Evaluation of Sotatercept Plus Background Therapy Versus Placebo in Intermediate- and High-risk Pulmonary Arterial Hypertension: A Phase 3 Randomized Study

Trial ID: 2023-509139-16-00
Protocol: A011-13
Sponsor: Acceleron Pharma Inc.

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Diseases & Conditions

Pulmonary arterial hypertension

Objectives

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effects of **sotatercept** treatment, in addition to background therapy, on time to clinical worsening (TTCW) in participants who are newly diagnosed with intermediate- or high-risk **pulmonary arterial hypertension** (PAH). This objective is clinically relevant as it aims to assess the potential of sotatercept to delay disease progression in a population at significant risk, thereby potentially improving patient outcomes and quality of life.

Participants

The clinical trial involves a total of **206 participants** who are newly diagnosed with **pulmonary arterial hypertension (PAH)** and are at intermediate or high risk of disease progression. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on documented diagnostic right heart catheterization within 12 months of screening, confirming a minimum pulmonary vascular resistance of 4 Wood units and a pulmonary capillary wedge pressure or left ventricular end-diastolic pressure of 15 mmHg or less. The trial includes individuals with idiopathic, heritable, drug/toxin-induced PAH, PAH associated with connective tissue disease, or PAH associated with simple congenital systemic-to-pulmonary shunts at least one year post-repair. Participants are required to have symptomatic PAH classified as WHO Functional Class II or III and must be on stable doses of a double or triple combination of background PAH therapies and diuretics for at least 90 days prior to screening. Lifestyle considerations such as diet and physical activity are not specified, but participants must have a six-minute walk distance of at least 150 meters, repeated twice at screening. The trial includes both vulnerable populations and requires adherence to specific contraceptive measures for participants of childbearing potential. The ability to comply with study visit schedules and protocol requirements is essential for participation.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **sotatercept** when added to background therapy in patients newly diagnosed with **pulmonary arterial hypertension** (PAH) at intermediate or high risk of disease progression. The trial aims to assess the effects of sotatercept on time to clinical worsening (TTCW) compared to placebo. The study is expected to run from September 2021 to August 2029, with a maximum treatment period of 47 weeks for each participant.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, documented diagnostic right heart catheterization, and stable background PAH therapy. The inclusion visit will ensure that participants meet all necessary conditions, including a minimum six-minute walk distance (6MWD) and appropriate risk scores. Following randomization, participants will attend regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. These visits will include assessments of exercise capacity, biomarkers, and functional class. The end-of-study visit will occur after the completion of the treatment period, where final evaluations will be conducted to assess the primary and secondary endpoints.

Participant involvement is expected to last approximately 47 weeks, with conditions for early termination including significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The primary endpoint focuses on TTCW, encompassing events such as all-cause death, non-planned PAH-related hospitalization, and deterioration in exercise performance. Secondary endpoints include improvements in 6MWD, NT-proBNP levels, and WHO functional class at 24 weeks. The study will utilize a subcutaneous route for the administration of sotatercept, with a maximum daily dose of 0.7 mg/kg and a total dose not exceeding 105 mg.

Treatment

The clinical trial involves the administration of **sotatercept**, a **solution for injection**. Sotatercept is a biological product with the active substance derived from a protein of other origin. It is administered subcutaneously using a syringe and needle or a prefilled syringe of sterile water for injection. 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 the treatment period. The maximum treatment period is 47 weeks. Sotatercept is identified by the sponsor product code MK-7962 and is manufactured by Merck & Co. Inc. The product is designated as an orphan drug under the designation number EU/3/20/2369.

The study also includes a **placebo** treatment, which is administered in a similar manner to the experimental medication. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. Both the experimental and placebo treatments are administered in conjunction with standard background therapy for pulmonary arterial hypertension (PAH), which is not specified in the trial data. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

Efficacy

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary efficacy endpoint is Time to Clinical Worsening (**TTCW**), which includes events such as all-cause death, non-planned pulmonary arterial hypertension (PAH)-related hospitalization of 24 hours or more, atrial septostomy, lung transplant, and deterioration in exercise performance due to PAH. This also encompasses worsening of WHO Functional Class (FC) from baseline, signs or symptoms of increased right heart failure, and the addition or change in the delivery route of background PAH therapy to parenteral.

Secondary endpoints will evaluate multicomponent improvement, including measures of participants achieving improvement in the 6-minute walk distance (6MWD), NT-proBNP levels, and WHO FC at Week 24. Additional assessments include achieving a low-risk category in the REVEAL Lite 2 risk score, using the simplified French Risk score calculator, maintaining or improving WHO FC at 24 weeks, and changes in the Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores of PAH-SYMPACT® at Week 24 versus baseline.

Inclusion and Exclusion Criteria

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Inclusion Criteria

"1. Age ≥ 18 years 2. Documented diagnostic right heart catheterization (RHC) within 12 months of screening documenting a minimum PVR of ≥ 4 Wood units and pulmonary capillary wedge pressure (PCWP) or left ventricular enddiastolic pressure (LVEDP) of ≤ 15 mmHg, with the diagnosis of WHO PAH Group 1 in any of the following subtypes: - Idiopathic PAH - Heritable PAH - Drug-/toxin-induced PAH - PAH associated with CTD - PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair 3. Symptomatic PAH classified as WHO FC II or III 4. Either REVEAL Lite 2 risk score ≥ 6 or COMPERA 2.0 risk score ≥ 2 (intermediate-low-risk or above) 5. Diagnosis of PAH within 12 months of screening and on stable doses of a double or triple combination of background PAH therapies and diuretics (if any) for at least 90 days prior to screening. Background PAH therapy and diuretics are further defined in Section 7.2. 6. 6MWD≥ 150 m repeated twice at screening at least 4 hours apart, but no longer than 1 week apart, and both values are within 15% of each other (calculated from the highest value). 7. Females of childbearing potential (as defined in Appendix 4) must meet the following criteria: •Have 2 negative urine or serum pregnancy tests as verified by the investigator during the Screening Period; •Agree to ongoing pregnancy testing (either urine or serum) during the course of the study and until 8 weeks after the last dose of the study drug •If sexually active with a male partner: - Used highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, AND - Agreed to use the same highly effective contraception in combination with a barrier method during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment •Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment 8. Male participants must meet the following criteria: -Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy -Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment 9. Ability to adhere to study visit schedule and understand and comply with all protocol requirements 10. Ability to understand and provide documented informed consent "

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Exclusion Criteria

1.Diagnosis of pulmonary hypertension (PH) WHO Groups 2, 3, 4, or 5 2.Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension, schistosomiasis-associated PAH, pulmonary veno occlusive disease and pulmonary capillary hemangiomatosis 3.Hgb at screening above gender-specific upper limit of normal (ULN), per local laboratory test 4.Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 180 mmHg or sitting diastolic BP > 110 mmHg during the Screening Visit after a period of rest 5.Baseline systolic BP < 90 mmHg at screening 6.Pregnant or breastfeeding women 7.Any of the following clinical laboratory values at the Screening Visit: •Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (as defined by MDRD equation) •Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels > 3 × ULN (For United Kingdom [UK], refer to the specific requirement in Appendix 6) •Platelet count < 50,000/mm3 (< 50.0 × 109/L) 8.Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 halflives for investigational biologics prior to the date of documented informed consent 9.Known allergic reaction to sotatercept (ACE-011), its excipients, or luspatercept 10.History of pneumonectomy 11.Pulmonary function test values of forced vital capacity < 60% predicted within 1 year prior to the Screening Visit 12.Stopped receiving any PH chronic general supportive therapy (e.g., diuretics, oxygen, anticoagulants, and digoxin) within 60 days prior to the Screening Visit 13.Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the Screening Visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible) 14.Untreated more than mild obstructive sleep apnea 15.History of known pericardial constriction 16.History of restrictive cardiomyopathy 17.History of atrial septostomy within 180 days prior to the Screening Visit 18.Electrocardiogram (ECG) with Fridericia's corrected QT interval > 500 ms during the Screening Period (For UK and South Korea, refer to the specific requirements in Appendix 6). 19.Personal or family history of long QT syndrome or sudden cardiac death 20.Left ventricular ejection fraction < 50% documented by a historical echocardiograph (ECHO) or cardiac magnetic resonance imaging (MRI) within the last 12 months prior to screening (if there is more than 1 assessment of left ventricular ejection fraction (LVEF), the value from the most recent measurement should be used in assessing eligibility) 21.Coronary artery disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months prior to the Screening Visit 22.Cerebrovascular accident within 3 months prior to the Screening Visit 23.Acutely decompensated heart failure within 30 days prior to the Screening Visit, as per investigator assessment 24.Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease 25.Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, and vasopressin) within 30 days prior to the Screening Visit 26.Active malignancy with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or prostate cancer that is not currently or expected, during the study, to be treated with radiation therapy, chemotherapy, and/or surgical intervention, or hormonal treatment.
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Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	01 Sept 2021	23
Belgium	Not Recruiting	01 Sept 2021	7
Croatia	Not Recruiting	01 Sept 2021	7
Czechia	Not Recruiting	01 Sept 2021	7
Denmark	Not Recruiting	01 Sept 2021	5
France	Not Recruiting	01 Sept 2021	43
Germany	Not Recruiting	01 Sept 2021	33
Greece	Not Recruiting	01 Sept 2021	11
Italy	Not Recruiting	01 Sept 2021	37
The Netherlands	Not Recruiting	01 Sept 2021	—