Impact of Inhaled Treprostinil Sodium on Ventilation Perfusion Matching

In patients with severe COPD where the FEV1 is 50% or less than predicted, emphysema and
obliterating bronchiolitis presenting a "ceiling" to any improvement in function that can be
achieved by therapies that dilate the airways or lessen inflammation. Such severe COPD is
commonly associated with pulmonary hypertension at rest or during exercise. Although hypoxia
has been classically considered to be the major pathogenic mechanism of pulmonary
hypertension in COPD and oxygen has been the mainstay of therapy, other mechanisms may play
important roles. Indeed, endothelial dysfunction can be observed in patients with mild to
moderate COPD who do not have hypoxemia and in smokers with normal lung function. In
addition, long-term oxygen therapy does not generally result in resolution of the pulmonary
hypertension. A key question that remains is whether the newer therapies for pulmonary
arterial hypertension (PAH) could improve pulmonary hypertension and therefore exercise
tolerance in COPD.

Unfortunately the use of non-selective pulmonary vasodilator therapy in oral, intravenous or
subcutaneous form for PAH patients who have unrelated concomitant COPD, is known to cause
worsening gas exchange and intensification of symptoms despite a decrease in pulmonary
vascular resistance and arterial pressures.

We hypothesize that an inhaled pulmonary vasodilator may not worsen ventilation-perfusion
mismatching by selectively vasodilating well ventilated areas in PAH patients with
concomitant COPD and in fact may improve ventilation perfusion matching leading to
preservation or improvement of oxygenation.

Inclusion Criteria:

- Subject has a diagnosis of PAH confirmed by right heart catheterization within the
last 12 months (defined by mean pulmonary artery pressure of greater than or equal to
25 with pulmonary capillary wedge pressure or left ventricular end-diastolic pressure
of less than or equal to 15).

- Subject is being initiated on inhaled treprostinil for treatment of PAH.

- Subject between 18 and 80 years of age at screening with a diagnosis of COPD
confirmed by spirometry within the last 6 months showing FEV1 > 40% predicted and
FEV/FVC of < 70.

- Baseline 6-minute walk distance > 150 meters.

- Subject has not been on any approved therapy for their PH for the last 90 days.

- If subject is being treated with conventional therapy for COPD, they must be
receiving a fixed regimen of these therapies for tat least 30 days prior to Baseline.

- Previous echocardiography with evidence of normal left systolic and diastolic
ventricular function, and absence of any clinically significant left sided heart
disease.

- If female, physiologically incapable of childbearing or practicing an acceptable
method of birth control as deemed appropriate by the physician or institution.

- If female, negative serum pregnancy test required at screening.

- Subject voluntarily gives informed consent.

Exclusion Criteria:

- The subject is pregnant or lactating.

- Subject has had a new type of chronic therapy for PH added within 90 days of
Baseline.

- Subject has had any medication started or discontinued for COPD within 30 days of
Baseline.

- Subject has any of the following: portal hypertension, chronic thromboembolic
disease, pulmonary veno-occlusive disease or other than those accepted as part of the
inclusion criteria or has had any atrial septostomy.

- Subject has a current diagnosis of uncontrolled sleep apnea as defined by their
physician.

- Subject has a history or current evidence of left-sided heart disease.

- Subject has interstitial lung disease as evidence by CT scan or restrictive pattern
on pulmonary function tests (FEV1/FVC > 70 and TLC < 80% predicted) or COPD with FEV1
< 40% predicted.

- Subject has a musculoskeletal disorder or any other disease that is likely to limit
ambulation, or is connected to a machine that is not portable.

- Subject is incapable of maintaining compliance throughout the course of the study.

- Any condition, in the investigator's opinion, would constitute an unacceptable risk
to the subject's safety.

- Subject is receiving an investigational drug, has an investigational device in place
or has participated in an investigational drug or device study within 30 days prior
to screening.

- Subjects without a telephone contact.