Table 2.

Emerging agents for the pharmacological management of hypertension

Agent and developer	Mechanism of action	Trial details	Comments
Esaxerenone (CS-3150) Daiichi Sankyo Co.	Non-steroidal inhibitor of the mineralocorticoid receptor [63]  Inhibits aldosterone-dependent sodium retention, causing decreased fluid reabsorption  Reduces proteinuria in CKD patients	Phase III [98]  368 patients with essential hypertension administered either esaxerenone 2.5 or 5 mg for 52 weeks  Completed but findings not yet reported Phase III [99]  1001 patients with essential hypertension received either esaxerenone 2.5 or 5 mg or eplerenone 50 mg for 12 weeks  Esaxerenone 5 mg reduced SBP by 4.8 mmHg, compared with 2.3 mmHg in the eplerenone group, with significant decrease in 24-h BP	Esaxerenone has a longer (18.6 h) half-life than eplerenone (5 h), and thus causes less fluctuations in 24 h BP reduction. It also does not have the unwanted effect of hyperkalemia seen with eplerenone No difference in the incidences of adverse effects in any groups Also shown to be well tolerated and effective in lowering SBP in patients with primary aldosteronism [100] Currently approved in Japan for the treatment of hypertension
Firibastat (RB 150) [68] Quantum Genomics SA	Inhibits aminopeptidase A, which converts angiotensin II into brain angiotensin III [67]  Decreased vasopressin release, increasing diuresis  Reduction in sympathetic tone and hence vascular resistance  Inhibition of the baroreflex response	Phase IIb [101]  256 overweight or obese hypertensive patients (54% Black or Hispanic) received firibastat 250 mg bid for 8 weeks. No placebo arm  Significant reduction in SBP by 10.5 mmHg in Black patients and 8.9 mmHg in non-Black patients Phase III [102]—expected completion December 2021  502 patients will receive firibastat 250 mg bid for 12 weeks or placebo in addition to current antihypertensives	Adverse effects were headache (4%) and skin reactions (3%). 7.5% recipients stopped the drug due to adverse effects (one serious) Potential alternative therapy for Black populations, with an 18% greater SBP decrease compared with non-African Americans
Bexagliflozin (EGT0001442) Theracos [103]	Inhibits sodium-glucose co-transporter-2. Several hypothesized mechanisms [79, 81]  Glycosuria-accompanied osmotic diuresis  Inhibits sodium reuptake in the proximal tubule  Upregulation of angiotensin 1–7 Reduction of serum uric acid	Phase III [104]  1700 patients with T2DM across 10 countries received either bexagliflozin 20 mg or placebo over 30 months  Modest reduction in SBP by 9.8 mmHg in the treatment arm, compared with 6.9 mmHg in the placebo arm Phase III [105]  680 hypertensive patients received either bexagliflozin 20 mg or placebo over 24 weeks	Incidence of adverse effects in the treatment group (36.7%) were similar to placebo (33%) The BEST trial was not specifically powered or designed to evaluate BP effects and the results of trials evaluating this are pending
Nesiritide Oslo University Hospital	Recombinant B-type natriuretic peptide [74]  Leads to vasodilation, natriuretic and diuretic effects	Phase I and II (TENSE1) [106]  15 patients will receive gradually increasing doses of either nesiritide or placebo bid Estimated completion in 2030	Degraded quickly by tissue proteases and therefore needs to be administered by continuous IV infusion
Vitamin D3 and Omega-3 fatty acids (antioxidants) Brigham and Women's Hospital	Vitamin D [107]  Negative regulator of the RAS by suppressing renin gene expression  Regulates vascular smooth muscle intracellular calcium concentrations Omega-3 fatty acids [108]  Vasorelaxant effects on vascular endothelial and smooth muscle cells through nitrous oxide  Inhibit inflammatory processes in arteries	Phase NA [109]  25,875 men and women with no prior history of hypertension will receive vitamin D3 2000 IU or omega-3 fatty acid 1 g	Ongoing trial investigating whether supplementation prevents the development of hypertension in people with normal BP
RLD2001-1 and HCP1904-1 Hanmi Pharma	NA	Phase III [110]  116 participants with hypertension will take either HCP1904-1 or RLD2001-1 once daily for 8 weeks	Estimated completion September 2021
Amlodipine/candesartan cilexetil (CKD-330) and D086 Chong Kun Dang Pharmaceutical	NA	Phase III [111]  154 patients with hypertension will either receive amlodipine/candesartan cilexetil and D086 combination therapy or placebo	Completed, no results posted. Also targeting dyslipidemias and T2DM

bid twice daily, BP blood pressure, CKD chronic kidney disease, IU international units, IV intravenous, NA not available, RAS renin-angiotensin system, SBP systolic blood pressure, T2DM type 2 diabetes mellitus