68Ga-FAPI PET/CT imaging to assess pulmonary artery and right ventricle remodeling SoFAPI study

The primary objective is to assess whether [68Ga]Ga-FAPI PET/CT imaging can non-invasively evaluate pulmonary artery remodeling in patients with pulmonary arterial hypertension (PAH). This imaging modality is clinically relevant as it may provide a non-invasive alternative to assess structural changes in the pulmonary vasculature, which are characteristic of PAH progression and response to therapy.

The secondary objectives include:

• Evaluating whether pulmonary artery remodeling, assessed with [68Ga]Ga-FAPI PET/CT imaging, decreases in PAH patients following 24 weeks of Sotatercept treatment

• Determining whether regional lung perfusion, assessed with [68Ga]Ga-MAA lung perfusion PET/CT imaging, improves after 24 weeks of Sotatercept treatment in PAH patients

• Investigating the association between right ventricle (RV) uptake on FAPI PET/CT imaging and RV dysfunction in PAH patients

• Assessing whether right ventricle activity, measured with [68Ga]Ga-FAPI PET/CT imaging, decreases after 24 weeks of Sotatercept treatment in PAH patients

• Examining the correlation between vascular remodeling on [68Ga]Ga-FAPI PET/CT and hemodynamic parameters obtained by right heart catheterization (RHC) in PAH patients

• Determining the correlation between vascular remodeling on [68Ga]Ga-FAPI PET/CT and 6-minute walking test (6MWT) results in PAH patients

• Evaluating the correlation between vascular remodeling on [68Ga]Ga-FAPI PET/CT and NYHA functional class in PAH patients

• Assessing the correlation between vascular remodeling on [68Ga]Ga-FAPI PET/CT and quality of life measures (Emphasis 10) in PAH patients

• Providing a description of imaging parameters

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population includes **adult** participants aged **18 years or older** of **both genders**. Eligible participants are diagnosed with **pulmonary arterial hypertension (PAH)** classified as **WHO Group 1**, including subtypes such as **idiopathic PAH**, **heritable PAH**, **drug/toxin-induced PAH**, PAH associated with **connective tissue disease**, or PAH associated with **simple congenital systemic-to-pulmonary shunts** at least one year following repair. Participants must have documented **right heart catheterization (RHC)** within 12 months of screening demonstrating a minimum **pulmonary vascular resistance (PVR)** of ≥4 Wood units and **pulmonary capillary wedge pressure (PCWP)** or **left ventricular end-diastolic pressure (LVEDP)** of ≤15 mmHg. The study population consists of symptomatic patients classified as **WHO functional class II or III** who are receiving bi- or tri-background therapy and will be initiated on **Sotatercept**. Participants must demonstrate the ability to adhere to the study visit schedule and provide written informed consent.

This is a Phase III clinical trial investigating the use of **[68Ga]Ga-FAPI PET/CT imaging** to assess **pulmonary artery** and **right ventricle** remodeling in patients with **pulmonary arterial hypertension**. The trial employs a non-randomized, open-label design without blinding or control groups. The primary objective is to evaluate whether [68Ga]Ga-FAPI PET/CT imaging can non-invasively assess pulmonary artery remodeling in patients diagnosed with PAH. The study involves the administration of two investigational medicinal products for imaging purposes: [68Ga]Ga-MAA solution administered **intravenously** at a maximum daily dose of 200 **MBq** and a maximum total dose of 400 MBq over 2 days, and 68-FAPI-46 injection administered intravenously at a maximum daily dose of 200 MBq and a maximum total dose of 400 MBq over 2 days. Additionally, participants will receive **Sotatercept** (Winrevair 45 mg or 60 mg powder and solvent for **solution for injection**) as auxiliary medication administered via **subcutaneous injection** at a maximum daily dose of 0.7 mg/kg and a maximum total dose of 6.1 mg/kg over 26 weeks. Sotatercept has been designated as an **orphan drug** under EU/3/20/2369.

Eligible participants must be 18 years of age or older with documented **right heart catheterization** within 12 months of screening, demonstrating a minimum **pulmonary vascular resistance** of at least 4 Wood units and **pulmonary capillary wedge pressure** or **left ventricular end-diastolic pressure** of 15 mmHg or less. The diagnosis must correspond to WHO PAH Group 1, including subtypes such as idiopathic PAH, heritable PAH, drug or toxin-induced PAH, PAH associated with **connective tissue disease**, or PAH associated with simple congenital systemic-to-pulmonary shunts at least one year following repair. Participants must be receiving bi- or tri-background therapy, present with symptomatic PAH classified as WHO functional class II or III, and be initiating treatment with Sotatercept. Participants must demonstrate the ability to adhere to the study visit schedule, understand and comply with all protocol requirements, and provide written informed consent.

The trial consists of multiple study visits over an estimated duration of approximately 26 weeks for individual participants. The screening visit (V0) includes baseline assessments and the first [68Ga]Ga-FAPI PET/CT imaging to evaluate pulmonary artery uptake. Follow-up visits (V1 and V2) occur after initiation of Sotatercept treatment, with V2 scheduled after 24 weeks of treatment. During these visits, repeat [68Ga]Ga-FAPI PET/CT imaging is performed to assess changes in pulmonary artery and right ventricle uptake, and [68Ga]Ga-MAA lung perfusion PET/CT is conducted to evaluate regional lung perfusion by quantifying the **pulmonary vascular obstruction index**. Additional assessments include hemodynamic parameters from right heart catheterization such as mean **pulmonary artery pressure**, **cardiac output**, **right atrial pressure**, **right ventricular pressure**, and pulmonary vascular resistance, as well as the **6-minute walking test**, **NYHA functional class**, **Nt-proBNP** levels, and quality of life measured by the Emphasis 10 questionnaire. The end-of-study visit coincides with the completion of the 24-week treatment period and final imaging assessments.

The primary endpoint is the presence or absence of [68Ga]Ga-FAPI uptake in pulmonary arteries on PET/CT imaging at baseline (V0), assessed visually by consensus of two nuclear medicine physicians using the surrounding vascular background as a reference. Secondary endpoints include [68Ga]Ga-FAPI uptake on pulmonary arteries at V1 and V2 following 24 weeks of Sotatercept treatment, evaluated using a visual scale and **standardized uptake value** (SUVmax). Regional lung perfusion assessed by pulmonary vascular obstruction index on [68Ga]Ga-MAA lung perfusion PET/CT at V1 and V2, [68Ga]Ga-FAPI uptake on the right ventricle (SUVmax) and its correlation with right ventricle dysfunction based on **tricuspid annular plane systolic excursion** less than 17 mm, and changes in right ventricle uptake at V1 and V2 are also evaluated. Correlations between [68Ga]Ga-FAPI uptake on pulmonary arteries (SUVmax) and hemodynamic parameters, 6-minute walking test results, NYHA functional class, Nt-proBNP levels, and quality of life measures are assessed. Additional secondary endpoints include qualitative and quantitative evaluation of imaging parameters such as image quality, reproducibility, acquisition time, radiation dose, ease of interpretation, technical success rate, inter-operator variability, and the impact of acquisition parameters on biomarker quantification.

The overall trial duration is estimated from August 15, 2025, for recruitment start to March 15, 2027, for study completion. Individual participant involvement is expected to last approximately 26 weeks from enrollment to the end-of-study visit. Conditions that may lead to early termination from the study include withdrawal of informed consent, inability to comply with study procedures, adverse events requiring discontinuation, or investigator discretion based on participant safety or protocol violations.

The experimental medication **[68Ga]Ga-MAA** is administered as a solution for **intravenous** use. The active substances are **gallium (68Ga)** and **human albumin as macroaggregates**. The maximum daily dose is 200 **MBq** (megabecquerels), with a maximum total dose of 400 MBq administered over a treatment period of 2 days.

The experimental medication **68-FAPI-46** is administered as an injection via the **intravenous route**. The active substance is **(S)-2,2',2''-(10-(2-(4-(3-((4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)-quinolin-6-yl)(methyl)amino)-propyl)piperazin-1-yl)-2-oxoethyl)-68Ga-[1,4,7,10]-tetraazacyclododecane-1,4,7-triyl)triacetate**. The maximum daily dose is 200 MBq, with a maximum total dose of 400 MBq over a 2-day treatment period.

**Winrevair** 60 mg is supplied as powder and solvent for solution for injection, reconstituted to a solution for injection containing **sotatercept** as the active substance. The medication is administered via **subcutaneous injection**. The maximum daily dose is 0.7 mg/kg body weight, with a maximum total dose of 6.1 mg/kg administered over a treatment period of 26 weeks. Winrevair has been designated as an **orphan drug** (EU/3/20/2369) and holds marketing authorization (EU/1/24/1850/003).

Winrevair 45 mg is supplied as powder and solvent for solution for injection, reconstituted to a solution for injection containing sotatercept as the active substance. The medication is administered via subcutaneous injection. The maximum daily dose is 0.7 mg/kg body weight, with a maximum total dose of 6.1 mg/kg administered over a treatment period of 26 weeks. This formulation also holds orphan drug designation (EU/3/20/2369) and marketing authorization (EU/1/24/1850/001).

The primary endpoint of efficacy will be assessed by evaluating **[68Ga]Ga-FAPI uptake** in pulmonary arteries on PET/CT imaging in patients with pulmonary arterial hypertension at baseline. The uptake will be assessed visually, with the outcome considered successful by consensus of two nuclear medicine physicians, using the surrounding vascular background as a reference. The assessment will be reported as a binary outcome (Yes/No).

Secondary efficacy endpoints include **[68Ga]Ga-FAPI uptake** on pulmonary arteries at follow-up visits, including after 24 weeks of treatment with **Sotatercept**. This will be assessed using a visual scale and the **Standardized Uptake Value (SUVmax)**. Regional lung perfusion will be evaluated by quantifying the **Pulmonary Vascular Obstruction Index (PVOI)** on **[68Ga]Ga-MAA** lung perfusion PET/CT at follow-up visits and after 24 weeks of treatment. **[68Ga]Ga-FAPI uptake** on the right ventricle will be measured using SUVmax and correlated with right ventricle dysfunction based on **Tricuspid Annular Plane Systolic Excursion (TAPSE)** less than 17 mm. Additional assessments include **[68Ga]Ga-FAPI uptake** on the right ventricle at follow-up visits. Correlations will be performed between **[68Ga]Ga-FAPI uptake** on pulmonary arteries (SUVmax) and hemodynamic parameters obtained from right heart catheterization, including mean pulmonary artery pressure, cardiac output, right atrial pressure, right ventricular pressure, and pulmonary vascular resistance. Further correlations will assess the relationship between **[68Ga]Ga-FAPI uptake** on pulmonary arteries (SUVmax) and the 6-minute walking test result, NYHA functional class, **Nt-proBNP** levels, and quality of life measured by the Emphasis 10 questionnaire in patients with pulmonary arterial hypertension. Qualitative and quantitative evaluation of imaging parameters will also be conducted, including image quality, reproducibility, acquisition time, radiation dose, ease of interpretation, technical success rate, inter-operator variability, and the impact of acquisition parameters on biomarker quantification.