A Phase Ⅰb/Ⅱa Clinical Study of IMC-003 Injection for the Treatment of Pulmonary Arterial Hypertension Receiving Background Therapy.

A Randomized, Double-blind, Placebo-controlled, Multiple-dose, Dose-escalation Phase Ib/IIa Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of IMC-003 Injection in Patients With Pulmonary Arterial Hypertension (PAH) Receiving Background Therapy.

This is a Phase Ib/IIa clinical study of IMC-003 treatment in pulmonary arterial hypertension (PAH) patients receiving background therapy

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 rate (eGFR) <60 mL/min/1.73m² (defined according to CKD-EPI 2021 formula).

  14) History of portal hypertension or chronic liver disease, including positive Hepatitis B surface antigen (HBsAg) and/or positive Hepatitis B core antibody (HBcAb) with HBV-DNA levels above the normal range; positive Hepatitis C virus (HCV) and positive HCV-RNA; positive HIV serology; positive Treponema pallidum antibody (TP-Ab) (if Treponema pallidum serology is positive, a non-Treponema pallidum serology test should be done, and if negative and judged by the investigator as a cured past syphilis infection, the patient can be included).

  15) Currently participating in other clinical studies; or has participated in a medical device or drug clinical study within 30 days before screening (except those who only signed the ICF but did not receive investigational drug or device intervention), or still within 5 half-lives (t1/2) of an investigational product (whichever is longer).

  16) Previously received treatment targeting the TGF-β superfamily (e.g., Sotatercept), including participation in clinical trials.

  17) Known allergies to large molecule protein products/monoclonal antibodies, the study drug or its excipients, or drugs of the same type.

  18) Started a cardiopulmonary rehabilitation exercise program within 90 days before screening, or planning to start one during the study (participants who have maintained a stable program and will continue during the study are eligible).

  19) History of opportunistic infections (e.g., invasive candidiasis or Pneumocystis pneumonia within 6 months before dosing); severe local infections (e.g., cellulitis, abscess) or systemic infections (e.g., sepsis) within 4 weeks before screening.

  20) Major surgery within 8 weeks before the first dose, or participants not fully recovered from previous surgery before the first dose.

  21) If receiving corticosteroid therapy, any of the following within 30 days before the first dose: taken >20 mg/day of prednisone (or equivalent) or started a new dose/change in dose ≤20 mg/day, the participant is excluded; stable ≤20 mg/day prednisone (or equivalent) within 30 days before the first dose is allowed. For connective tissue disease-associated pulmonary arterial hypertension patients on immunosuppressive therapy, if the treatment has been stable for less than 3 months prior to dosing; any participant who has received CRA-T therapy is excluded.

  22) History of malignancy or current malignancy (excluding basal cell carcinoma excised with no evidence of metastasis for 3 years, or treated cervical intraepithelial neoplasia with unknown recurrence status).

  23) Autoimmune disease, except for PAH etiology-related diseases included in this study.

  24) History of chronic kidney disease, or acute kidney injury requiring acute dialysis within 3 months before screening regardless of past kidney disease history.

  25) Pregnant or breastfeeding women. 26) Participants deemed unsuitable for the study by the investigator.