Vardenafil Inhaled for Pulmonary Arterial Hypertension PRN Phase 2B Study

Inclusion Criteria:

1. Must be between 18 and 80 years of age, inclusive.

2. Must be willing and able to provide written, signed informed consent after thenature of the study has been explained, and prior to undergoing any research-relatedprocedures.

3. Must be willing and able to comply with all scheduled visits, treatment plan,laboratory tests, and other study procedures.

4. Able to exercise during CPET and ambulate independently.

5. Diagnosis documented and confirmed by Right Heart Catheterization (RHC)-confirmedWHO Group 1 PAH in any of the following 3 categories:

6. Idiopathic, primary, or familial pulmonary arterial hypertension (IPAH, PPH, orFPAH) OR

7. PAH associated with one of the following connective tissue diseases: i) Systemic sclerosis (scleroderma) ii) Limited scleroderma iii) Mixed connectivetissue disease iv) Systemic lupus erythematosus v) Overlap syndrome vi) Otherautoimmune disorders OR c) PAH associated with: i) Human immunodeficiency virus (HIV) infection. ii) Simple, congenital systemic-to-pulmonary shunts at least 1-yearpost-surgical repair. iii) Exposure to drugs, chemicals, and toxins, such as fenfluramine derivatives,other anorexigens, toxic rapeseed oil, or L-tryptophan.

8. Subjects with a diagnosis of HIV must have stable disease, defined by:

9. Unchanged medication treatment regimen for HIV for at least 8 weeks prior tobeginning Visit 1 Screen assessments.

10. No active opportunistic infection during the Screening Period.

11. No hospitalizations for HIV for at least 4 weeks prior to beginning Visit 1Screen assessments.

12. The patient must have adequate, documented test results that exclude chronicthromboembolic pulmonary hypertension (CTEPH).

13. Previous diagnosis of PAH, but with the following conditions:

14. Stable PAH without significant adjustments of disease-specific background PAHtherapy, at least 3 months prior to the Baseline CPET procedure. Stable isdefined as no change in PAH -specific drug therapy within 3 months of ScreeningVisit 1, and for the duration of the study, and no change in dose ofPAH-specific drug(s) within 1 month of Screening.AND

15. If on corticosteroids, has been receiving a stable dose of ≤ 20 mg/day ofprednisone (or equivalent dose of other corticosteroid) for at least 30 daysprior to the Baseline CPET.

16. PFT within 6 months prior to signing the Informed Consent Form that fulfills thefollowing criteria:

17. FEV1 ≥ 60% predicted (pre-bronchodilators).

18. FEV1 / FVC ≥ 60% (pre-bronchodilators).

19. FVC ≥ 60% predicted.

20. Has had RHC performed and documented prior to Screening that meets the followinghemodynamic criteria:

21. mPAP ≥ 20 mmHg.

22. PVR ≥ 300 dyn·s/cm5.

23. PCWP or LVEDP of ≤ 12 mmHg if PVR ≥ 300 to < 500 dyn∙s/cm5, or PCWP or LVEDP ≤ 15 mmHg if PVR ≥ 500 dyn∙s/cm5.

24. Has WHO/New York Heart Association (WHO/NYHA) functional class II-IV symptomatology.

25. On stable oral PAH disease-specific background therapy of oral or inhaled therapies (any combination of an endothelin receptor antagonist, phosphodiesterase type 5inhibitor, and/or a prostacyclin or prostacyclin receptor agonist). Stable isdefined as no change in PAH-specific drug therapy within 3 months of Screening Visit 1, and for the duration of the study, and no change in dose of PAH-specific drug(s)within 1 month of Screening. Parenteral prostacyclin subjects will be limited to upto 20% of a particular cohort with approval of Sponsor Medical Monitor. Sotaterceptsubjects should have been on sotatercept for a minimum of 6 months at the time ofscreening. Sotatercept subjects will be limited to 20% of a particular cohort withapproval of the Sponsor Medical Monitor.

26. Must be able to walk a distance of ≥ 150 meters in the Baseline 6MWTs. This will bedetermined using the mean of the two 6MWT results done during Screening. Iftolerable by the subject, the 2 Baseline 6MWTs will be conducted at Visit 1 with aminimum of 2 hours of rest between the first and second tests.

27. Has a VE/VCO2 slope ≥ 36 during the Baseline CPET as assessed by the study CPET CoreLaboratory.

28. Evidence of good effort on the Baseline CPET reaching a peak RER > 1.0 asassessed by the study CPET Core Laboratory.

29. Peak VO2 ≤ 20 ml/min/kg during the Baseline CPET as assessed by the study CPET CoreLaboratory.

30. If the subject is taking the following concomitant medications which may affect PAH,the subject must be on a stable therapeutic dose for at least 1 month prior to thestart of Screening and the dosage maintained throughout the study.

31. Vasodilators (including calcium channel blockers - specify the indication e.g.,PAH, hypertension, Raynaud's disease), digoxin, or L-arginine supplement.

32. If the subject is taking a vitamin K antagonist anticoagulant, thenanticoagulation status should be maintained/stable in the therapeutic range forat least 1 month before the start of Screening.

33. Sexually active subjects must be willing to use an acceptable method ofcontraception while participating in the study through the 30-day post-treatmentsafety follow-up telephone call. Acceptable methods of contraception includehormonal birth control (oral, intravaginal, transdermal, implantable, orintrauterine device/system [IUD/IUS]), IUDs (non-hormonal), vasectomy (in malepartner), or any double-barrier methods (combination of male condom and spermicidewith either cap, diaphragm, or sponge).

34. Female subjects of childbearing potential must have a negative pregnancy test (urineor serum) at Screening and must agree to additional urine pregnancy tests prior toeach dose of study medication while participating in the study.

35. Female subjects considered not of childbearing potential include those who arepost-menopausal (defined as cessation of regular menstrual periods for at least 1year) or have documented evidence of surgical sterilization at least 6 months priorto Screening.

36. No evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),clinically, by polymerase chain reaction (PCR) test, or antigen test as required bylocal site infection control policies at the Screening Visit. Subjects with previouscoronavirus disease 2019 (COVID-19) infection must have returned to functionalbaseline prior to entering Screening for this study.

Exclusion Criteria:

Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:

1. Baseline systemic hypotension defined as mean arterial pressure (MAP) < 50 mmHgor SBP < 90 mmHg at Screening.

2. History of chronic uncontrolled asthma; subjects with inability to use, or may havepotential difficulties using, an inhaler device.

3. Use of continuous, supplemental oxygen. Subject must be able to complete exercisetests without the use of supplemental oxygen. NOTE: Use of nocturnal oxygen is acceptable.

4. Requirement of intravenous inotropic therapies within 30 days prior to the BaselineCPET procedure.

5. Use of riociguat (Adempas®) as background PAH therapy as of 1 month prior toinitiating Screening or during the study through the end of Visit 4.

6. Use of oral, topical, or inhaled nitrates within 2 weeks prior to the Baseline CPETprocedure.

7. Has history of uncontrolled systemic hypertension as evidenced by sitting SBP > 175 mmHg or sitting diastolic blood pressure (DBP) > 110 mmHg at Screening.

8. Portopulmonary hypertension, portal hypertension, or chronic liver diseasedetermined to be Child-Pugh B or C, including hepatitis B virus and/or hepatitis Cvirus (HCV). Subjects who have had a previous infection with HCV and who have anegative viral load after receiving a course of curative treatment are

9. Subjects who have 3 or more of the following left ventricular disease/dysfunctionrisk factors are not eligible:

10. Hypertension requiring medication therapy.

11. Diabetes mellitus - any type.

12. History of significant coronary artery disease (CAD) established by any one ofthe following: i) Myocardial infarction within 12 months of screening ii) Percutaneous coronaryintervention within 12 months of screening iii) Angiographic evidence of CAD (> 50% stenosis in at least 1 vessel) either by invasive angiography or by CTangiography. iv) Positive stress test imaging, either pharmacologic or with exercise. v) Previouscoronary artery surgery. vi) Chronic stable angina.

13. Uncorrected right-to-left shunt, clinically relevant persistently patent foramenovale in the judgement of the Investigator or known Eisenmenger's physiology.

14. Paroxysmal or uncontrolled atrial fibrillation (defined as a resting heart rategreater than or equal to 110 bpm).

15. Chronic renal insufficiency as defined by serum creatinine > 2.5 mg/dL or has anestimated glomerular filtration rate (eGFR) < 30 mL/min utilizing theModification of Diet in Renal Disease (MDRD) Study equation at Screening or requiresdialytic support.

16. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value thatis ≥ 3x the upper limit of the normal range.

17. Platelets below 50,000/μL at Screening.

18. Hemoglobin (Hgb) concentration < 9 g/dL at Screening.

19. Malignancy within 2 years prior to Screening with the exception of localizednon-metastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervixexcised with curative intent.

20. Recent history (within 6 months prior to Screening) of, or current alcohol ordrug/solvent use disorder as assessed by the Investigator.

21. Known hypersensitivity to active drug substance (vardenafil) or drugs of the sameclass, or any excipients of the drug formulation(s).

22. Documented history of hypotension including fainting, syncope, orthostatichypotension, and/or vasovagal reactions.

23. Vision loss due to non-arteritic anterior ischemic optic neuropathy or other opticperfusion impairment.

24. History of sudden sensorineural hearing loss.

25. Male subjects with a corrected QT interval using Fridericia's formula (QTcF) > 450 msec and female subjects with QTcF > 470 msec on ECG measured at Screening. (Correction of the actual QTc for the conduction defect of left bundle-branch can bemade by subtracting the prolongation of the QRS due to the block from the actualQTc. Correction for the right bundle-branch block can be made by subtracting 20 msecfrom the actual QTc).

26. Pregnant or breastfeeding at Screening or planning to become pregnant (self orpartner) at any time while participating in the study.

27. Participation in a drug, device, or other interventional clinical study, other thana post-marketing observational extension study, within 30 days prior to Screening.

28. Enrolled in an exercise training program within 12 weeks prior to beginning Visit 1Screening assessments and must agree not to enroll in an exercise training programduring the study. Subjects enrolled in an exercise program more than 12 weeks priorto beginning Visit 1 Screening assessments may be enrolled if they agree to maintaintheir current level of physical activity throughout the duration of the study.

29. Has a concurrent disease or condition that in the view of the PrincipalInvestigator, places the potential subject at high risk of poor treatment complianceor of not completing the study, or would interfere with study participation or wouldaffect safety.

30. Has received the SARS-CoV-2 vaccine or booster within 1 week prior to Screening

31. Post COVID-19 chronic symptoms ("Long COVID") at Screening. NOTE: Investigators,study staff, or their immediate family members may not participate in the study.