Effects of Inhaled Treprostinil Sodium for the Treatment of Pulmonary Hypertension Associated With Idiopathic Pulmonary Fibrosis

This is Phase 2, multi-center, open-label, four-cohort study in subjects with pulmonary
hypertension (PH) associated with idiopathic pulmonary fibrosis (IPF). Each cohort of four
subjects will receive a single dose of inhaled treprostinil sodium. Cohorts will be enrolled
sequentially, starting with the lowest dose of 18 mcg. Each cohort escalate by 18 mcg
increments, resulting in four cohorts of 18, 36, 54, and 72 mcg doses. Decisions to escalate
to the next dose cohort will be based upon the data from the previous completed lower dose
cohort of four subjects. Approximately 16 subjects are expected to receive study drug,and
approximately four center in the United States with expertise in IPF will participate in this
study.

Inclusion Criteria:

- 35 to 80 years of age

- Male or female

- Diagnosis of IPF

1. Investigator diagnosis based on history, physical examination, HRCT,and pulmonary
function testing

2. Clinical symptoms of IPF for at least three months prior to Visit 1

3. High Resolution CT scan showing definite or probable IPF (any time in the past).
Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT
scan must also be present (at any time in the past)

4. Surgical lung biopsy showing usual interstitial pneumonia, or transbronchial lung
biopsy that was not diagnostic of an alternative condition. For patients younger
than 50 years, a surgical lung biopsy is required (at any time in the past)

5. FVC ≥ 30 % and < 70% of predicted value within three months prior to Visit 1

6. DLCO ≥ 15% and <70% of predicted value within three months prior to Visit 1.

- Diagnosis of PH

1. Previously documented radiographic or echocardiographic findings suggestive of
pulmonary hypertension

2. Prior right heart catheterization diagnostic of pre-capillary pulmonary
hypertension. [The presence of pre-capillary pulmonary hypertension will be
verified by right heart catheterization during Study Visit 3, before enrollment
and administration of study drug].

- No changes in concomitant medications prescribed to treat PAH or IPF for 30 days to
Visit 1

- Females of childbearing potential may participate only if they are not currently
pregnant or lactating and are either one of the following:

1. Surgically sterile

2. At least 1 year post-menopausal

3. Practicing an acceptable method of birth control for at least 30 prior to the
Visit 1 with plans to continue this method for the duration of their
participation in the study.

- An echocardiogram will be performed at Visit 2. Only those subjects with Visit 2
echocardiographic findings that strongly suggest the presence of pulmonary
hypertension, will proceed to Visit 3. Acceptable findings include any of the
following:

1. TR velocity greater than 3.5 m/sec

2. TR velocity greater than 3.0 m/sec with right ventricular enlargement or
dysfunction

- A right heart catheterization will be performed at Visit 3. Only those subjects with
Visit 3 right heart catheterization findings that establish the presence of pulmonary
hypertension will proceed to enrollment and study drug administration. Acceptable
findings must include all of the followings:

1. mean PA pressure equal or greater than 25 mm HG

2. pulmonary capillary wedge pressure equal or less than 15 mm Hg

3. pulmonary vascular resistance greater than 3 mmHg/min

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if ANY of the following criteria
apply:

- History of known or suspected pulmonary embolism or deep venous thrombosis

- Clinical evidence of left-sided heart disease

- Presence of atrial fibrillation (determined from 12 lead ECG at Visit 1 or 2)

- Other medical condition or drug exposure known to be associated with pulmonary
fibrosis (e.g., rheumatoid arthritis, lupus, scleroderma, etc.) or pulmonary arterial
hypertension (e.g., connective tissue disease, congenital heart disease, portal
hypertension, HIV infection, drug and toxins, etc.)

- Upper or lower respiratory infection within 30 days prior to Visit 1

- Hospitalization for respiratory illness within 30 days prior to Visit 1

- Diagnosis of any other clinically significant illness that, in the opinion of the
investigator, might put the subject at risk of harm from participation in the study or
might adversely effect the interpretation of the study data. (e.g., significant liver
or kidney disease, etc.)

- History of recurrent symptoms that might, in the opinion of the investigator,
adversely effect the interpretation of the study data (e.g., severe headaches,
diarrhea, jaw pain, syncope, nausea,vomiting, etc.)

- Current treatment with any medication that is approved by the US FDA to treat
pulmonary hypertension (e.g., epoprostenol(Flolan), treprostinil (Remodulin), iloprost
(Ventavis), bosentan(Tracleer), ambrisentan (Letairis), sildenafil (Revatio), etc.,),
or tadalafil (Cialis)

- Current treatment with an anticoagulant

- A reactive screen for hepatitis B surface antigen, or the hepatitis C antibody, or HIV
antibody as tested at Visit 1.

- Use of any inhaled tobacco products or significant history of drug abuse within 90
days prior to Visit 1

- The subject has an echocardiogram performed at Visit 2 that demonstrate findings that
are indicative of left ventricular or valvular disease. Findings that will be
considered evidence of left ventricular or valvular disease, and therefore exclude the
subject from proceeding to Visit 3 are any of the following:

1. LVEF < 55%

2. Moderate to Severe mitral regurgitation or aortic regurgitation

3. Any mitral stenosis or aortic stenosis

4. Grade 2 or 3 diastolic dysfunction by Doppler

- Use of any investigational drug, or participation in any investigational study within
the 30 days prior to Visit 1.