A Phase 2 Study to Determine the Safety and Efficacy of AIR001 in Subjects With Pulmonary Arterial Hypertension (PAH)

The primary objective of this study is to evaluate the efficacy of inhaled nebulized AIR001
administered, for 16 weeks, according to 3 treatment arms (80 mg once daily, 46 mg 4 times
daily, or 80 mg 4 times daily) in subjects with World Health Organization (WHO) Group 1
Pulmonary Arterial Hypertension (PAH), as determined by change in Pulmonary Vascular
Resistance (PVR) from Baseline to Week 16 measured immediately post completion of AIR001
nebulization (as soon as feasible).

Inclusion Criteria:

1. Signed and dated informed consent document

2. Able to comply with study procedures

3. Diagnosis of PAH as classified by:

1. Idiopathic (IPAH) or heritable(HPAH); or

2. PAH associated with CTD; Systemic Sclerosis, Limited Scleroderma, Mixed, SLE, or
overlap syndrome;

3. PAH associated with HIV ii. Simple, congenital shunts at least one year post
repair. iii. Exposure to legal drugs, chemicals and toxins

4. Cardiac catheterization prior to Screening with:

1. mPAP ≥ 25 mmHg (at rest);

2. PCWP ≤ 15 mmHg; and

3. PVR > 3 mmHg/L/min or 240 dyn.sec/cm5

5. A qualification cardiac catheterization, to confirm the persistence and severity of
PAH, if the diagnostic catheterization was performed more than 30 days prior to
Baseline

1. Confirms diagnosis;

2. PVR above 300 dyn.sec/cm5 to demonstrate the persistence and severity of PAH;
and

3. No change in disease-specific PAH therapy since the qualification
catheterization used

6. Newly diagnosed PAH on no disease-specific PAH therapy or previously diagnosed on
oral disease-specific PAH therapy for 90 days prior with either an ETRA and/or PDE-5i

7. Has PFTs within 180 days prior to Baseline with no evidence of significant
parenchymal lung disease defined as:

- FEV1 ≤ 70% (predicted) (pre-bronchodilators);

- FEV1/FVC ≤ 70% (pre-bronchodilators); or

- Total lung capacity < 70% (predicted).

8. Has WHO/NYHA FC II- IV.

9. ≥ 18 and ≤ 75 years.

10. Weight ≥ 40 kg.

11. Has 6MWT distance at least 50 meters.

12. Had a V/Q scan or pulmonary angiogram prior to Screening that shows no evidence of
thromboembolic disease

13. If on the following: vasodilators (including calcium channel blockers), digoxin,
spironolactone, or L-Arginine; must be on a stable dose 30 days prior to Baseline and
maintained throughout the study

14. If on corticosteroids, has been receiving a stable dose of ≤ 20 mg/day of prednisone
(or equivalent dose, if other corticosteroid) for at least 30 days

15. Women of childbearing potential must be using at least one form of medically
acceptable contraception. Women who are surgically sterile or those who are
post-menopausal for at least 2 years are not considered to be of childbearing
potential. Men who are not sterile must also agree to use contraception

Exclusion Criteria:

1. Participation in a device or other interventional clinical studies, within 30 days of
Baseline and during study participation

2. Participation in a cardio-pulmonary rehabilitation program based upon exercise within
30 days prior to Baseline and/or during the study

3. Has uncontrolled systemic hypertension: SBP > 160 millimeter of mercury (mmHg) or DBP
> 100 mmHg during Screening

4. SBP < 90 mmHg at Screening or Baseline

5. History of orthostatic hypotension or at the time of Screening; defined as a drop in
SBP by ≥ 20 mmHg or DBP of ≥ 10 mmHg during Screening

6. History of left-sided heart disease and/or clinically significant cardiac disease,
including:

1. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater
than mild;

2. Pericardial constriction;

3. Restrictive or congestive cardiomyopathy;

4. Left ventricular ejection fraction < 40%

5. Left ventricular shortening fraction < 22% by ECHO prior to Screening;

6. Symptomatic coronary disease

7. Significant (2+ for regurgitation) valvular disease other than TR or PR

8. Acutely decompensated heart failure within 30 days prior to Baseline

9. History of atrial septostomy within 180 days prior to Baseline

10. History of obstructive sleep apnea (treated, untreated or resolved)

11. Diagnosis of Down syndrome

12. Moderate to severe hepatic impairment

13. Has chronic renal insufficiency as defined by serum creatinine > 2.5 mg/dL or has an
eGFR < 30 mL/min at Screening, or requires dialysis

14. Has a Hgb concentration < 8.5 g/dL at Screening

15. Personal or family history of the following:

1. Congenital or acquired methemoglobinemia;

2. RBC CYPB5 reductase deficiency

16. G6PD deficiency or any contraindication to receiving methylene blue

17. For subjects with HIV any of the following:

- Concomitant active opportunistic infections 180 days prior to Screening;

- Detectable viral load within 90 days of Screening;

- T-cell count < 200 mm3 within 90 days of Screening;

- Changes in antiretroviral regimen within 90 days of Screening;

- Using inhaled pentamidine

18. Receiving chronic treatment with prostacyclin/prostacyclin analogue within 60 days of
Baseline

19. Requirement of intravenous inotropes within 30 days prior to Baseline

20. The use of oral or topical nitrates (nitroglycerin, glyceryl trinitrate (GTN),
isosorbide dinitrate, and isosorbide mononitrate) within 30 days prior to Baseline
and until EOS or Termination

21. Known or suspected hypersensitivity or allergic reaction to sodium nitrite or sodium
nitrate

22. History of malignancy within 5-years prior to Baseline

23. Other severe acute or chronic medical or laboratory abnormality that may increase the
risk associated with study participation

24. Has a disorder that compromises the ability to give informed consent

25. Is currently pregnant or breastfeeding or intends to become pregnant

26. Investigators, study staff or their immediate families