Evaluation of Sotatercept (MK-7962) Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Pediatric Pulmonary Arterial Hypertension

The primary objectives of this Phase 2 open-label study are to evaluate the **safety** and **tolerability** of **sotatercept** over a 24-week treatment period in children aged 1 to less than 18 years with **pulmonary arterial hypertension** (PAH) who are on standard care. Additionally, the study aims to assess the **pharmacokinetics** (PK) of sotatercept during the same period. These objectives are clinically relevant as they provide critical information on the potential risks and benefits of sotatercept in a pediatric population, which is essential for determining its suitability and dosage for treating PAH in children.

The secondary objective is to evaluate the **pharmacodynamics** of sotatercept over the 24-week treatment period. This will help in understanding the drug's mechanism of action and its effects on the body, which is crucial for optimizing therapeutic strategies and improving patient outcomes in the management of PAH.

The clinical trial involves a total of **40 participants** diagnosed with **pulmonary arterial hypertension** (PAH). The study population includes both male and female subjects, with an age range that encompasses adults. Participants were selected based on documented historic diagnostic right heart catheterization confirming PAH WHO Group 1, among other subtypes. The trial population is required to be on stable doses of background PAH therapy, which may include phosphodiesterase-5 inhibitors, endothelin receptor antagonists, soluble guanylate cyclase stimulators, or prostanoids. Lifestyle considerations include adherence to specific contraceptive measures for both male and female participants during the intervention period and for at least 16 weeks after the last dose of the study intervention. The trial also involves a vulnerable population, indicating additional ethical considerations in the study design.

The clinical trial is designed to evaluate the **safety** and tolerability of **sotatercept** over a 24-week treatment period in children aged 1 to less than 18 years with **pulmonary arterial hypertension** (PAH) who are on standard care. This is a Phase 2, open-label study, which means that both the researchers and participants know which treatment is being administered. The trial will assess the pharmacokinetics (PK) and pharmacodynamics of sotatercept, administered as a **solution for injection** via the subcutaneous route. The study is expected to run from January 2023 to September 2028, with participant involvement lasting up to 78 weeks.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on documented right heart catheterization and stable background PAH therapy. The inclusion criteria require participants to be on a stable dose of PAH therapy and adhere to specific contraceptive guidelines. The primary endpoints include measuring serum trough concentration, area under the curve at steady state, and the percentage of participants experiencing adverse events. Secondary endpoints focus on changes in exercise capacity, cardiac function, and quality of life metrics.

Study visits will be scheduled at regular intervals to monitor safety, efficacy, and any adverse events. Follow-up visits will include assessments of laboratory parameters, blood pressure, and the presence of anti-drug antibodies. The end-of-study visit will conclude the participant's involvement, with final evaluations of the primary and secondary endpoints. Participants may be withdrawn from the study early if they experience significant adverse events or fail to comply with study protocols. The trial aims to provide comprehensive data on the use of sotatercept in the pediatric population with PAH, contributing to the understanding of its safety and efficacy in this demographic.

The clinical trial involves the administration of **sotatercept**, a **biological** agent classified as a **protein** of other origin. Sotatercept is provided in the form of a **solution for injection** and is identified by the sponsor product code MK-7962. The pharmaceutical form is specifically designed for subcutaneous administration. The dosing regimen for sotatercept is calculated based on body weight, with a maximum daily dose of 0.7 mg/kg and a cumulative maximum dose of 76.2 mg/kg over the treatment period. The maximum treatment duration is set at 78 weeks. Sotatercept is not formulated specifically for pediatric use, although the trial targets a pediatric population. The product is manufactured by Merck & Co. Inc. and holds an orphan drug designation under the number EU/3/20/2369.

In addition to the experimental treatment with sotatercept, participants will continue to receive standard-of-care therapy for pulmonary arterial hypertension (PAH). This standard-of-care therapy is not specified in the trial data but typically includes medications such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, or prostacyclin analogs, depending on the individual patient's treatment plan. The trial does not include a placebo or comparator treatment group. Compliance with the dosing schedule and administration of sotatercept will be monitored throughout the study to ensure adherence to the protocol and to evaluate the safety and tolerability of the treatment over the 24-week period.

The efficacy of sotatercept in the clinical trial will be assessed using a combination of primary and secondary endpoints. Primary endpoints include pharmacokinetic parameters such as Serum Trough Concentration (Ctrough) of **sotatercept**, Area Under the Curve at Steady State (AUCss), and Area Under the Curve from 0 to 3 weeks (AUC0-3 weeks). Additionally, safety-related endpoints will be evaluated, including the percentage of participants experiencing at least one adverse event (AE), the percentage of participants discontinuing the study drug due to an AE, and various laboratory parameters such as hemoglobin concentration, hematocrit, RBC count, reticulocyte count, platelet count, blood pressure, and the titer of anti-drug antibodies (ADA) to sotatercept.

Secondary endpoints focus on clinical efficacy measures, including the mean change from baseline in the 6-Minute Walk Distance (6MWD), Tricuspid Annular Plane Systolic Excursion (TAPSE), Pulmonary Artery Systolic Pressure (PASP), Right Ventricular Fractional Area Change (RVFAC), Eccentricity Index, Right Ventricular (RV) Function, Cardiac Output, Pulmonary Arterial Pressure (PAP), and Pediatric Quality of Life (PedsQL) Generic Score. Additionally, changes in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) levels and the percentage of participants who either improved or maintained their World Health Organization Functional Class (WHO FC) will be assessed. These parameters will be measured at specified timepoints throughout the study to evaluate the efficacy of sotatercept in treating pulmonary arterial hypertension (PAH) in the pediatric population.