RTN-001 for Uncontrolled Hypertension

Inclusion Criteria: 1. Provision of written informed consent before any study-specific procedure. 2. Male or female patients age 18 to 70 years, inclusive, at the Screening Visit. 3. Uncontrolled HTN despite being on a stable regimen of ≥ 2 antihypertensive medications in the following drug classes: ACE-inhibitors, ARBs, beta blockers, calcium channel blockers, mineralocorticoid receptor antagonists, or diuretics. A stable regimen is defined as being on the same medications and the same dose for at least 30 days before screening. A combination pill containing 2 separate classes of antihypertensive drugs is considered 2 antihypertensive medications. 4. Mean BP of ≥ 130/80 mm Hga. 5. Men and nonpregnant, nonlactating women. Women must be either: * Naturally postmenopausal defined as ≥ 1 year without menses and follicle-stimulating hormone ≥ 40.0 IU/L, or * Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal ligation, or Women of childbearing potential must be willing to use 2 acceptable methods of birth control (unless they have agreed to follow the definition of true abstinence). The minimal requirement for adequate contraception should be started the day of Visit T1 (Day 1), continuing during the Treatment Period and for at least 30 days after the last dose of study drug. Acceptable methods of birth control include: * Oral, implantable, injectable, or topical birth control medications. Note: Oral birth control medication must be started ≥ 30 days before the first dose of treatment in the Placebo Run-in. * Placement of an intrauterine device with or without hormones. * Barrier methods including condom or occlusive cap with spermicidal foam or spermicidal jelly. * Vasectomized male partner who is the sole partner for this patient. * True abstinence when this is the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception. 6. Body mass index of 18 to 35 kg/m2. 7. Negative prestudy urine drugs of abuse screen (with the exception of tetrahydrocannabinol \[THC\]). 8. If taking a PDE5 inhibitor for erectile dysfunction, must be willing to pause use during the study period. Only patients with uncontrolled HTN on ≥ 2 accepted classes of antihypertensive drugs who continue to satisfy the inclusion criteria above, are \> 80% compliant during the Placebo Run-in dosing of 3 tablets QD of single-blind placebo and have successfully completed the baseline 24 hour ABPM will be randomly assigned to treatment with RTN-001 or matching placebo. aThe initial BP inclusion criterion will be ≥ 130/80 mm Hg. After approximately 25% of patients (80 patients) have been randomly assigned to study treatment, the actual baseline BP of randomized patients will be reviewed to ensure target distribution of BP at study entry. If the mean baseline SBP is not within the target range of approximately 145 mm Hg, the inclusion criterion may be modified to reflect a higher BP inclusion criterion. Exclusion Criteria: 1. Currently enrolled in a study with an investigational product or any other type of medical research within 30 days before randomization. 2. Mean seated SBP \> 170 mm Hg and/or DBP \> 110 mm Hg. 3. Current or planned use of nitrates and/or alpha-blockers or other drugs known to affect BP during the study period (except for those allowed in the protocol; Section 5.9.2) including SGLT2 inhibitors and GLP-1 agonists. 4. Regular user of PDE5 inhibitors or cannot/is unwilling to refrain from use of PDE5 inhibitors for 7 days before and during their participation in the study. 5. History of hypotension, fainting spells, or blackouts, including orthostatic hypotension. 6. Malignant HTN, primary aldosteronism, or secondary HTN. 7. Active pancreatitis. 8. A history of drug abuse. 9. Abuses alcohol defined as average weekly intake greater than 21 units for males or 14 units for females. One unit is equivalent to a 12 oz beer, 1 measure of spirits, or 1 glass of wine. 10. History or presence of gastrointestinal, hepatic, or renal disease or other conditions that would be known to interfere with the absorption, distribution, metabolism, or excretion of drugs. 11. Recent (within 3 months before the Screening Visit \[Visit S1\]) myocardial infarction; unstable angina leading to hospitalization; uncontrolled, symptomatic cardiac arrhythmia (or medication for an arrhythmia that was started or dose changed within 3 months of screening); coronary artery bypass graft; percutaneous coronary intervention; carotid surgery or stenting; cerebrovascular accident; transient ischemic attack; endovascular procedure or surgical intervention for peripheral vascular disease; or plans to undergo a major surgical or interventional procedure (eg, percutaneous coronary intervention, coronary artery bypass graft, carotid or peripheral revascularization). Patients with implantable pacemakers or automatic implantable cardioverter defibrillators may be considered if deemed by the Investigator to be stable for the previous 3 months. 12. Uncontrolled hypothyroidism, including thyroid-stimulating hormone \> 1.5 × the upper limit of normal (ULN) at the Screening Visit (Visit S1); patients stabilized on thyroid replacement therapy for at least 6 weeks before randomization are allowed. 13. Liver disease or dysfunction, including: 1. Positive serology for hepatitis B surface antigen and/or hepatitis C antibodies at the Screening Visit (Visit S1), or 2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥ 2 × ULN, and/or total bilirubin (TB) ≥ 2 × ULN at the Screening Visit (Visit S1). If TB ≥ 1.2 × ULN, a reflex indirect (unconjugated) bilirubin will be obtained, and if consistent with Gilbert's syndrome or if the patient has a history of Gilbert's syndrome, the patient may be enrolled in the study. Note: At the discretion of the Investigator, a repeat of ALT and/or AST may be completed before randomization. For those patients who have a repeat ALT and/or AST, the repeat value will be used to determine eligibility. Also, if the patient tests positive for the hepatitis C antibody, but the optional reflexive test for hepatitis C RNA is negative, the patient can be enrolled. 14. Renal dysfunction or glomerulonephritis, including estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula \< 45 mL/min/1.73 m2 at the Screening Visit (Visit S1). Note: a single repeat qualifying eGFR, performed at the discretion of the Investigator, is acceptable. 15. Gastrointestinal conditions or procedures (including weight loss surgery \[eg, Lap-Band or gastric bypass\] that may affect drug absorption. 16. Hematologic or coagulation disorders or a hemoglobin level \< 10.0 g/dL at the Screening Visit (Visit S1). 17. Active malignancy, including a malignancy requiring surgery, chemotherapy, and/or radiation in the 5 years before Screening. Nonmetastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ are allowed. 18. Unexplained creatine kinase (CK) \> 3 × ULN at any time before randomization, which is not associated with recent trauma or physically strenuous activity. Patients with an explained CK elevation must have a single repeat CK ≤ 3 × ULN before randomization. 19. Blood donation, participation in multiple blood draws, clinical study, major trauma, blood transfusion, or surgery with or without blood loss within 30 days before randomization. 20. Use of any experimental or investigational drug(s) within 30 days before Screening. 21. An employee or contractor of the facility conducting the study, or a family member of the principal investigator, co-investigator, or any Sponsor personnel 22. Is considered to be unsuitable for any other reason that may either place the patient at increased risk during participation or interfere with the interpretation of study outcomes by the Investigator, after reviewing the medical and psychiatric history, physical examination, and laboratory evaluation.