Effect of CS1 in Subjects With Pulmonary Arterial Hypertension

Inclusion Criteria:

Subjects will be eligible for inclusion in the study if they meet all of the following criteria:

1. Subject must be willing and able to sign a written informed consent prior to anystudy-related procedures and able to understand and follow instructions; return tothe study unit for specified study visits; and able to participate in the study forthe entire period.

2. Subject is male or female, aged 18 to 80 years.

3. Subject must have a body mass index (BMI) 18 to 40 kg/m2 at Screening. If BMI is >35kg/m2, subject chest circumference should be <65 inches (165 cm).

4. Subject with PAH belonging to 1 of the following subgroups of NICE ClinicalClassification of PAH category:

5. Idiopathic PAH.

6. Heritable PAH.

7. Drug or toxin-induced (anorexigen or methamphetamine use).

8. PAH associated with connective tissue disease.

9. Subject with PAH who are symptomatic and have reduced exercise capacity dueprimarily to their PAH diagnosis, having been assessed by qualified individual, ie,physician, physician assistant, or nurse practitioner, to be in NYHA/WHO functionalclass II or III and having an RRS 2.0 of 6 to 10.

10. PAH therapy at stable doses of standard-of-care therapies for at least 90 days priorto screening.

11. Subject has most recent (within the last 36 months) hemodynamic assessment of PAH byRHC demonstrating a persistent resting mPAP ≥25 mm Hg and resting mean pulmonaryvascular resistance (PVR) ≥5 Wood Units with Pulmonary Capillary Wedge Pressure ≤15mmHg.

12. Subject is willing to undergo CardioMEMS PA Sensor implantation and RHC prior torandomization or has had the CardioMEMS PA Sensor implanted previously.

13. Subject has a 6-minute walk distance (6MWD) ≥150 meters (m) and <550 m at Screening.

14. Female subject of childbearing potential must be willing and able to practiceeffective contraception during the study and continuing contraception for 30 daysafter their last dose of study drug. A female subject of non-childbearing potentialis defined as being surgically sterilized by bilateral tubal ligation, bilateraloophorectomy, or hysterectomy. A female subject 45 to 60 years of age, who ispost-menopausal for at least 1 year, and has a follicle-stimulating hormone levelconfirmation indicating post menopausal status will be considered ofnon-childbearing potential. A female subject >60 years of age is considered postmenopausal and of non childbearing potential.

Exclusion Criteria:

Subjects will be excluded from the study if they meet any of the following criteria:

1. Subject has pulmonary hypertension category 2 to 5.

2. Subject has adult congenital heart disease (ACHD).

3. Subject has concomitant medical or psychiatric disorder, condition, history, or anyother condition that in the opinion of the Investigator would either put the subjectat risk or impair the subject's ability to participate in or complete therequirements of the study or confound the objectives of the study.

4. Subject has a concomitant medical disorder that is expected to limit the subject'slife-expectancy to ≤1 year.

5. Subject has RRS 2.0 score of ≤5 or ≥11.

6. Subject has heart fai

7. lure with preserved ejection fraction defined as those with >50% ejection fraction (with signs and symptoms of heart failure) or left atrial volume (LAV) >34 mL/ m2.

8. Subject is not able to have CardioMEMS PA Sensor implanted due to:

9. An active, ongoing infection defined as being febrile, an elevated white bloodcell count, on intravenous antibiotics, and/or positive cultures (blood,sputum, or urine).

10. History of current or recurrent (≥2 episodes within 5 years prior to consent)pulmonary emboli and/or deep vein thromboses.

11. Cannot tolerate RHC.

12. PA branch inner diameter <7 mm in a descending branch within the left or rightlower lung lobe (target implant vessel).

13. Unable to take dual antiplatelet or anticoagulation therapy for 1 month afterCardioMEMS PA Sensor implantation.

14. Subject is likely to undergo lung transplantation within the next 6 months.

15. Subject has untreated, moderate to severe obstructive sleep apnea.

16. Subject has evidence of significant chronic thromboembolic disorder as determined bythe Investigator or recent pulmonary embolism within 6 months prior to Screening (see also exclusion criterium 7b).

17. Subject has uncontrolled hypertension (˃160/100 mmHg, confirmed by duplicate seatedreadings) at 2 or more historical visits within 3 months prior to Screening.

18. Subject has sustained systolic blood pressure <95 mmHg and/or diastolic bloodpressure <50 mmHg (confirmed by duplicate seated readings) on at least 3 consecutiveoccasions (self monitored or office) prior to or at Screening, or overt symptomatichypotension.

19. Subject has sustained resting heart rate >120 beats per minute (confirmed byduplicate assessments of office vital signs) or consecutive electrocardiogram (ECG)assessments on at least 3 consecutive occasions prior to or at Screening.

20. Subject has a history of a bleeding disorder.

21. Subject has thrombocytopenia: platelets <150,000/mm3.

22. Subject has known porphyria, mitochondrial, or urea cycle disease.

23. Subject has a history of chronic pancreatic disease.

24. Subject is a pregnant or lactating female.

25. Subject has a positive result from serology testing at Screening for humanimmunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV); but if the subject has a historical diagnosis (prior to Screening) of beingpositive for HIV, HBsAg, or HCV, must be clinically stable and if on therapy, be onstable therapy for at least 3 months prior to Screening. A subject should not haveactive coronavirus disease 19 (COVID-19); however, those with previous COVID 19 arepermitted.

26. Subject has participated in another investigational drug study within 30 days priorto Screening or is participating in a non medication study which, in the opinion ofthe Investigator, would interfere with the study compliance or outcome assessments.

27. Subject is on regular treatment with sodium valproate/valproic acid (VPA), otheranti-epilepsy drugs, or other prohibited medications that cannot be discontinued atthe Screening Visit (V1).

28. Subject is on regular anticoagulation or on dual antiplatelet therapy (DAPT) thatcannot be discontinued at the Screening Visit (V1); however, during the BaselinePeriod following CardioMEMS PA Sensor implantation, DAPT is allowed according toclinical practice for up to 4 weeks. A low daily dose aspirin (<125 mg) is allowed,ie, "baby" aspirin.

29. Subject has more than mild mitral or aortic valve disease, left ventricular ejectionfraction (LVEF) <50%, or left ventricular regional wall motion abnormalitysuggestive of active coronary artery disease on 2D-echocardiogram at Screening.

30. Subject has a forced expiratory volume in 1 second (FEV1)/forced vital capacity <70% (absolute), FEV1 ≤50% or total lung capacity (TLC) <70% predicted on pulmonaryfunction testing (PFT); for potential subjects with TLC 60 to 69% predicted, noncontrasted computerized tomography (CT) scan must be performed to exclude subjectswith more than mild interstitial lung disease. PFTs should have been obtained within 3 years prior to Screening.

31. Subject has clinically significant renal dysfunction as measured by the estimatedGlomerular Filtration Rate (eGFR) of <30 mL/min/1.73m2 as calculated by Modificationof Diet in Renal Disease (MDRD) at Screening.

32. Subject has significant liver dysfunction as measured by any one of the following atScreening (including subjects with acute or chronic hepatitis as well as subjectswith own or family history of serious hepatitis, especially drug related):

33. Alanine aminotransferase (ALT) >2.0 × upper limit of normal (ULN).

34. Aspartate aminotransferase (AST) >2.0 × ULN.

35. Serum bilirubin ≥1.6 mg/dL or >2.0 × ULN.

36. Subject has a known history of substance abuse including alcohol abuse within the 1year prior to Screening that in the opinion of the Investigator would impair thesubject's ability to participate in or complete the requirements of the study.

37. Subjects with any major surgical procedure or trauma within 30 days prior toScreening or planned surgical procedure during the study period.

38. Subject with any inpatient hospitalization (defined as >23 hours) within 30 daysprior to Screening.

39. Subject enrolled within 90 days prior to Screening or plans to enroll during thestudy into a cardiopulmonary rehabilitation program.

40. Subject has known hypersensitivity to study drug or any of the excipients of thedrug formulation.