An open-label extension of study AC-066A301 investigating the safety and tolerability of ACT-385781A in patients with pulmonary arterial hypertension (PAH)

1.1 Pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial
vasoconstriction and vascular remodeling resulting in a progressive increase in
pulmonary arterial pressure and pulmonary vascular resistance, ultimately
leading to right ventricular failure and death. PAH is defined as a resting
mean pulmonary arterial pressure (mPAP) > 25 mm Hg and pulmonary capillary
wedge pressure (PCWP) <= 15 mm Hg [Badesch 2009]. If left untreated, the
prognosis for PAH patients is poor; untreated patients have a median life
expectancy of 2.8 years from diagnosis [D*Alonzo 1991]. Currently approved
treatments include prostanoids, endothelin receptor antagonists (ERAs), and
hosphodiesterase-5 inhibitors (PDE-5). Significant morbidity and mortality
remain despite these treatments. The pathophysiology of PAH involves multiple
pathways, which are influenced by many overlapping secondary messenger systems.
Vasoconstriction, obstructive remodeling of the pulmonary vessel wall,
inflammation, and thrombosis within the pulmonary arteries are promoted by
activation of these pathways, and lead to elevated pulmonary arterial pressure
(PAP) and pulmonary vascular resistance (PVR), and eventually right ventricular
failure.

1.2 Prostacyclin pathway
Patients with PAH have been shown to have a deficiency of prostacyclin (PGI2;
IP) and PGI2 synthase, which led to the hypothesis that targeting the PGI2
pathway with IP receptor agonists could be beneficial. PGI2, a metabolite of
arachidonic acid, is produced by both endothelial and smooth muscle cells in
the vasculature and is a potent endogenous vasodilator and inhibitor of
platelet aggregation and smooth muscle cell
proliferation through its activity at the IP receptor [O*Grady 1980]. Several
drugs acting on the IP receptor have already been approved for the treatment of
PAH. The first was epoprostenol, approved in 1995 for World Health Organization
(WHO)/New York Heart Association (NYHA) Functional Class III -IV idiopathic PAH
(iPAH) and PAH associated with scleroderma, and shown to improve exercise
tolerance and survival in iPAH [Barst 1996]. Approved prostacyclin analogs in
the United States include: intravenous prostacyclin (epoprostenol sodium or
Flolan®), subcutaneous or intravenous treprostinil sodium (Remodulin®) and
inhaled iloprost (Ventavis®).

1.3 ACT-385781A (Epoprostenol for injection)
ACT-385781A (Epoprostenol for injection, EFI) is a new formulation containing
the same active ingredient as Flolan. The new formulation includes the omission
of sodium chloride, the substitution of mannitol by sucrose, the substitution
of L-glycine by L-arginine, and a higher pH.

To assess safety and tolerability of EFI patients with PAH.

Multicentre, open-label (one group), Phase 3b study

This is an open-label extension of study AC-066A301 investigating the safety
and tolerability of EFI in patients with pulmonary arterial hypertension (PAH).
The treatment duration is unspecified. Study treatment ends after patients
receive authorization and reimbursement for commercially-obtained EFI, and thus
transition from study medication to commercial medication. Although the
treatment duration is unspecified, it is estimated to extend up to 2 years.
Patients are followed for an additional 30 days post-study treatment for safety
reporting. Monthly phone visits are conducted by investigative sites for as
long as the patient is participating in the study. Patients will return for
clinical visits as part of routine clinical practice, but clinical visits are
not specified per protocol except for the EOT visit.

Study Risks: The study medication (EFI) and study procedures may have risks and
discomforts (side effects). During studies with EFI, safety information was
collected. The most common reported side effects were: bleeding,
increased/decreased heart rate, low blood pressure, unease/discomfort in the
stomach, nausea, vomiting, diarrhea, pain at injection site, chest pain,
infection in the bloodstream, catheter-related infections, jaw pain, joint
pain, headache, dizziness, anxiety, nervousness, rash, facial flushing. Serious
adverse events that were reported in the core part of this study included
complications associated with the drug delivery device which were not suspected
to be related to the study medication. One patient experienced a catheter
related infection of his central venous catheter requiring hospitalization.

It is still possible that complications and side effects of EFI, which ar still
unknown at this tile, may occur. The patient will be informed in a timely
manner about any new information on EFI that may be relevant for his/her
decision to continue the participation in this clinical research study.