What is a potential new drug target for treating hypertension?

Novel Drug Targets for Hypertension

Aldosterone synthase inhibitors (baxdrostat and lorundrostat) represent the most promising new drug target for hypertension, having demonstrated significant blood pressure reduction in phase 2 trials of patients with uncontrolled hypertension. 1

Emerging Therapeutic Targets for Hypertension

Several novel drug targets show promise for hypertension management, particularly for patients with resistant hypertension:

Most Promising New Targets

• Aldosterone synthase inhibitors (baxdrostat and lorundrostat) have significantly lowered blood pressure in patients with uncontrolled hypertension in phase 2 trials 1
• Dual endothelin-A and -B receptor antagonists (aprocitentan) reduced both office and 24-hour blood pressure compared to placebo in patients with resistant hypertension in a phase 3 trial 1, 2
• RNA interference agents (zilebesiran) administered subcutaneously inhibit hepatic angiotensinogen synthesis and have shown sustained blood pressure reduction over approximately 6 months with a single dose 1

Additional Promising Targets

• Angiotensin receptor-neprilysin inhibitors (ARNi) like sacubitril/valsartan have demonstrated BP-lowering properties and have been used at higher doses (200-400mg daily) for treating hypertension in research studies 1
• SGLT2 inhibitors have shown favorable effects on cardiovascular events and renal hemodynamics, with modest blood pressure lowering confirmed in small trials among adults with hypertension 1
• GLP-1 agonists have preliminary data supporting their role in hypertension management 1
• Non-steroidal mineralocorticoid receptor antagonists (finerenone) show potential for managing hypertension 1

Clinical Evidence for Endothelin Receptor Antagonists

Endothelin receptor antagonists represent a particularly promising class:

• Aprocitentan, a dual endothelin-A and -B receptor antagonist, was recently approved in early 2024 specifically for treatment of resistant hypertension 2
• In a phase 3 multicenter study of 730 adults with systolic blood pressure ≥140 mm Hg on standard background therapy, aprocitentan (12.5mg, 25mg) demonstrated superiority to placebo in reducing sitting systolic blood pressure at week 4 2
• The blood pressure-lowering effect persisted through week 40, demonstrating long-term efficacy 2
• Endothelin-1 (ET-1) is the most potent vasoconstrictor in the cardiovascular system and regulates basal vascular tone and glomerular hemodynamics 3
• ET receptor antagonists have shown particular efficacy in low-renin models and salt-sensitive models of hypertension, which are consistent with resistant hypertension 4, 2

Advantages of Novel Targets Over Conventional Therapy

• Current first-line therapies (thiazide diuretics, ACE inhibitors, ARBs, calcium channel blockers) fail to control blood pressure in many patients, with only 44% of US adults with hypertension achieving control to <140/90 mm Hg 5
• Novel targets like endothelin receptor antagonists may provide benefits beyond blood pressure reduction by improving end-organ function in a pressure-independent manner 6
• These new agents target different pathophysiological pathways than conventional therapies, offering potential for synergistic effects when used in combination 1
• Targeting multiple pathways simultaneously addresses the multifactorial nature of hypertension, particularly in resistant cases 1

Considerations for Implementation

• While these novel targets show promise, most still require supportive evidence from cardiovascular outcomes trials prior to guideline endorsement and routine use in hypertension 1
• The 2024 ESC guidelines acknowledge these emerging therapies but emphasize the need for more definitive outcome data 1
• When considering new drug targets, priority should be given to those that demonstrate not only blood pressure reduction but also improvements in cardiovascular and renal outcomes 1, 3

Conclusion

Aldosterone synthase inhibitors, dual endothelin receptor antagonists, and RNA interference agents targeting hepatic angiotensinogen represent the most promising new drug targets for hypertension, particularly for patients with resistant hypertension. Among these, aprocitentan has already received regulatory approval and demonstrated significant efficacy in clinical trials, making endothelin receptor antagonism a particularly compelling new target for hypertension management.