Mineralys Therapeutics Presents Target-HTN Phase 2 Trial Results at 2023 AHA Hypertension Scientific Sessions

September 12, 2023 — Mineralys Therapeutics, Inc. has presented final results from the Target-HTN Phase 2 trial of lorundrostat, a highly selective aldosterone synthase inhibitor, in individuals with uncontrolled hypertension (uHTN) and resistant hypertension (rHTN).

The clinical-stage biopharmaceutical company, focused on developing medicines to target hypertension, chronic kidney disease and other diseases driven by abnormally elevated aldosterone, issued a detailed statement on the data, which was presented during a late-breaking science session at the 2023 American Heart Association (AHA) Hypertension Scientific Sessions, held in Boston from September 7–10. "Aldosterone Synthase Inhibition with Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial," was simultaneously published in the Journal of the American Medical Association (JAMA).

The company reported, in a September 10 statement, that Target-HTN trial results demonstrate treatment with lorundrostat at doses of 50mg and 100mg once daily (QD) led to a statistically and clinically significant reduction of systolic blood pressure (BP) in inadequately controlled hypertensive individuals on at least two background antihypertensive medications. The reduction in BP was particularly evident among participants with hypertension and concomitant obesity.

“The final results from our Target-HTN trial demonstrate lorundrostat had a robust, double-digit reduction in systolic blood pressure with a well-tolerated profile in the intention-to-treat population of individuals with uncontrolled hypertension and resistant hypertension,” said Jon Congleton, Chief Executive Officer of Mineralys Therapeutics. “In support of our targeted development strategy for lorundrostat, a pre-specified sub-analysis of subjects with elevated BMI demonstrated enhanced reduction in systolic blood pressure that is likely due, in part, to visceral fat driving abnormal aldosterone levels,” he further stated, adding, “Results from the Target-HTN trial were instrumental in our decision to advance the ongoing pivotal program and we look forward to announcing the results from our initial pivotal study expected in the first half of 2024.”

“Despite the multitude of currently available treatments, half of all patients treated for hypertension are not able to reach their blood pressure goal. Up to 25 percent of all people with hypertension exhibit abnormal aldosterone levels,” said Luke Laffin, M.D., lead investigator and co-director of the Center for Blood Pressure Disorders in the Heart, Vascular & Thoracic Institute at Cleveland Clinic. “Importantly, the Target-HTN study of lorundrostat demonstrated data compelling enough to warrant its advancement into late-stage clinical trials, representing a first-in-class milestone that will further the goal of understanding a new way of treating uncontrolled and treatment-resistant hypertension that takes the underlying causes into account.”

Key clinical data from Target-HTN suggest robust BP reductions in the treatment of patients with uHTN and rHTN, according to the company, which offered the following summary findings:

- Target-HTN successfully met its primary endpoint, demonstrating a statistically significant change from baseline in systolic automated office BP (AOBP) with lorundrostat 50mg (n=28) and 100mg (n=25) QD doses versus placebo (n=29):

-13.7 mmHg systolic AOBP change at 50mg QD, or -9.6 mmHg placebo-adjusted change (p=0.01)

-11.9 mmHg systolic AOBP change at 100mg QD, or -7.8 mmHg placebo-adjusted change (p=0.04)

Key secondary endpoint results demonstrated a change in diastolic AOBP of -7.1 mmHg with 50mg QD (or -5.5 mmHg placebo-adjusted change; p=0.02) and -5.8 mmHg with 100mg QD (or -4.1 mmHg placebo-adjusted change; p=0.09). Other secondary endpoints, including assessment of 24-hour average BP, supported the efficacy of the QD dosing regimen.

A pre-specified analysis examined the impact of body mass index (BMI) on the degree of BP lowering with lorundrostat, testing the hypothesis that aldosterone-dependent hypertension may be more significant in obese individuals. It noted: with 50mg QD, changes in systolic AOBP were 2.2 mmHg in subjects with a BMI 25-30 kg/m2, versus -16.7 in subjects with a BMI ≥30 kg/m2 (placebo-adjusted; p<0.01); With 100mg QD, changes in systolic AOBP were -4.5 mmHg in subjects with a BMI 25-30 kg/m2, versus -12.3 in subjects with a BMI ≥30 kg/m2 (placebo-adjusted; p=0.03). Key safety and tolerability findings from Target-HTN suggest lorundrostat was well‐tolerated with a favorable safety profile, particularly with 50mg lorundrostat QD: Lorundrostat was well tolerated at all dose levels.

There was a modest, dose-dependent increase in mean serum potassium (0.25-0.29 mmol/L) and low incidence of elevated serum potassium (3.6% subjects with serum potassium levels above 6.0 mmol/L). Researchers also noted that three serious adverse events occurred, only one (worsening of pre-existing hyponatremia with 100mg lorundrostat QD) was deemed treatment-related.

The company further reported the Target-HTN trial results support the transition to late-stage development of lorundrostat as a treatment for inadequately controlled hypertension. The Company’s ongoing pivotal development program for lorundrostat to treat uHTN and rHTN is currently enrolling subjects in the Advance-HTN trial, and the Phase 3 Launch-HTN trial is expected to be initiated 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 on BP for the treatment of uncontrolled and resistant hypertension 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 QD, 50mg QD, 100mg QD, 12.5mg twice daily [BID], and 25mg BID) were compared to placebo in hypertensive subjects.

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.

In its statement, the company, based in Radnor, PA, described Lorundrostat as being a proprietary, orally administered, highly selective aldosterone synthase inhibitor being developed for the treatment of uncontrolled hypertension and chronic kidney disease (CKD). 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 percent reduction in plasma aldosterone concentration in hypertensive subjects.

More information: www.mineralystx.com