Evaluation of Sotatercept in Combination with Maximum Tolerated Background Therapy in Patients with WHO Functional Class III/IV Pulmonary Arterial Hypertension

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effects of **sotatercept** treatment, in addition to maximum tolerated background therapy, compared to placebo, on the time to the first event of all-cause death, lung transplantation, or hospitalization due to worsening **Pulmonary Arterial Hypertension (PAH)** lasting 24 hours or more. This study targets participants with World Health Organization (WHO) Functional Class III or IV PAH who are at high risk of mortality. The clinical relevance of this objective lies in its potential to improve survival outcomes and reduce the need for invasive procedures in a population with significant morbidity and mortality risks.

The clinical trial involves a total of **99 participants** diagnosed with **Pulmonary Arterial Hypertension (PAH)**. The study population includes both male and female subjects, aged between 18 to 75 years. Participants are required to have a documented diagnosis of WHO PAH Group 1, with subtypes including idiopathic, heritable, drug/toxin-induced, PAH associated with connective tissue disease, or PAH associated with simple congenital systemic-to-pulmonary shunts. The trial specifically targets individuals classified as WHO Functional Class III or IV, indicating a high risk of mortality. Participants must be clinically stable and on stable doses of maximum tolerated double or triple background PAH therapies for at least 30 days prior to screening. The selection process ensures that participants can adhere to the study visit schedule and comply with all protocol requirements. Both genders are included, and the study considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified, but participants must be able to provide written informed consent and comply with contraceptive requirements if applicable.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **sotatercept** when added to maximum tolerated background therapy in participants with **Pulmonary Arterial Hypertension (PAH)** classified as World Health Organization (WHO) Functional Class III or IV at high risk of mortality. The primary objective is to assess the effects of sotatercept on the time to first event of all-cause death, lung transplantation, or PAH worsening-related hospitalization of 24 hours or more. The trial is expected to run from October 2021 to January 2026, with an estimated participant involvement duration of up to 40 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnostic right heart catheterization, and stability on background PAH therapies. Following successful screening, participants will be randomized to receive either sotatercept or placebo, both administered subcutaneously. Study visits will include regular follow-up assessments to monitor safety, efficacy, and adherence to the protocol. The end-of-study visit will occur after the completion of the treatment period, where final evaluations will be conducted.

Participants are expected to adhere to the study visit schedule and comply with all protocol requirements. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events, or withdrawal of consent. The primary endpoint is the time to first event of all-cause death, lung transplantation, or PAH worsening-related hospitalization. Secondary endpoints include overall survival, transplant-free survival, and changes in various clinical parameters such as REVEAL Lite 2.0 risk score, NT-proBNP levels, and 6-minute walk distance. The study aims to provide comprehensive data on the potential benefits of sotatercept in this high-risk patient population.

The clinical trial involves the administration of **sotatercept**, a **biological** agent, in the form of a **solution for injection**. Sotatercept is provided by Merck & Co. Inc. and is identified by the sponsor product code MK-7962. The active substance, sotatercept, is a protein of other origin, and it is administered subcutaneously. The dosing regimen for sotatercept is based on body weight, with a maximum daily dose of 0.7 mg/kg and a total maximum dose of 105 mg over a treatment period of up to 40 weeks. The administration is facilitated by a syringe and needle or a prefilled syringe of sterile water for injection, both of which have a CE mark. Participant compliance with the dosing schedule is monitored throughout the study.

The trial also includes a **placebo** group, which receives a lyophilisate and solvent for solution for injection. The placebo is administered in a manner identical to the experimental treatment, ensuring blinding of the study. The placebo is not associated with any active substance and serves as a control to evaluate the efficacy and safety of sotatercept when added to maximum tolerated background therapy for participants with pulmonary arterial hypertension (PAH) classified as WHO Functional Class III or IV at high risk of mortality. The placebo administration follows the same subcutaneous route and dosing schedule as the experimental treatment to maintain consistency across the study arms.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is defined as the time to the first event of all-cause death, lung transplantation, or hospitalization related to the worsening of **Pulmonary Arterial Hypertension (PAH)** lasting 24 hours or more. This endpoint is critical in evaluating the impact of the treatment on the progression of the disease and overall patient survival.

Secondary endpoints include a variety of measures to provide a comprehensive assessment of the treatment's efficacy. These include overall survival, transplant-free survival, and the proportion of participants experiencing a mortality event at the end of the study. Additionally, changes from baseline in the REVEAL Lite 2.0 risk score at week 24, the proportion of participants achieving a REVEAL Lite 2.0 risk score of 7 or less at week 24, and changes in NT-proBNP levels, mean pulmonary arterial pressure (mPAP), and pulmonary vascular resistance (PVR) at week 24 will be evaluated. Other secondary endpoints include the proportion of participants showing improvement in WHO Functional Class at the end of the double-blind, placebo-controlled treatment period, changes from baseline in the 6-minute walk distance (6MWD), cardiac output (CO), and EQ-5D-5L index score at week 24.

The efficacy parameters will be measured and collected at specified time points, such as baseline and week 24, using validated scales and laboratory tests. These assessments will be conducted in a manner consistent with clinical trial protocols to ensure the reliability and validity of the data collected. The analysis of these endpoints will provide insights into the therapeutic benefits of sotatercept when added to maximum tolerated background therapy in participants with PAH at high risk of mortality.