This is a Phase 2 dose-titration study designed to evaluate the safety and efficacy of MANP subcutaneous injection compared to placebo in reducing baseline daytime systolic blood pressure (SBP), derived from 24-hour ambulatory blood pressure monitoring (ABPM), in subjects with hypertension who are taking 3 or more antihypertensive medications with different mechanisms of action.

Inclusion Criteria:

Subjects will be eligible for enrollment in the study only if they meet ALL the following criteria at time of Screening:

• Male or female subjects aged 18 - 80 years, inclusive, at the screening visit.
• Female subjects must not be of childbearing potential
• Subjects must be taking appropriate doses of 3 or more antihypertensive drugs with different mechanisms of action. One of which must be a diuretic and the other must be an ACEi or ARB at atleast 50% of the maximum recommended dose for hypertension.
• Subjects must have a seated (5 minutes) systolic blood pressure ≥ 140 mmHg and SBP ≥135 mmHg by ABPM prior to randomization (T1).
• Subjects must have a CKD-EPI eGFR ≥ 30 mL/min/1.73m2
• A subset of the subjects with an eGFR between 20-30 ml/min/1.73m2 will be included, not to exceed 10% of the total study subjects.
• Subjects must have a BMI between 18 - 40 kg/m2.
• Subjects who engage in sexual intercourse in which their partner could become pregnant must agree to use a barrier method of birth control (i.e., vaginal/penile condom) with spermicide for the duration of the study and for 90 days after the last dose of study drug or be at least 6 weeks post-vasectomy with confirmation by post-vasectomy semen analysis. In addition, subjects may not donate sperm for the duration of the study and for 90 days after the last dose of study drug.

Exclusion Criteria:

Subjects meeting ANY of the following criteria at time of Screening will be excluded from enrollment:

• Subjects with an average sitting systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥ 110 mmHg at Screening (SV), or prior to randomization at T1.
• Subjects with a history of secondary hypertension, including but not limited to coarctation of the aorta, primary hyperaldosteronism, renal artery stenosis, Cushing's disease, pheochromocytoma, and polycystic kidney disease. If the subject has not previously been evaluated for secondary hypertension, investigators are responsible for evaluating all potential secondary causes of hypertension in accordance with current practices and clinical guidelines before entering the patient into the study.
• Subjects with an HbA1c ≥ 8% at screening (SV)
• Subjects who have experienced myocardial infarction, unstable angina, or a cerebrovascular accident (CVA) within 6 months of the Screening Visit; or sick sinus syndrome or second- or third-degree atrioventricular block, or recurrent atrial tachyarrhythmia, recurrent ventricular tachycardia, or symptomatic bradycardia.
• Subjects who have an implanted cardioverter defibrillator (ICD) that has been fired for any arrhythmia within 3 months of Screening (SV) or implanted pacemakers.
• Subjects with congestive heart failure (New York Heart Association [NYHA] class II-IV)
• Subjects with hemodynamically significant valvular heart disease
• Subjects undergoing hemodialysis or peritoneal dialysis, or history of renal transplant.
• Subjects who have diagnosis or recurrence of malignancy within the past 3 years
• Subjects with a documented history of sleep apnea, with a prescription for CPAP therapy.
• Women of childbearing potential
• Subjects who are pregnant or breastfeeding

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