Mineralys Therapeutics, Inc. announced that full results from the Target-HTN Phase 2 trial of lorundrostat, a highly selective aldosterone synthase inhibitor, in individuals with uncontrolled hypertension and treatment-resistant hypertension (rHTN) were published in the Journal of the American Medical Association. In the Target-HTN Phase 2 trial, lorundrostat demonstrated a significant, double-digit reduction in SBP with a well-tolerated profile in the intent-to-treat population of uHTN and rHTN. Subjects with an elevated BMI, and participants taking a thiazide-type diuretic, demonstrated an enhanced reduction in SBP.

The publication notes that blood pressure guidelines recommend similar medication combinations for most patients, regardless of underlying comorbidities or the dominant underlying contributor to hypertension, and that new treatments are needed as management of blood pressure in the U.S. is relatively poor, and hypertension remains a major cause of excess morbidity and mortality. The trial results support further study of lorundrostat as a treatment for uHTN, including the Company?s ongoing pivotal development program for lorundrostat to treat uHTN and rHTN. Under this program, the Company is currently enrolling subjects in the pivotal Advance-HTN trial and expects to initiate the pivotal Launch-HTN trial in the second half of the year, with topline data expected in the first half of 2024 and mid-2025, respectively.

The Target-HTN (NCT05001945) Phase 2 proof-of-concept trial was a randomized, double-blind, placebo-controlled, dose-ranging, multicenter trial conducted in the U.S. The trial was designed to evaluate the safety, efficacy, tolerability and dose response of orally administered lorundrostat for the treatment of uHTN and rHTN when used as add-on therapy to stable background treatment of two or more antihypertensive agents in 200 male and female subjects 18 years of age or older. Five active doses of lorundrostat (12.5mg once daily QD, 50mg QD, 100mg QD, 12.5mg twice daily, and 25mg BID) were compared to placebo in hypertensive subjects. Pharmacokinetic, pharmacodynamic and response data established that a once-daily dosing regimen was optimal.

Adverse events observed were a modest increase in serum potassium, decrease in estimated glomerular filtration rate, urinary tract infection and hypertension with one serious adverse event possibly related to study drug being hyponatremia. Having sustained, elevated blood pressure (or hypertension) increases the risk of heart disease, heart attack and stroke, which are leading causes of death in the U.S. In 2020, more than 670,000 deaths in the U.S. included hypertension as a primary or contributing cause. Hypertension and related health issues resulted in an average annual economic burden of about $130 billion each year in the U.S., averaged over 12 years from 2003 to 2014.

Less than 50% of hypertension patients achieve their blood pressure goal with currently available medications. Abnormally elevated aldosterone levels are a key factor in driving hypertension in up to 25% of all hypertensive patients. Lorundrostat is a proprietary, orally administered, highly selective aldosterone synthase inhibitor being developed for the treatment of uncontrolled hypertension and chronic kidney disease.

Lorundrostat was designed to reduce aldosterone levels by inhibiting CYP11B2, the enzyme responsible for its production. Lorundrostat has 374-fold selectivity for aldosterone-synthase inhibition versus cortisol-synthase inhibition in vitro, an observed half-life of 10-12 hours and demonstrated approximately a 70% reduction in plasma aldosterone concentration in hypertensive subjects.