A Study of GMA301 in Subjects With Pulmonary Arterial Hypertension
A Study of GMA301 in Subjects With Pulmonary Arterial Hypertension
A Randomized, Placebo-Controlled, Double-blind, Dose Escalation Study to Assess Safety,
 Efficacy and Pharmacokinetics of GMA301 Injection in Subjects with Pulmonary Arterial
 Hypertension
Inclusion Criteria:

 Subjects must meet all of the following criteria:

 1. Male or female, aged 18 to 75 years inclusive

 2. WHO Group 1 PAH related to one of the following conditions:

 1. Idiopathic

 2. Heritable

 3. Drugs or toxins-induced

 4. Associated with connective tissue disease

 5. Associated with congenital heart disease if subjects underwent surgical
 correction more than 12 months before Screening

 3. Symptoms due to PAH are consistent with WHO functional class II- III;

 4. Have not taken endothelin receptor antagonists (ERAs) within 3 months before
 randomization.

 5. Has been taking at least one oral PAH targeted drug that has been approved by local
 guidelines for at least 3 months before screening with stable dosage and the disease
 did not worsen during this period.

 6. Right heart catheterization (RHC) result meets below criteria when screening.

 1. Mean pulmonary arterial pressure (PAP) ≥25 mmHg

 2. Pulmonary vascular resistance (PVR) >3 Woods units

 3. PA wedge pressure (PAWP) ≤15 mmHg * if a subject has undergone RHC within 3
 months before screening, the waveform results will serve as baseline data if they
 meet entry criteria; and the RHC at Screening will not be repeated.

 7. Has a six-minute walk test (6MWT) with distance between 150 to 450 meters at
 Screening.

 8. The dosage of digitalis drugs or L-arginine supplementation must be stable for at
 least 1 month before Screening, if applicable.

 9. No new use of an IV diuretic, cardiotonic or vasoactive drug within 30 days before
 screening.

 10. Both male and female subjects agree to use a medically acceptable method of
 contraception throughout the entire study period from informed consent signing to 90
 days after last dose, if the possibility of conception exists. Medically acceptable
 methods of contraception include oral, implantable, or injectable contraceptives
 (starting 2 months before dosing); diaphragm with vaginal spermicide; intrauterine
 device; condom and partner using vaginal spermicide; and surgical sterilization (6
 months after surgery). Women who are surgically sterile or those who are
 postmenopausal for at least 2 years are not considered to be of childbearing
 potential. Eligible male and female subjects must agree not to participate in a
 conception process (i.e. active attempt to become pregnant or to impregnate, sperm
 donation, in vitro fertilization) during the study and for 90 days after the last dose
 of study drug.

 11. Body weight no less than 40 kg at Screening.

 12. Able to understand and willing to sign the Informed Consent Form (ICF) and comply with
 the study procedures.

 Exclusion Criteria:

 Subjects who meet any of the following criteria will not be allowed to participate in this
 study:

 1. Diagnosed with WHO Group II, III, IV, V of PH;

 2. Using calcium channel blockers when Screening;

 3. BP>160/100mmHg at Screening;

 4. Systolic BP <90 mmHg at Screening;

 5. Pulmonary function test: FEV1<60% of predicted, TLC<60% of predicted, DLCO<60% of
 predicted;

 6. One of the following tests with confirmed pulmonary embolism and/or chronic
 thrombo-embolic pulmonary hypertension (CTEPH) following initial diagnosis of PAH:

 1. Pulmonary ventilation/perfusion scan

 2. CT pulmonary angiogram

 3. Contrast dye pulmonary angiogram

 7. History of sleep apnea.

 8. Limited full participation in the 6MWT due to arthritic, neuromuscular, vascular or
 other diseases unrelated to PAH.

 9. History of acute cardiovascular and/or cerebrovascular events within 6 months before
 screening.

 10. Echocardiogram (ECHO) demonstrating at least one of the following:

 1. LVEF <50%

 2. Mean end-diastolic left ventricular septal and posterior wall thickness of >12 mm

 3. Left atrial (LA) area on apical 4 chamber view >20 cm2

 4. LA volume by biplane modified Simpsons or area-length methods >55 mL

 5. LA volume index >29 mL/m2

 6. Significant valvular heart disease including moderate or severe mitral or aortic
 stenosis with an aortic valve area <1.0 cm2 or mitral valve area <1.5 cm2),
 greater than moderate aortic or mitral regurgitation, greater than moderate
 tricuspid or pulmonic stenosis

 11. Restrictive, dilated or hypertrophic cardiomyopathy or constrictive pericarditis

 12. Using non-oral prostacyclin when screening;

 13. Laboratory parameters during screening:

 1. Baseline aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2
 times the upper limit of normal (ULN) or total bilirubin ≥1.5 times ULN

 2. Estimated glomerular filtration rate (eGFR) <60 mL/min by Cockcroft-Gault formula

 3. Hemoglobin concentration ≤100 g/L at screening

 14. QTc interval by Fridericia's criteria (QTcF) ≥500 msec at screening

 15. Malignancy within 5 years before screening visit (with the exception of localized
 non-metastatic basal cell carcinoma of the skin, non-metastatic carcinoma of the
 prostate or in-situ carcinoma of the cervix excised with curative results)

 16. Alcohol or drug abuse within 1 year before screening

 17. A psychiatric, addictive or other disorder that compromises the ability to give
 informed consent for participating in this study

 18. History of organ transplantation

 19. Pregnant or nursing females

 20. History of HIV

 21. Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), or HIV
 antibody (HIV-ab).

 22. Enrolled in another interventional study within 30 days before screening.

 23. Any condition that, in the opinion of the investigator, prevents a potential subject
 from safely participating in the study.