REGN5381 in Adult Participants With Heart Failure With Reduced Ejection Fraction (NATRIX-BNP)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of a Single Dose of REGN5381, an NPR1 Monoclonal Antibody Agonist, in Patients With Chronic Heart Failure With Reduced Ejection Fraction

This study is researching an experimental drug called REGN5381 (called "study drug"). The study is focused on patients with heart failure with reduced ejection fraction (ie, the heart is not functioning as well as it should).

The aim of the study is to see how safe, tolerable, and effective the study drug is.

The study is looking at several other research questions, including:

• What side effects may happen from taking the study drug
• How much study drug is in the blood at different times
• Whether the body makes antibodies against the study drug (which could make the study drug less effective or could lead to side effects)

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Placebo; Drug: REGN5381

Detailed Description

Enrollment for the Part A2 low eGFR cohort has been closed

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Liège, Belgium, 4000
    • Centre Hospitalier Régional de la Citadelle
  • Hainaut
    • Gilly, Hainaut, Belgium, 6060
      • Grand Hôpital de Charleroi
  • Limburg
    • Alken, Limburg, Belgium, 3570
      • Anima Research Center
  • Oost-Vlaanderen
    • Aalst, Oost-Vlaanderen, Belgium, 9300
      • Onze Lieve Vrouw Ziekenhuis Aalst
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3000
      • UZ Leuven
  • West Flanders
    • Bruges, West Flanders, Belgium, 8000
      • Algemeen Ziekenhuis St Jan Brugge Oostende Av
  • West Vlaanderen
    • Kortrijk, West Vlaanderen, Belgium, 8500
      • Algemeen Ziekenhuis Groeninge
    • Ostend, West Vlaanderen, Belgium, 8400
      • AZ Oostende
• Bulgaria
  • Haskovo, Bulgaria, 6300
    • MHAT Haskovo
  • Plovdiv, Bulgaria, 4000
    • University Multiprofile Hospital for Active Treatment Plovdiv
  • Sofia, Bulgaria, 1618
    • Arensia Exploratory Medicine Clinic at MBAL Sveta Sofia
• Czechia
  • Brandýs nad Labem-Stará Boleslav, Czechia, 25001
    • Medicus Services s.r.o.
  • Jaroměř, Czechia, 55101
    • Edumed
  • Central Bohemian
    • Prague, Central Bohemian, Czechia, 15006
      • Fakultni nemocnice v Motole
  • South Moravian
    • Brno, South Moravian, Czechia, 62500
      • University Hospital Brno
• Georgia
  • Tbilisi, Georgia, 0112
    • Arensia Exploratory Medicine at the Research Institute of Clinical Medicine
• Greece
  • Chaïdári, Greece, 12462
    • General University Hospital Attikon
  • Larissa, Greece, 41110
    • Larissa University Hospital
  • Attica
    • Athens, Attica, Greece, 11527
      • First Cardiology Clinic University of Athens
  • Attikh
    • Athens, Attikh, Greece, 11521
      • Athens Naval Hospital
• Moldova
  • Chisinau, Moldova, MD-2025
    • Pmsi Republican Clinical Hospital Timofei Mosneaga
• Poland
  • Lodz, Poland, 90-549
    • Medical University of Lodz
  • Żychlin, Poland, 62-571
    • NZOZ Gemini
  • Kuyavian-Pomeranian Voivodeship
    • Torun, Kuyavian-Pomeranian Voivodeship, Poland, 87-100
      • Wojewodzki Szpital Zespolony - Ludwik Rydygier Provincial Hospital
  • Masovian Voivodeship
    • Warsaw, Masovian Voivodeship, Poland, 02-097
      • UCK Medical University of Warsaw
  • Łódź Voivodeship
    • Skierniewice, Łódź Voivodeship, Poland, 96-100
      • Clinmedica Research sp zo.o.
• Romania
  • Bucharest, Romania, 11658
    • Arensia Exploratory Medicine Clinic at Monza Bucharest
  • Cluj-Napoca, Romania, 400006
    • Sc Arensia Exploratory Medicine Srl
• South Africa
  • Gauteng
    • Benoni, Gauteng, South Africa, 1500
      • Worthwhile Clinical Trials
    • Groenkloof, Gauteng, South Africa, 0181
      • Into Research
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa, 4321
      • Dr M I Sarvan,R Moodley & partners
  • Western Cape
    • Kuils River, Western Cape, South Africa, 7580
      • Kuils River Hospital
• South Korea
  • Seoul, South Korea, 8308
    • Korea University Guro Hospital
  • Gangwon-do
    • Wŏnju, Gangwon-do, South Korea, 26426
      • Wonju Severance Christian Hospital
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Seoul National University Bundang Hospital
  • Seodaemun-gu
    • Seoul, Seodaemun-gu, South Korea, 03722
      • Severance Hospital at Yonsei University College of Medicine
• Spain
  • Seville, Spain, 41009
    • Hospital Universitario Virgen Macarena Unidad Coronaria 1 planta
  • Valencia, Spain, 46015
    • Hospital Arnau de Vilanova
  • Cadiz
    • Villamartín, Cadiz, Spain, 11650
      • Virgen de las Montañas Hospital
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Universitario Virgen de la Arrixaca
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85015
      • Arensia Exploratory Medicine Clinic
  • California
    • Torrance, California, United States, 90509
      • Harbor UCLA Medical Center
  • Florida
    • Miami, Florida, United States, 33186
      • Flourish Research - Miami (Kendall) (Formerly Clinical Site Partners)
    • Winter Park, Florida, United States, 32789
      • Flourish Research - Orlando (Formerly Clinical Site Partners)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria

1. Body mass index (BMI) between 18 and 45 kg/m^2, inclusive, at initial screening visit
2. Diagnosis of chronic heart failure
3. Left ventricular ejection fraction 20-49% by echocardiogram performed within 3 months of screening
4. Plasma NT-proBNP ≥800 pg/mL (or ≥1000 pg/mL if in atrial fibrillation) at screening (visit 1) and NT-proBNP ≥600 pg/mL (or ≥800 pg/mL if in atrial fibrillation) approximately 30 days prior to randomization (visit 5)
5. Receiving optimized standard of care therapy for heart failure as described in the protocol

6. Sacubitril-valsartan treatment:

   a. Treatment with sacubitril-valsartan at screening and at baseline permitted in Part A2 sacubitril-valsartan cohort and in Part B if supported by safety data from the Part A2 sacubitril-valsartan cohort as described in the protocol

7. Estimated Glomerular Filtration Rate (eGFR) levels:

   1. eGFR of ≥30 mL/min/1.73 m2 according to locally used formula (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] preferred), at screening (visit 1) or approximately 30 days prior to randomization (visit 5) as described in the protocol

Key Exclusion Criteria

1. Hospital discharge within 180 days of anticipated randomization
2. Resting SBP that remains out of range after two repeated measurements prior to randomization as described in the protocol
3. Current or recent diagnosis of acute coronary syndrome or myocardial infarction as described in the protocol
4. History of symptomatic autonomic dysfunction as evidenced by orthostatic hypotension and/or syncope
5. Unexplained syncope <12 months prior to initial screening or during the Run-in period
6. History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric, or neurological disease, as assessed by the investigator that may confer unreasonable risk to the participant's participation in the study
7. Uncorrected congenital heart disease
8. Cardiac surgery within 6 months prior to screening or any planned surgery during the study
9. Implantation of a cardiac resynchronization therapy device in the prior 90 days, or planned during the study, or planned device optimization 30 days prior to randomization or during the study
10. Current chronic lung disease requiring long-term oxygen therapy

Note: Other protocol-defined inclusion/ exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A1 High Dose; Single ascending dose cohort	Drug: REGN5381; Single dose intravenous (IV) infusion
Experimental: Part A1 Low Dose; Single ascending dose cohort	Drug: REGN5381; Single dose intravenous (IV) infusion
Experimental: Part A1 Optional; Single ascending dose cohort	Drug: REGN5381; Single dose intravenous (IV) infusion
Experimental: Part B High Dose	Drug: REGN5381; Single dose intravenous (IV) infusion
Experimental: Part B Low Dose	Drug: REGN5381; Single dose intravenous (IV) infusion
Experimental: Part A2 High Dose, sacubitril-valsartan group; Single ascending dose cohort	Drug: REGN5381; Single dose intravenous (IV) infusion
Experimental: Part A2 Low Dose, sacubitril-valsartan group; Single ascending dose cohort	Drug: REGN5381; Single dose intravenous (IV) infusion
Placebo Comparator: Placebo for Part A2, sacubitril-valsartan group	Drug: Placebo; Single dose IV infusion
Placebo Comparator: Part A1 and Part B Placebo Only	Drug: Placebo; Single dose IV infusion
Experimental: Part A2 High Dose, Low estimated glomerular filtration rate (eGFR) group; Single ascending dose cohort. Note: This group has been closed	Drug: REGN5381; Single dose intravenous (IV) infusion
Experimental: Part A2 Low Dose, Low eGFR group; Single ascending dose cohort. Note: This group has been closed	Drug: REGN5381; Single dose intravenous (IV) infusion
Placebo Comparator: Placebo for Part A2, Low eGFR group; Note: This group has been closed	Drug: Placebo; Single dose IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in circulating N-Terminal pro-Brain Natriuretic Peptide (NTproBNP)	Day 8

Secondary Outcome Measures

Outcome Measure	Time Frame
Severity of TEAEs	Through week 16
Change from baseline in circulating NT-proBNP	Week 2
Change from baseline in circulating NT-proBNP	Week 3
Change from baseline in circulating NT-proBNP	Week 4
Change from baseline in circulating NT-proBNP	Up to week 16
Concentrations of REGN5381 in serum	Through week 16
Occurrence of Treatment Emergent Adverse Events (TEAEs)	Through week 16
Change from baseline in Systolic Blood Pressure (SBP)	Each visit through week 16
Change from baseline in Diastolic Blood Pressure (DBP)	Each visit through week 16
Change from baseline in Mean Arterial Pressure (MAP)	Each visit through week 16
Change from baseline in Heart Rate (HR)	Each visit through week 16
Incidence of Anti-Drug Antibodies (ADAs) to REGN5381	Through week 16
Magnitude of ADAs to REGN5381	Through week 16

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trials Administrator, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2024
• Primary Completion (Actual): September 17, 2025
• Study Completion (Actual): December 29, 2025

Study Registration Dates

• First Submitted: January 23, 2024
• First Submitted That Met QC Criteria: January 23, 2024
• First Posted (Actual): February 1, 2024

Study Record Updates

• Last Update Posted (Estimated): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Heart failure with reduced ejection fraction (HFrEF); Reduced ejection fraction; N-terminal pro-brain natriuretic peptide (NT-proBNP) hormone
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: R5381-HF-22118; 2023-508568-31-00 (Ctis: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing

IPD Sharing Time Frame

When Regeneron has:

• received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication or has globally discontinued development of the product for all indications on or after April 2020 and has no plans for future development
• made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry)
• the legal authority to share the data, and
• ensured the ability to protect participant privacy

• IPD Sharing Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes