Sponsor decision

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)

Enrollment for the Part A2 low eGFR cohort has been closed

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

All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing

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

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