• Percentage of subjects reporting one or more treatment emergent adverse events from Day 1 through end of the study. [ Time Frame: Week 56 ] [ Designated as safety issue: Yes ]
• Percentage of subjects reporting symptomatic hypotension from Day 1 through the end of the study. [ Time Frame: Week 56 ] [ Designated as safety issue: Yes ]
• Change from Baseline in Electrocardiograms. [ Time Frame: Week 56 ] [ Designated as safety issue: Yes ]
• Change from Baseline in Clinical Laboratory Chemistry results. [ Time Frame: Week 56 ] [ Designated as safety issue: Yes ]
• Change from Baseline in Clinical Laboratory Hematology results. [ Time Frame: Week 56 ] [ Designated as safety issue: Yes ]
• Change from Baseline in Clinical Laboratory Urinalysis results. [ Time Frame: Week 56 ] [ Designated as safety issue: Yes ]

• Change from baseline in diastolic blood pressure measurements. [ Time Frame: Weeks 4, 8, 12, 16, 26, 36, 46, 56 ] [ Designated as safety issue: No ]
• Change from baseline in systolic blood pressure measurements. [ Time Frame: Weeks 4, 8, 12, 16, 26, 36, 46, 56 ] [ Designated as safety issue: No ]

This purpose of this study is to evaluate the long-term safety and tolerability of TAK-491 in individuals with essential hypertension.

Hypertension affects approximately 50 million individuals in the United States. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. According to the World Health Organization, hypertension is the most common attributable cause of preventable death in developed nations, as uncontrolled hypertension greatly increases the risk of cardiovascular disease, cerebrovascular disease, and renal failure. Despite the availability of antihypertensive treatments, hypertension remains inadequately controlled; only about one-third of patients continue to maintain control successfully.

Takeda Global Research and Development is developing TAK-491 for the treatment of essential hypertension. This study is being conducted to demonstrate the long-term safety and tolerability of TAK-491 in individuals with essential hypertension.

Study participation is anticipated to be approximately 1 year and 1.5 months. and subjects will be required to return to the clinic for 10 study visits.

• Drug: Cohort 1
• Drug: Cohort 2

Inclusion Criteria

• Essential hypertension (diastolic blood pressure greater than or equal to 95 mm Hg and less than or equal to 119 mm Hg at Screening Day minus 7 and enrollment visit. For diabetic subjects and subjects with chronic kidney disease, diastolic blood pressure must be greater than or equal to 85 mm Hg and less than or equal to109 mm Hg).
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
• Clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory unless the results are deemed not clinically significant for inclusion into this study by the investigator.

Exclusion Criteria

• Systolic blood pressure greater than 185 mm Hg.
• Expected to take angiotensin II receptor blockers other than the study drug.
• Taking more than two (2) antihypertensive agents.
• Hypersensitive to angiotensin II receptor blockers, thiazide-type diuretics or sulfonamide-derived compounds.
• Recent history (within the last 6 months) of myocardial infarction, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, cerebrovascular accident, or transient ischemic attack.
• History of moderate to severe heart failure or hypertensive encephalopathy.
• Clinically significant cardiac conduction defects (eg, 3rd degree atrioventricular block, sick sinus syndrome).
• Secondary hypertension of any etiology.
• Known or suspected unilateral or bilateral renal artery stenosis.
• Severe renal dysfunction or disease (based on calculated creatinine clearance less than 30 mL/min/1.73 m2) at Screening.
• History of drug abuse or a history of alcohol abuse within the past 2 years.
• Previous history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. (This criterion does not include those subjects with basal cell or Stage 1 squamous cell carcinoma of the skin).
• Uncontrolled diabetes mellitis with poor glucose control at Screening based on glycosylated hemoglobin greater than 8.5%)
• Alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
• Serum potassium level of greater than the upper limit of normal, per the central laboratory reference ranges at Screening.
• Currently is participating in another investigational study or has participated in an investigational study within 30 days prior to enrollment.
• Any other serious disease or condition at Screening (or enrollment) that would compromise subject safety, might affect life expectancy, or make it difficult to successfully manage and follow the subject according to the protocol.
• Randomized in a previous TAK-491 study.