Safety and Tolerability of Single Ascending Intravenous (IV) Doses of REGN5381 in Adult Heart Failure Patients With Elevated Pulmonary Capillary Wedge Pressure

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the safety and tolerability of single doses of REGN5381 in patients with heart failure with evidence of congestion The secondary objectives of the study are to: Evaluate the effects of single doses of REGN5381 on hemodynamic parameters Evaluate the effects of REGN5381 on a clinical biomarker of heart failure severity Characterize the pharmacokinetics (PK) of single doses of REGN5381 Assess the immunogenicity of REGN5381

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of REGN5381, an NPR1 Agonist, in Heart Failure Patients With Elevated Pulmonary Capillary Wedge Pressure

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: REGN5381
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Body mass index (BMI) between 18 and 35 kg/m2, inclusive, rounded to the nearest whole number Ambulatory patients with New York Heart Association (NYHA) class II/III heart failure and at least 1 sign and/or symptom of congestion (eg, dyspnea on exertion, worsening edema, orthopnea, etc.) Left ventricular ejection fraction (LVEF) <50% on echocardiogram (ie, HFrEF patients) within 6 months prior to randomization (only for Group A and Group B) Left ventricular ejection fraction (LVEF) ≥50% on echocardiogram (ie, HFpEF patients) within 6 months prior to randomization (only for Group C) NT-proBNP >1000 pg/mL or Brain Natriuretic Peptide (active form) (BNP) >300 pg/mL as described in the protocol within 30 days prior to randomization measured by the local laboratory Pulmonary capillary wedge pressure (PCWP) ≥15 mmHg ans Right artrail pressure (RAP >5 on right heart catheterization (RHC) the morning of anticipated study drug dose administration Systolic blood pressure (SBP) ≥100 mmHg at the screening visit and on day -1 Hematocrit >30% at the screening visit and day -1 Key Exclusion Criteria: Currently taking IV vasodilators and/or inotropes Taking sacubitril/valsartan (only for Group A and Group C) Taking a phosphodiesterase (PDE) inhibitor (eg, sildenafil), or a soluble guanylate cyclase stimulator (SGCS; ie, vericiguat) within 2 weeks of the screening visit or planning on taking valsartan/sacubitril, a PDE inhibitor, or a SGCS at any point during the study More than moderate valvular regurgitation/stenosis on echocardiogram within 6 months prior to randomization Known infiltrative or hypertrophic cardiomyopathy Acute coronary syndrome within prior 6 months of randomization History of cardiac arrest Cardiac surgery within 3 months of randomization Pacemaker or defibrillator placement within prior 30 days of randomization Severe chronic obstructive pulmonary disease (COPD) (defined as Forced Expiratory Volume in 1st second [FEV1] <50% of predicted or Global Initiative for Chronic Obstructive Lung Disease [GOLD] 3 or 4) Pulmonary arterial hypertension (World Health Organization [WHO] Group 1) Congenital heart disease (repaired or unrepaired) Inability to lie flat for cardiac catheterization Note: Other protocol-defined Inclusion/ Exclusion Criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Randomized 3:1; limited to patients with heart failure with reduced ejection fraction (HFrEF) not taking sacubitril/valsartan | Drug: REGN5381<br>* Single dose administered via IV infusion<br>Drug: Placebo<br>* Single dose administered via IV infusion<br>|
| Experimental: Group B<br>Randomized 3:1; limited to patients with HFrEF taking sacubitril/valsartan | Drug: REGN5381<br>* Single dose administered via IV infusion<br>Drug: Placebo<br>* Single dose administered via IV infusion<br>|
| Experimental: Group C<br>Randomized 3:1; limited to patients with HFpEF (not taking sacubitril/valsartan) | Drug: REGN5381<br>* Single dose administered via IV infusion<br>Drug: Placebo<br>* Single dose administered via IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs) |  | Through the end-of-study (EOS) visit up to 78 days post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pulmonary capillary wedge pressure (PCWP) |  | Over 6 hours post-dose administration | 
| Change from baseline right atrial pressure (RAP) |  | Over 6 hours post-dose administration | 
| Change from baseline cardiac output (CO) |  | Over 6 hours post-dose administration | 
| Change from baseline systemic vascular resistance (SVR) |  | Over 6 hours post-dose administration | 
| Change from baseline mean pulmonary artery pressure (mPAP) |  | Over 6 hours post-dose administration | 
| Change from baseline pulmonary vascular resistance (PVR) |  | Over 6 hours post-dose administration | 
| Change from baseline in systolic blood pressure (SBP) |  | Over the first 6 hours, 24 hours post-dose administration (day 1), through the EOS visit up to 78 days post-dose | 
| Change from baseline in diastolic blood pressure (DBP) |  | Over the first 6 hours, 24 hours post-dose administration (day 1), through the EOS visit up to 78 days post-dose | 
| Change from baseline in mean arterial pressure (MAP) |  | Over the first 6 hours, 24 hours post-dose administration (day 1), through the EOS visit up to 78 days post-dose | 
| Change from baseline in pulse rate (PR) |  | Over the first 6 hours, 24 hours post-dose administration (day 1), through the EOS visit up to 78 days post-dose | 
| Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) |  | To 6 hours, 24 hours post-dose administration (day 1), through the EOS visit up to 78 days post-dose | 
| Concentrations of REGN5381 in serum |  | Through the EOS visit, up to 78 days post-dose | 
| Immunogenicity, as measured by anti-drug antibodies (ADA) to REGN5381 |  | Through the EOS visit, up to 78 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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New York Heart Association (NYHA) class II/III, Elevated Pulmonary Capillary Wedge Pressure, Reduced Left Ventricular Ejection Fraction