Inhaled Nitrite in Subjects With Pulmonary Hypertension

Screening Visit:Initial screening evaluations including physical examination, medical
history, and clinical laboratory assessments will be conducted to determine study
eligibilities during a routine clinic visit at the UPMC HVI, CLC or inpatient at UPMC
Presbyterian. Subjects who meet the inclusion criteria and none of the exclusion criteria
will be entered into the study.

Day 1: This study visit will occur on the same day subjects are scheduled for their
clinically indicated right heart catheterization or who volunteer for a research right heart
catheterization for this specific study. Subjects on oral background PAH therapy (ETRA or
PDE5I) will be instructed to hold their regimen on the day of the study visit.

Subjects will receive nebulized AIR001 doses escalated based upon safety and tolerability.
The dose of inhaled nitrite will be delivered via electronic nebulizer. During the study
right heart/pulmonary artery hemodynamics will be measured as well as noninvasive systemic
blood pressure monitoring. Subjects will be tested for the changes in pulmonary vascular
resistance (PVR) using standard clinical protocol hemodynamic recordings of right atrial,
right ventricular, and pulmonary artery pressures, in addition to cardiac output at time
zero,

3 Day phone follow up

30 Day follow up visit: All subjects enrolled in the study will be followed for 30 days (+/-
5 day window) after completion of the study treatment. A physical exam and clinical labs will
be obtained at this visit.

Inclusion Criteria:

Diagnosis of RHC confirmed WHO Group I PAH n=20

Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of
the following connective tissue diseases:

PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic
rapeseed oil Stable PAH for at least 3 months if on therapy This patient population is
closed to enrollment. Target enrollment of 20 subjects has been met

WHO Group II Pulmonary Hypertension n=20 Pulmonary capillary wedge pressure PWCP greater
than 15 AND Transpulmonary Gradient TPG greater than12

WHO Group III PH n = 10

- Has WHO functional class II through IV symptoms

- Had the diagnosis of PH confirmed by a cardiac catheterization Both WHO Group I PAH
and WHO Group III PH

WHO GROUP I PAH, II and III PH Age 18 and older Able to participate in right heart
catheterization Evidence of a personally signed and dated informed consent document
indicating that the subject has been informed of all pertinent aspects of the study
Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures

Exclusion Criteria

Age less than 18 years

Baseline systemic hypotension, defined as MAP less than 50 mmHg

Required intravenous inotropes within 30 days prior to study participation;

Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure
greater than160 mm Hg or sitting diastolic blood pressure greater than100 mm Hg at
screening

Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or
hepatitis C with evidence of recent infection and/or active virus replication defined as
moderate to severe hepatic impairment Child-Pugh Class B-C

Has chronic renal insufficiency as defined by serum creatinine greater than 2.5 mgdL at
screening or requires dialytic support

Has a hemoglobin concentration less than 9 gdL at Screening

History of atrial septostomy within 6 months prior to Day 1 visit

Repaired or unrepaired congenital heart disease CHD

Pericardial constriction

Confirmed diagnosis of restrictive or congestive cardiomyopathy;

Left ventricular ejection fraction 40 percent by multiple gated acquisition scan MUGA,
angiography or echocardiography

Symptomatic coronary disease with demonstrable ischemia;

Other severe acute or chronic medical or laboratory abnormality that may increase the risk
associated with study participation or investigational product administration or may
interfere with the interpretation of study results and, in the judgment of the
investigator, would make the subject inappropriate for entry into this study

Has a psychiatric, addictive or other disorder that compromises the ability to give
informed consent for participating in this study. This includes subjects with a recent
history of abusing alcohol or illicit drugs 30 days prior to study screening Day 0and for
the duration of the study

Poorly controlled asthma defined by active wheezing and or cough with FEV1 less than 70
percent predicted, responsive to inhaled BD greater than 15 percent increase in FEV1 with
BD

Investigators, study staff or their immediate families

Clinically significant intercurrent illness (including lower respiratory tract infection)
or clinically significant surgery within 4 weeks before the administration of study drug

Personal or family history of congenital or acquired methemoglobinemia

Personal or family history of RBC CYP B5 reductase deficiency

Known or suspected hypersensitivity or allergic reaction to sodium nitrite Personal history
of glucose-6-phosphate dehydrogenase G6PD deficiency or any contraindication to receiving
methylene blue

If female, is pregnant or breast feeding, or has a positive pregnancy test result predose

Receipt of an investigational product or device, or participation in a drug research study
within a period of 15 days or 5 half-lives of the drug, whichever is longer before the
first dose of study drug

Blood loss or blood donation greater than 550 mL within 90 days or plasma donation greater
than 500 mL within 14 days before administration of study drug

RHC less than 2 weeks from treatment visit unless clinically indicated