A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled
Study to Evaluate the Efficacy and Safety of JTT-251 Administered for 24
Weeks to Participants with Heart Failure with Reduced Ejection Fraction

1. Male or female, age 18 to 85 years (inclusive), at the Screening Visit;
2. Participants with a clinical diagnosis of symptomatic HF >=3 months prior to the Screening Visit;
3. Participants with NYHA functional class II or III at the Screening Visit;
4. Participants must be on stable, guideline-directed medical therapy for HF, consistent with AHA, ACC, HFSA or ESC guidelines for at least 30 days prior to the Screening Visit. These therapies include an ACEI or ARB with/without a neprilysin inhibitor, in combination with an evidence-based β-blocker and a MRA, in appropriate participants, or documentation justifying why optimal therapy is not being used (e.g., intolerance, contraindication, participant preference or physician*s judgement);
5. Participants must have a documented history of LVEF <=35% within 6 months prior to the Screening Visit using any of the following modalities: echocardiography, single-photon emission computed tomography (SPECT), multigated acquisition (MUGA), computed tomography (CT) scanning, magnetic resonance imaging (MRI) or ventricular angiography; if more than one measurement was performed, then the most recent one should be used for eligibility;
Note: If LVEF measurement was obtained >6 months prior to the Screening Visit, a local echocardiography measurement and interpretation will be used to determine eligibility (i.e., LVEF <=35%).
6. Participants with a plasma NT-pro-BNP level >=900 pg/mL at the Screening Visit;
7. Females may participate if they meet one of the following criteria:
• surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or
• post-menopausal, as defined by: 1) Permanent cessation of menstruation for >=12 months without an alternative medical cause [regardless of follicle-stimulating hormone (FSH) value] at the Screening Visit, or 2) Cessation of menstruation for <12 months and FSH >40 mIU/mL at the Screening Visit.
All other females will be considered of childbearing potential and must either:
a. practice abstinence, or
b. have same-sex partner, or
c. use one highly effective contraceptive method of birth control, which includes intrauterine devices, male partner sterilization (at least six months prior to screening with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate, and the vasectomized male partner should be the sole partner for that participant), tubal ligation, bilateral tubal occlusion, intrauterine hormone-releasing systems, or
d. use a double-barrier method of birth control, which includes a combination of male condom with either diaphragm, cervical cap or vaginal sponge, all with spermicide.
Note: Concomitant use of a female condom and a male condom is not considered an acceptable double barrier method of contraception for the study.
The above-described contraception methods must be maintained during treatment and until 30 days after the last dose of study drug.
8. Males must either practice abstinence, have same-sex partner, use a barrier contraceptive method with spermicide (for the duration of the treatment period and until 30 days after the last dose of study drug), or be sterilized at least six months prior to screening (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
Notes: Males with sterile or post-menopausal female partners are not
required to use contraception if said female partner is the sole partner
for that participant. Males must not donate sperm for the duration of the
study and for 30 days after the last dose of study drug.
9. Able and willing to give written informed consent.

1. Participants with confirmed acute MI (i.e., Type 1) within 30 days prior to the Screening Visit or unstable angina, a history of coronary revascularization (percutaneous coronary intervention and/or coronary artery bypass grafting) or other cardiovascular surgery within 90 days prior to the Screening Visit;
2. Participants whose HF is due to congenital heart disease, active myocarditis or constrictive pericarditis;
3. Participants who have received a heart transplant or are on a transplant list or who have a history of LV assist device implantation;
4. Participants with severe stenotic valvular disease or severe outflow tract obstruction;
5. Participants with a history of stroke or cerebral transient ischemic attack within 30 days prior to the Screening Visit;
6. Participants who started cardiac resynchronization therapy within 90 days prior to the Screening Visit;
Note: Implantable cardioverter defibrillator (ICD) placement alone or generator change is acceptable.
7. Participants with planned cardiovascular surgery and/or cardiac resynchronization therapy during the double-blind treatment period;
8. Participants who were admitted to hospital for HF within 30 days prior to Visit 2;
9. Participants with known active liver disease or with aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) >3.0x upper limit of normal (ULN) or total bilirubin >1.5x ULN at the time of screening;
Note: Participants with documented benign liver condition that can result in elevated bilirubin levels (e.g., Gilbert*s Syndrome) are eligible to participate in the study.
10. Participants unable to perform a six minute walk distance (6MWD) test at Visit 2;
11. Participants with resting symptomatic hypotension or uncontrolled hypertension (i.e., systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg) at the Screening Visit;
12. Participants with clinically significant chronic renal insufficiency (i.e., estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 using the 4-variable Modification of Diet in Renal Disease [MDRD] formula) or who are on or indicated to start renal dialysis within the next 90 days;
eGFR (in mL/min/1.73 m2) = 175 × Serum Creatinine -1.154 × age -0.203 × 1.212 (for black participant) × 0.742 (for female participant)
13. Diabetic participants with hemoglobin A1c (HbA1c) >10% measured at the Screening Visit;
14. Participants with hemoglobin <8 g/dL at the Screening Visit;
15. Participants currently receiving or have received an investigational product (including an investigational drug or other investigational therapeutic intervention) within 28 days, five half-lives or twice the duration of the biological effect of the investigational product, if known (whichever is longer) prior to the Screening Visit;
16. Participants with a history of recreational drug abuse within six months of the Screening Visit;
Note: Medical marijuana prescribed by a physician is acceptable.
17. Participants with a history of alcohol abuse within six months of the Screening Visit;
18. Participants with an ANC <1200/µL at the Screening Visit;
19. Participants with systemic effects of untreated active infection(s) (e.g., fever >=100.4°F [38.0°C]) at Visit 2;
Note: Participants with successfully treated infections or infections that required antibiotics will be permitted if resolved >7 days prior to Visit 2.
20. Participants who test positive for human immunodeficiency virus (HIV) antibodies at the Screening Visit;
21. Participants with current malignancies or who are receiving or require active cancer treatment (exceptions include adequately treated or excised non-metastatic basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ);
22. Participants who have unstable physical or major psychiatric conditions (e.g., schizophrenia, clinically unstable major psychiatric disorder) that would put the participant at risk, or would interfere with study procedures according to the Investigator*s clinical judgement;
23. Females who are pregnant as determined by a positive serum human chorionic gonadotropin (hCG) test result at the Screening Visit or urine hCG at Visit 2;
Note: Any positive urine pregnancy test result at Visit 2 must be verified with a serum pregnancy test prior to randomization.
24. Females who are lactating at the Screening Visit or at Visit 2;
25. Participants who are unwilling or unable to comply with the requirements of the study.