A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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This study evaluates the effect of sotatercept (ACE-011) in adults with pulmonary arterial hypertension (PAH). Each eligible participant will receive standard of care (SOC) plus sotatercept (ACE-011) for a 24-week treatment period, followed by an 18-month extension period, and an 8-week follow-up period.

Detailed Description
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This is a Phase 2a, single-arm, open-label, multicenter exploratory study to determine the effects of sotatercept plus SOC in adults with WHO functional class III PAH. All eligible participants will receive SOC plus sotatercept at a starting dose level of 0.3 mg/kg by subcutaneous (SC) injection for Cycle 1 and escalating to 0.7 mg/kg at Cycle 2 for the remainder of the treatment period. Participants will be required to attend clinic visits once every three weeks for the 24-week treatment period and once every three weeks for the 18-month extension period to perform one or more protocol specified evaluations. Evaluations include hemodynamic measures collected during right heart catheterization (RHC) with invasive cardiopulmonary exercise test (iCPET), and cardiac magnetic resonance imaging (MR), 6-minute walk distance (6MWD), pharmacokinetic parameters, pharmacodynamic parameters, anti-drug antibody testing, and adverse events.

Official Title
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A Phase 2a Single-Arm, Open-Label, Multicenter Exploratory Study to Assess the Effects of Sotatercept (ACE-011) for the Treatment of Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Biological: Sotatercept
* Other: SOC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Documented findings on RHC at any time prior to Screening consistent with a diagnosis of World Health Organization (WHO) pulmonary hypertension Group 1: PAH of any of the following subtypes: Idiopathic PAH Heritable PAH Drug- or toxin-induced PAH PAH associated with connective tissue disease PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair Symptomatic pulmonary hypertension classified as WHO functional class III Screening RHC documenting a minimum PVR of ≥ 4 Wood units Pulmonary function tests within 6 months prior to Screening as follows: Total lung capacity > 70% predicted; or if between 60% to 70% predicted, or not possible to be determined, confirmatory high-resolution computed tomography (CT) indicating no more than mild interstitial lung disease per investigator interpretation or Forced expiratory volume (first second) (FEV1)/forced vital capacity (FVC) > 70% predicted For subjects with a history of lobectomy or pneumonectomy, and for whom there are no population-based normalization methods, assessment based on residual lung volume will be permitted to assess eligibility. Ventilation-perfusion (VQ) scan (or, if unavailable, a negative CT pulmonary angiogram [CTPA] or pulmonary angiography result), any time prior to Screening or conducted during Screening Period with normal or low probability result 6MWD ≥ 100 and ≤ 550 meters repeated twice during Screening Period and both values within 15% of each other, calculated from the highest value Combination PAH therapy at stable (per investigator) dose levels for at least 90 days prior to Cycle 1 Day 1 (C1D1) Exclusion Criteria: Participants will be excluded from the study if they meet any of the following criteria: Started or stopped receiving any general supportive therapy for pulmonary hypertension (e.g., diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to C1D1 (Cycle 1 Day 1) Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to C1D1 History of atrial septostomy within 180 days prior to Screening History of more than mild obstructive sleep apnea that is untreated History of portal hypertension or chronic liver disease, defined as mild to severe hepatic impairment (Child-Pugh Classes A to C) History of human immunodeficiency virus infection-associated PAH Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) Uncontrolled systemic hypertension as evidenced by sitting systolic BP > 160 mm Hg or sitting diastolic BP > 100 mm Hg during Screening after a period of rest Systolic BP < 90 mm Hg during Screening or at baseline History of known pericardial constriction Electrocardiogram (ECG) with QTcF > 480 msec during Screening or C1D1 History of personal or family history of long QTc syndrome or sudden cardiac death History of restrictive or constrictive cardiomyopathy Left ventricular ejection fraction < 45% on echocardiogram performed within 6 months of Screening OR pulmonary capillary wedge pressure (PCWP) > 15 mm Hg on RHC during baseline evaluation Any current symptomatic coronary disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain in the past 6 months prior to Screening) Acutely decompensated heart failure within 30 days prior to C1D1, as per investigator assessment Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sotatercept<br>Each participant will receive SOC plus sotatercept at a dose of 0.3 mg/kg SC for Cycle 1. (Each cycle will be 21 days.) From Cycle 2 through Cycle 9, the dose will be escalated to 0.7 mg/kg SC. Dosing will be every three weeks during the 24-week treatment period and 18-month extension period. | Biological: Sotatercept<br>* Sotatercept injection<br>* Other names: ACE-011;Other: SOC<br>* SOC therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peak Oxygen Uptake (VO2 Max) at 24 Weeks | Each participant's VO2 max was measured by an invasive cardiopulmonary exercise test (iCPET) at baseline and at 24 weeks. | Baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Right Ventricular Stroke Volume (RV SV) at 24 Weeks | Each participant's RV SV was measured by cardiac MRI at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in Right Ventricular End-Systolic Volume (RV ESV) at 24 Weeks | Each participant's RV ESV was measured by cardiac MR imaging at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in Right Ventricular End-Diastolic Volume (RV EDV) at 24 Weeks | Each participant's RV EDV was measured by cardiac MR imaging at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Percent Change From Baseline in Right Ventricular Ejection Fraction (RV EF) at 24 Weeks | Each participant's RV EF was measured by cardiac MR imaging at baseline and at 24 weeks. | Baseline and 24 Weeks | 
| Change From Baseline in Right Ventricular Stroke Volume Index (RV SVI) at 24 Weeks | Each participant's RV SVI was measured by cardiac MR imaging at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in Right Ventricular (RV) Mass at 24 Weeks | Each participant's RV mass was measured by cardiac MR imaging at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in Ventilatory Efficiency (VE/VCO2 Slope) at 24 Weeks | VE/VCO2 slope refers to the slope of the regression line of Minute Ventilation (VE) in liters/minute in the Y-axis and corresponding carbon dioxide production per minute (VCO2) in liters/minute in the X-axis plotted with multiple measurements taken during exercise. Each participant's VE/VCO2 slope at peak exercise was measured by an iCPET at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in Cardiac Index at 24 Weeks | Each participant's cardiac index at peak exercise was measured by iCPET at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in Mean Pulmonary Arterial Pressure at 24 Weeks | Each participant's pulmonary arterial pressure at peak exercise was measured by iCPET at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in Arteriovenous O2 Content Difference (Ca-vO2) at 24 Weeks | Each participant's Ca-vO2 at peak exercise was measured by iCPET at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks | Each participant's PVR, at resting supine, was measured by right heart catheterization (RHC) at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks | 6MWD is measured by an exercise test known as 6MWT that assesses aerobic capacity and endurance. It measures the distance covered over a time of 6 minutes and is used as an outcome measure by which to compare changes in performance capacity. Each participant's 6MWD was measured at baseline and at 24 weeks. An increase in the distance walked during the 6MWT indicates improvement in basic mobility. | Baseline and 24 weeks | 
| Change From Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks | Each participant's laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were measured at baseline and at 24 weeks. | Baseline and 24 Weeks | 
| Change From Baseline in WHO (World Health Organization) Functional Class at 24 Weeks | The World Health Organization (WHO) functional class describes how severe a person's pulmonary hypertension symptoms are. There are four different classes - I is the mildest and IV the most severe form of pulmonary hypertension. | Baseline and 24 Weeks | 
| Number of Participants With One or More Adverse Events (AEs) | An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Up to 24 weeks | 
| Number of Participants Who Experienced One or More Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH) | Events that indicate clinical worsening of PAH include death, need for and/or worsening-related listing for lung and/or heart transplant, need to initiate an approved PAH SOC rescue therapy, PAH-specific hospitalization, or functional deterioration (worsened WHO Functional Class AND 15% decrease in 6MWD). | Up to 102 weeks | 
| Observed Trough Concentration (Ctrough) of Sotatercept at Cycle 9 | Ctrough is the plasma concentration of a drug prior to administration. | Day 1 of Cycle 9 (Each cycle was 21 days.) | 
| Maximum Plasma Concentration (Cmax) of Sotatercept at Cycle 9 | Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Cmax parameter is derived from this preliminary popPK modeling. | Day 1 of each 21-day cycle: Cycles 1-9 | 
| Minimum Plasma Concentration (Cmin) of Sotatercept at Cycle 9 | Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Cmin parameter is derived from this preliminary popPK modeling. | Day 1 of each 21-day cycle: Cycles 1-9 | 
| Average Concentration (Cavg) of Sotatercept at Cycle 9 | Cavg is calculated by area under the plasma concentration versus dosing interval time curve at steady-state divided by the dosing interval. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Cavg parameter is derived from this preliminary popPK modeling. | Day 1 of each 21-day cycle: Cycles 1-9 | 
| Area Under the Concentration-Time Curve From 0 to T (AUC0-T) of Sotatercept at Cycle 9 | AUC0-T (area under the plasma concentration versus time curve from time zero after a dose is given to a period of one 21-day cycle) is a measure of the mean concentration levels of a drug in the plasma at steady state. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The AUC0-T parameter is derived from this preliminary popPK modeling. | Day 1 of each 21-day cycle: Cycles 1-9 | 
| Apparent Terminal Half-life (t1/2 ) of Sotatercept at Cycle 9 | t1/2 is the elimination half-life of study drug: the time it takes for half of the study drug in the blood plasma to dissipate. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The t1/2 parameter is derived from this preliminary popPK modeling. | Day 1 of each 21-day cycle: Cycles 1-9 | 
| Apparent Serum Clearance (CL) of Sotatercept at Cycle 9 | Apparent serum CL is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The apparent serum CL parameter is derived from this preliminary popPK modeling. | Day 1 of each 21-day cycle: Cycles 1-9 | 
| Apparent Volume of Distribution (Vz/F) of Sotatercept at Cycle 9 | Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Vz/F parameter is derived from this preliminary popPK modeling. | Day 1 of each 21-day cycle: Cycles 1-9 | 
| Absorption Rate Constant (Ka) of Sotatercept at Cycle 9 | Ka is the proportionality constant that relates the rate of drug absorbed into the body. Ka is a value used to describe the rate at which a drug enters into the system. It is expressed in units of time. PopPK modeling approach was used to build a population PK model that captures the totality of the observed data from Cycles 1 to 9. The Ka parameter is derived from this preliminary popPK modeling. | Day 1 of each 21-day cycle: Cycles 1-9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAH