Long-term Evaluation of Sotatercept in Combination with Background Therapy for Pulmonary Arterial Hypertension in Adult Patients

The primary objective of this open-label, long-term follow-up study is to evaluate the long-term **safety** and tolerability of **sotatercept** when added to background therapy in adult participants with **Pulmonary Arterial Hypertension (PAH)**. This is clinically relevant as it aims to determine the sustained safety profile of sotatercept, which is crucial for its potential integration into long-term treatment regimens for PAH, a progressive and life-threatening condition.

The secondary objective is to follow participants from parent sotatercept studies who were treated with sotatercept or placebo and assess continued efficacy. This objective is important to understand the long-term benefits and sustained efficacy of sotatercept in managing PAH symptoms and progression.

The clinical trial involves a total of **331 participants** diagnosed with **Pulmonary Arterial Hypertension (PAH)**. The study population includes both male and female adults, with an age range that encompasses individuals from young adults to older adults. Participants were selected based on their completion of a prior PAH sotatercept clinical study, ensuring they met all parent study requirements without early discontinuation. The trial does not specify particular lifestyle considerations such as diet or physical activity. However, it is noted that the population includes a vulnerable group, which may imply additional considerations for participant safety and compliance. The study aims to evaluate the long-term safety and tolerability of sotatercept when added to existing PAH therapy, focusing on adult participants who have demonstrated the ability to adhere to study protocols and provide informed consent.

The clinical trial is designed to evaluate the long-term safety and tolerability of **sotatercept** when added to background therapy for the treatment of **Pulmonary Arterial Hypertension (PAH)**. This is an open-label, long-term follow-up study involving adult participants who have completed a prior sotatercept clinical study. The trial is structured as a Phase III study, focusing on the assessment of adverse events, anti-drug antibodies, clinical laboratory assessments, vital signs, and 12-lead electrocardiograms as primary endpoints. Secondary endpoints include the 6-minute walk distance, N-terminal pro-hormone B-type natriuretic peptide levels, World Health Organization functional class, pulmonary vascular resistance, overall survival, and the Simplified French Risk score.

The trial is expected to run from April 30, 2021, to June 28, 2028. Participants will be involved in the study for a maximum treatment period of 84 weeks. The study involves a series of visits, starting with an inclusion (screening) visit to confirm eligibility based on the completion of a prior sotatercept study and adherence to protocol requirements. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, with assessments conducted at each visit. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected.

Participants are required to adhere to specific inclusion criteria, such as the completion of a prior sotatercept study and the ability to comply with study requirements. Female participants of childbearing potential must agree to use effective contraception and undergo regular pregnancy testing. Male participants must agree to use condoms and refrain from donating sperm. Conditions that may lead to early termination from the study include non-compliance with the study protocol or the occurrence of significant adverse events. The study drug, sotatercept, is administered subcutaneously as a solution for injection, with a maximum daily dose of 0.7 mg/kg and a total dose not exceeding 105 mg.

The clinical trial involves the administration of **sotatercept**, a **biological** medicinal product, formulated as a **solution for injection**. Sotatercept is identified by the sponsor product code MK-7962 and is produced by Merck & Co. Inc. The active substance, sotatercept, is a protein of other origin, also known by the synonym ACE-011. The medication is administered subcutaneously using a syringe and needle or a prefilled syringe of sterile water for injection, both of which have a CE mark. The dosing regimen for sotatercept is set at a maximum daily dose of 0.7 mg/kg, with a total maximum dose of 105 mg over a treatment period of 84 days. The trial aims to evaluate the long-term safety and tolerability of sotatercept when added to background therapy for pulmonary arterial hypertension (PAH).

In addition to the experimental treatment, participants will continue to receive standard-of-care therapy for PAH as part of their background treatment regimen. This non-experimental treatment is not specified in detail within the trial documentation but is assumed to be consistent with current clinical guidelines for the management of PAH. Compliance with the dosing schedule and administration of sotatercept will be monitored throughout the study to ensure adherence to the protocol and to assess the safety and efficacy of the treatment.

The efficacy of **sotatercept** in the clinical trial will be assessed using several secondary endpoints. These include the 6-minute walk distance (6MWD), which measures the distance a participant can walk in six minutes as a test of aerobic capacity and endurance. Additionally, the levels of N-terminal pro-hormone B-type natriuretic peptide will be evaluated, as this biomarker is indicative of heart stress and function. The World Health Organization (WHO) functional class will be used to categorize the severity of **Pulmonary Arterial Hypertension (PAH)** symptoms. Pulmonary vascular resistance will also be measured to assess the resistance in the pulmonary circulation, which is a critical factor in PAH. Overall survival rates will be monitored to determine the long-term benefits of the treatment. Lastly, the Simplified French Risk score will be utilized to evaluate the risk profile of participants, providing a comprehensive assessment of the treatment's impact on disease progression.