission, Uptravi will open up the
prostacyclin pathway to many more patients."

A CHMP positive opinion is one of the final steps before marketing
authorization is granted by the European Commission. The European Commission
is expected to issue a final decision by early April 2016.

ABOUT THE GRIPHON STUDY DATA

GRIPHON was a long-term, global Phase III study in 1,156 patients treated for
up to 4.2 years. The GRIPHON study, in which more than 80% of patients were
already receiving PAH-specific therapies, showed that the risk of the primary
composite endpoint was reduced by 40% (p<0.0001) with selexipag compared to
placebo.

The benefit of selexipag was consistent across pre-specified patient subgroups
such as disease etiology, functional class and baseline PAH therapy,
including patients already receiving combination therapy with an ERA and a
PDE-5 inhibitor.

Titrating selexipag to an individualized maintenance dose based on
tolerability was effective in achieving long-term outcome benefits across the
tested dose range. The dosing in GRIPHON was initiated at 200 micrograms
(mcg) twice daily (b.i.d) and increased weekly in steps of 200 mcg up to a
maximum of 1600 mcg b.i.d. After titrating to each patient's individual
highest tolerated dose, the benefit was consistent across the pre-specified
low (200, 400 mcg b.i.d), medium (600, 800, 1'000 mcg b.i.d) and high
maintenance (1'200, 1'400, 1'600 mcg b.i.d) dose groups.

###

NOTES TO EDITOR:

REGULATORY STATUS OF SELEXIPAG

In December 2014, Actelion submitted the registration dossier for selexipag to
both the US FDA and Europe's EMA. Approval from the FDA was received on 21
December 2015, approval was also received from Health Canada on 21 January
2016. Submission of the registration dossier to other health authorities is
ongoing, with regulatory reviews underway in Australia, Japan, New Zealand,
South Korea, Switzerland, Taiwan and Turkey.

ABOUT UPTRAVI®(SELEXIPAG) [2-7]

Uptravi (selexipag), originally discovered and synthesized by Nippon Shinyaku,
is a potent, oral, selective IP prostacyclin receptor agonist formulated as a
tablet.

Uptravi and its major metabolite selectively target the prostacyclin receptor
(also called IP receptor). The IP receptor is one of 5 major types of
prostanoid receptor (IP, EP, DP, TP, FP). Prostacyclin activates the IP
receptor to induce vasodilation and inhibit proliferation of vascular smooth
muscle cells.

ABOUT THE GRIPHON STUDY [1]

GRIPHON, (Prostacyclin (PG
I2)R
eceptor agonist InP
ulmonary arterialH
ypertensiON
) was a randomized, multicenter, double-blind, placebo-controlled trial
evaluating the long-term efficacy and safety of oral selexipag in patients
with PAH.

The GRIPHON study was the largest randomized, controlled, outcome trial ever
conducted in PAH patient population, enrolling 1,156 patients in 181 centers
from 39 countries in North and Latin America, Europe, and Asia-Pacific.
Patients received twice daily administration of selexipag or placebo and were
also permitted to receive background PAH-specific therapy of an endothelin
receptor antagonist and/or a phosphodiesterase-5 inhibitor when on a stable
dose for at least 3 months. At baseline, 80% of patients were receiving oral
medication specific for PAH: either an ERA, a PDE-5 inhibitor, or a
combination of the two.

This pivotal, event-driven study was designed to demonstrate a prolongation in
time to the first morbidity or mortality event for selexipag compared to
placebo and to evaluate the safety profile of selexipag in PAH patients. All
morbidity and mortality events reported by the investigators were adjudicated
by a three person independent Critical Event Committee blinded to the study
treatment.

ABOUT THE SAFETY AND TOLERABILITY IN GRIPHON

Overall, 41 (7.1%) patients in the placebo group and 82 (14.3%) in the
selexipag group prematurely discontinued treatment due to an adverse event.
The most frequent adverse events leading to treatment discontinuation in the
selexipag group (>1% difference between selexipag and placebo) were headache
(3.3%), diarrhea (2.3%), and nausea (1.7%). Hyperthyroidism occurred in eight
selexipag-treated patients and led to treatment discontinuation in one
patient. No serious adverse events were reported more frequently (>1%
difference between selexipag and placebo) in the selexipag group.
Prostacyclin-associated adverse events were more frequent during the
titration phase, where they were used to define the individualized highest
tolerated dose.

THE ROLE OF THE PROSTACYCLIN PATHWAY [7]

The prostacyclin pathway is one of the 3 best characterized pathways involved
in the pathophysiology and treatment of PAH. Prostacyclin is a prostanoid and
serves as a signaling molecule in the human body. It is produced, like other
vasoactive substances, by endothelial cells. Prostacyclin induces
vasodilation, is anti-proliferative, has anti-inflammatory effects and
inhibits platelet aggregation. In certain disease conditions, the production
of prostacyclin by the endothelium is impaired, allowing for example, the
deleterious effects of excessive levels of endothelin or thromboxane to
predominate.

PULMONARY ARTERIAL HYPERTENSION (PAH)

PAH is a chronic, life-threatening disorder characterized by abnormally high
blood pressure in the arteries between the heart and lungs of an affected
individual. The symptoms of PAH are non-specific and can range from mild
breathlessness and fatigue during normal daily activity to symptoms of right
heart failure and severe restrictions on exercise capacity and ultimately
reduced life expectancy.

PAH is one group within the classification of pulmonary hypertension (PH).
This group includes idiopathic PAH, heritable PAH and PAH caused by factors
which include connective tissue disease, HIV infection and congenital heart
disease.

The last decade has seen significant advances in the understanding of the
pathophysiology of PAH, which has been paralleled with developments of
treatment guidelines and new therapies. Drugs targeting the three pathways
that have been established in the pathogenesis of PAH are endothelin receptor
antagonists (ERAs), prostacyclin analogs and phosphodiesterase-5 inhibitors.
PAH treatments have transformed the prognosis for PAH patients from
symptomatic improvements in exercise tolerance 10 years ago to delayed
disease progression today. Improved disease awareness and evidence-based
guidelines developed from randomized controlled clinical trial data have
highlighted the need for early intervention, goal-oriented treatment and
combination therapy.

ABOUT THE ACTELION / NIPPON SHINYAKU ALLIANCE

Actelion and Nippon Shinyaku entered into an exclusive worldwide alliance in
April 2008 to collaborate on selexipag, a first orally-available, selective
prostacyclin IP receptor agonist for patients suffering from PAH. This
compound was originally discovered and synthesized by Nippon Shinyaku.
Actelion is responsible for global development and commercialization of
selexipag outside Japan, while the two companies will co-develop and
co-commercialize in Japan. Nippon Shinyaku will receive milestone payments
based on development stage and sales milestones as well as royalties on any
sales of selexipag.
...

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