📋 Eligibility rules (as published)
Inclusion Criteria:
1. Participants aged 18-75 years old (inclusive), any gender;
2. Patients diagnosed with WHO Group 1 pulmonary arterial hypertension (PAH) via right heart catheterization (RHC) before dosing (see Appendix 1), including the following subtypes:
* Idiopathic PAH;
* Heritable PAH;
* Drug- or toxin-induced PAH;
* Inactive, connective tissue disease-associated PAH;
* Simple congenital heart disease with left-to-right shunt-related PAH, at least 1 year post-repair surgery;
3. Symptomatic pulmonary arterial hypertension, WHO functional class II or III ;
4. Must also meet the following hemodynamic criteria:
* Mean pulmonary arterial pressure (mPAP) at rest ≥25 mmHg;
* Pulmonary arterial wedge pressure (PAWP) ≤15 mmHg;
5. Pulmonary vascular resistance (PVR) measured by RHC within 10 days before initial dosing ≥5 Wood Units (400 dyn·sec·cm-5), prior RHC results before screening are acceptable if they meet study requirements;
6. Receiving stable doses of background PAH therapy (i.e., for at least 90 days before first dosing, individualized target doses for each therapy reached and stable); for subcutaneous prostacyclin users, a 10% variation around the optimal dose is allowed following medical practice, detailed as follows:
* Background PAH therapy refers to approved PAH-specific drugs, including ERA and/or PDE-5i or sGC stimulators and/or prostacyclin analogs or receptor agonists (subcutaneous). Note: PAH background therapy drugs should meet the following doses: Macitentan 10 mg qd, Ambrisentan 10 mg qd; Sildenafil ≥20 mg tid, Tadalafil 20-40 mg qd; Riociguat 2 mg or 2.5 mg tid; Selexipag 0.8-1.6 mg bid; Subcutaneous treprostinil ≥20 ng/kg/min. Note: Drugs used for acute pulmonary vasoreactivity testing are not considered background therapy.
7. During screening and within 10 days before first dosing, the mean of two 6-minute walk distance (6MWD) tests should be ≥150m and ≤450m, with a maximum difference of 15% (based on the higher value); the two tests should be at least 4 hours apart and no longer than 1 week apart (if the difference exceeds 15%, repeat once within 4 hours to 1 week).
8. Female participants of childbearing potential must have a negative serum pregnancy test before dosing, agree to regular urine or serum pregnancy tests during treatment (any one), use highly effective contraception before dosing, during treatment (including dosing interruption) and for 16 weeks (112 days) after the last dose, and avoid blood or egg donation for 16 weeks (112 days) after the last dose.
9. Male participants agree to use condoms, defined as using latex condoms or non-latex condoms made from non-natural (animal) membranes (e.g., polyurethane) during sexual activity with pregnant women or women of childbearing potential during the dosing period (including any interruption) and for 16 weeks (112 days) after the last dose, even if they have successfully undergone a vasectomy, and to avoid donating sperm during this time;
10. Participants understand and follow the study procedures, voluntarily participate, and sign the informed consent form.
Exclusion Criteria:
1\) Diagnosed with WHO Group 2, 3, 4, or 5 pulmonary hypertension. 2) Diagnosed with the following PAH subtypes in WHO Group 1:
* HIV-associated PAH
* Portal hypertension-associated PAH
* Schistosomiasis-associated PAH
* PAH associated with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis
* PAH patients with known positive acute pulmonary vasoreactivity test 3) History of echocardiogram within 6 months before screening showing left ventricular ejection fraction \<45%, or pre-dose echocardiogram showing left ventricular ejection fraction \<45%, or as assessed by the investigator, acute decompensated heart failure occurring within 30 days before screening, or evidence or history of clinically significant heart disease (including but not limited to: significant (≥2+) mitral or aortic valve regurgitation, restrictive or congestive cardiomyopathy, or pericardial constriction).
4\) Poorly controlled hypertension at rest during the screening period: seated systolic BP \>160 mmHg or seated diastolic BP \>100 mmHg, or pre-dose systolic BP \<90 mmHg on Day 1.
5\) Pre-dose ECG Fridericia corrected QT interval (QTcF) ≥470 ms for men, ≥480 ms for women, or personal/family history of long QT syndrome (LQTS) or sudden cardiac death.
6\) Any symptomatic coronary artery disease event (previous myocardial infarction, PCI, CABG, or angina), or history of cerebrovascular accident within 3 months before screening. Note: if coronary angiography shows no obstruction (lumen stenosis ≤50%), angina may not be an exclusion.
7\) Use of IV positive inotropic agents (such as dobutamine, dopamine, norepinephrine, vasopressin, milrinone, levosimendan, etc.) within 30 days before the screening visit.
8\) History of arterial or deep vein thrombosis within 6 months before dosing, or any spontaneous bleeding of any severity within 2 months before dosing.
9\) Untreated mild or more severe obstructive sleep apnea history. 10）Previous or planned heart or lung transplant, or expected lifespan \<12 months as assessed by the investigator.
11\) Diagnosed with chronic obstructive pulmonary disease (COPD) or other clinically significant lung diseases.
12\) Exclusion if there is evidence of interstitial lung disease (ILD) from a chest CT within 1 year before screening or a lung function test (PET) within 6 months before screening; if these test results are not available, or if the chest CT within 1 year shows mild or more severe ILD, a lung function test (PET) or chest CT must be done during the screening period, and patients with ILD detected are excluded.
13\) Before administration, hemoglobin (Hb) \> the upper limit of normal (ULN) for their gender or \<90 g/L, platelet count ≤100×10⁹/L, neutrophils \<1.5×10⁹/L, AST or ALT \>3×ULN, total bilirubin \>1.5×ULN, estimated glomerular filtration ra
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