Ps-c37-5: new therapeutic perspectives for blood pressure control: dexfadrostat phosphate, a novel aldosterone synthase inhibitor, in patients with primary aldosteronism

Objective: Aldosterone, the primary mineralocorticoid produced by the adrenal gland, regulates fluid homeostasis by stimulating sodium reabsorption in exchange for potassium in the distal tubules and collecting duct of the kidney. Aldosterone synthase (CYP11B2) is the rate-limiting enzyme for aldosterone biosynthesis. Patients with primary aldosteronism (PA) are characterized by an uncontrolled, excess production of aldosterone and are at higher risk of stroke, atrial fibrillation, and heart failure compared to patients with essential hypertension. Furthermore, PA increases the risk of death even after initiation of medical treatment to control blood pressure. Therefore, PA is the compelling indication to demonstrate the value for an aldosterone synthase inhibitor (ASI) as targeted treatment. Previous attempts to eliminate the excessive spontaneous aldosterone synthesis defining PA have been unsuccessful, particularly due to the unintended inhibition of other steroid hormones. Dexfadrostat phosphate is a novel ASI that acts directly on CYP11B2, targeting the root cause of primary aldosteronism. Design and method: Dexfadrostat phosphate was first investigated in patients with PA diagnosed within 1 year of study entry according to medical guidelines including a suppression test to demonstrate autonomous aldosterone production. Eligibility was verified and approved by a Central Review panel. Following a 2-week placebo-controlled run-in period, enrolled patients were randomized to one of three doses of dexfadrostat taken orally, once daily. After 8 weeks of treatment, patients were switched to placebo and followed for an additional 2 weeks. Blood samples were taken at 2-week intervals and evaluated in a central laboratory for steroid and peptide hormone as well as electrolyte levels. Blood pressure was measured in the office during each clinic visit. Ambulatory systolic blood pressure (aSBP) was monitored over 24-hours at baseline and after 8 weeks of dexfadrostat treatment. Results: All endpoints of the study were met with high significance. Dexfadrostat phosphate treatment was safe and well tolerated. We present the effects on the aldosterone-to-renin ratio (ARR) and subsequent blood pressure reduction, the correction of hypokalemia, and the persistence and reversal of therapeutic effects upon drug withdrawal. Conclusions: The phase 2 study in patients evaluated the ability of dexfadrostat phosphate to deliver both biochemical (ARR, potassium) and subsequent clinical (aSBP) correction of the consequences of uncontrolled aldosterone production. By demonstrating its clinical utility in a rarely diagnosed indication of extreme aldosterone dysregulation, the potential of dexfadrostat phosphate may well expand to address essential hypertension, chronic kidney disease, hypokalemia, volume expansion and organ remodeling.