TEPH: Telaglenastat Efficacy in Pulmonary Hypertension

Inclusion Criteria: 1. Male or female age 18- 75 years old. 2. Able to provide written informed consent. 3. Able to comply with study procedures, able to undergo cardiac catheterization and exercise testing. 4. For Group 1and 3 PH, prior right heart catheterization (RHC) should show documented diagnosis of precapillary PH at mean pulmonary arterial pressure (mPAP \> 20 mm Hg, PCWP\<15 mm Hg, and PVR\>3.5 WU) at screening.. Minimum pulmonary vascular resistance (PVR) of \>3.5 Wood units by RHC at screening AT screening and on at least 30 days of stable medical therapy. 5. For Group 2 PH-HFpEF, documented transthoracic echocardiogram or cardiac MRI with LV ejection fraction ≥50%, along with meeting at least one of the following criteria by echo: Echocardiographic/MRI evidence of (1) diastolic dysfunction, (2) left atrial enlargement (LA diameter \>3.6 cm). Prior right heart catheterization data indicating PCWP\>15 mm Hg, mPAP \> 20 mm Hg and PVR\>3.5 WU. Stable heart failure therapy for at least 30 days. 6. Symptomatic PH classified as WHO functional class II or III. 7. Body mass index (BMI) 18 to 40 kg/m2 at Screening. If BMI is \>35 kg/m2, subject chest circumference should be \<65 inches (165cm). 8.6-minute walk distance (6MWD) ≥100 meters (m) and \<550 m at Screening. 9.For Group 1 PH, patients on SOC medical treatment for PH with vasodilators or sotatercept are required to have been receiving a stable dose for at least 3 months before undergoing randomization. 10.For Group 3 PH-ILD, documented diagnosis of presence of interstitial lung disease (diffuse parenchymal lung disease) by high resolution lung CT scan within 1year of randomization. Patients with Group 3 PH with connective tissue disease should have confirmed baseline FVC \<70% within 1 year of randomization. For subjects with a history of lobectomy or pneumonectomy, and for whom there are no population-based normalization methods, assessment based on residual lung volume will be permitted to assess eligibility. Patients receiving drug treatment (i.e., pirfenidone or nintedanib) for their underlying lung disease or pulmonary hypertension (i.e., inhaled Treprostinil, tadalafil or sildenafil) should receive a stable dose for at least 30 days before undergoing randomization. 11.Women of childbearing potential must be willing and able to practice medically acceptable effective contraception during the study and continuing contraception for 30 days after their last dose of study drug. Women who are surgically sterile or those who are post-menopausal for at least 2 years are not considered to be of childbearing Exclusion Criteria: 1. Group 3 PH-ILD, patients receiving approved therapies other than inhaled Treprostinil, tadalafil or sildenafil for PAH less than 30 days before randomization are not eligible for enrollment. 2. Group 1 PH, patients naïve to medical treatment for PH are not eligible for enrollment. 3. History of lung reduction surgery or likely to undergo lung transplantation within the next 6 months. 4. Enrolled in, or planned participation in, device or other interventional clinical studies or cardio-pulmonary rehabilitation programs, based upon exercise within 90 days of Screening or during study participation. 5. Patients with other secondary causes of PH including, but not limited to, left or right heart failure, valvular heart disease, chronic obstructive lung disease, atrial septal defect with left to right shunt, and sleep apnea will be excluded if it was the primary cause of PAH. 6. Diagnosed with significant (≥2+ regurgitation) mitral regurgitation or aortic regurgitation. 7. Adult congenital heart disease (ACHD) 8. Left ventricular ejection fraction (LVEF) \<50%. 9. Uncontrolled hypertension (SBP\>160 mm Hg, DBP\>90). 10. Sustained systolic blood pressure (SBP) \<95 mmHg and/or diastolic blood pressure (DBP) \<50 mmHg (confirmed by duplicate seated readings) on at least 3 consecutive occasions (self-monitored or office) prior to or at Screening, or overt symptomatic hypotension. 11. Sustained resting heart rate (HR) \>120 beats per minute (confirmed by duplicate assessments of office vital signs) or consecutive electrocardiogram (ECG) assessments on at least 3 consecutive occasions prior to or at Screening. 12. Concomitant medical or psychiatric disorder, condition, history, or any other condition that, in the opinion of the Investigator, would either put the participant at risk or impair their ability to participate in or complete the requirements of the study or confound the objectives of the study. 13. Concomitant medical disorder that is expected to limit the subject's life-expectancy to ≤1 year. 14. Untreated, moderate to severe obstructive sleep apnea 15. Evidence of thrombocytopenia (platelets \<150,000/mm3, significant chronic thromboembolic disorder, or recent pulmonary embolism within 6 months prior to Screening. 16. History of a bleeding disorder. 17. Known porphyria, mitochondrial, or urea cycle disease. 18. History of chronic pancreatic disease 19. Pregnant or lactating female. 20. Active coronavirus disease 19 (COVID-19); however, those with previous COVID-19 are permitted. 21. Participated in another investigational drug study within 30 days prior to Screening or is participating in a non-medication study which, in the opinion of the Investigator, would interfere with the study compliance or outcome assessments 22. Glomerular Filtration Rate (GFR) of \<30 mL/min/1.73m2. 23. Significant liver dysfunction as measured by any one of the following at Screening (including subjects with acute or chronic hepatitis as well as subjects with own or family history of serious hepatitis, especially drug related): * Alanine aminotransferase (ALT) \>2.0 × upper limit of normal (ULN) * Aspartate aminotransferase (AST) \>2.0 × ULN * Serum bilirubin ≥1.6 mg/dL or \>2.0 × ULN 24. Known history of substance abuse including alcohol abuse within the 1 year prior to Screening that in the opinion of the Investigator would impair the subject's ability to participate in or complete the requirements of the study 25. Any major surgical procedure or trauma within 30 days prior to Screening or planned surgical procedure during the study period. 26. Any inpatient hospitalization (defined as \>23 hours) within 30 days prior to screening. 27. Known hypersensitivity to study drug or any of the excipients of the drug formulation. 28. The discretion of the primary investigator