Lorundrostat Shows Promise in Treatment of Uncontrolled and Resistant Hypertension in trials

Lorundrostat demonstrated strong efficacy and safety in the pivotal Phase 3 Launch-HTN and Phase 2 Advance-HTN trials. These studies evaluated the oral aldosterone synthase inhibitor for treating uncontrolled hypertension (uHTN) and resistant hypertension (rHTN).

Both trials successfully achieved statistical significance and were clinically meaningful in their pre-specified primary efficacy endpoints and demonstrated a favorable safety and tolerability profile.

“The positive results and clinically meaningful reduction in blood pressure observed in the Launch-HTN and Advance-HTN trials show us that lorundrostat has the potential to be a transformative new therapy for the approximately 15 to 20 million patients with uncontrolled hypertension in the United States,” stated Jon Congleton, Chief Executive Officer of Mineralys Therapeutics. “We have now completed three successful clinical trials demonstrating the efficacy, safety and tolerability of lorundrostat and the importance of targeting dysregulated aldosterone. We believe the clinical profile observed for lorundrostat supports the potential regulatory approval of this novel agent and its significant commercial value. We appreciate the commitment and hard work of the clinical investigators, site staff, the Mineralys and Cleveland Clinic research teams, and especially the trial subjects who volunteered to participate in our program.”

Efficacy Results

The Launch-HTN trial was a global, randomized, double-blinded, placebo-controlled Phase 3 trial, which enrolled eligible adult participants who failed to achieve their blood pressure goal despite being on two to five antihypertensive medications. Launch-HTN reflects the real-world setting for clinicians by utilizing automated office blood pressure (AOBP) measurement and allowing participants to stay on their existing medications. The trial met its endpoints demonstrating clinically meaningful, statistically significant mean reduction from baseline in placebo-adjusted systolic blood pressure at week six and the benefit was sustained with potential further reduction through week 12.

• The change in blood pressure in response to lorundrostat in subjects using two background antihypertensives (uncontrolled) or three to five (resistant) were similar, and both were statistically significantly different from the response in those taking placebo.

The Advance-HTN trial was a randomized, double-blind, placebo-controlled Phase 2 pivotal trial that evaluated the efficacy and safety of lorundrostat for the treatment of confirmed uHTN or rHTN, when used as add-on therapy to an optimized background treatment of two or three antihypertensive medications in adult subjects. The trial met its primary endpoint, with placebo-adjusted reduction from baseline in systolic blood pressure assessed with 24-hour average blood pressure measurement at week 12 of -7.9 mmHg in subjects treated with 50 mg of lorundrostat. Other prespecified outcome measures, including measures of efficacy in the dose-escalation cohort, safety and tolerability, were consistent with those observed in the Launch-HTN trial.

Safety and Tolerability Results

We believe clinical safety findings, including hypotension, serum potassium, eGFR and serum cortisol, from both pivotal trials, support a favorable benefit-risk profile.

In the Launch-HTN trial there were 12 subjects (2.2%) and two subjects (0.7%) with treatment-emergent serious adverse events (SAEs) in the 50 mg and 50 mg with optional dose escalation to 100 mg arms, respectively, compared with eight subjects (3.0%) in the placebo arm. There was only one subject (0.1%) in the trial with treatment-related SAEs that occurred in the 50 mg arm.

The incidence of hyperkalemia (serum potassium above 6.0 mmol/L) in the 50 mg and 50mg to 100mg arms, respectively, was 1.1% and 1.5% in the Launch-HTN trial and 5.3% and 7.4% in the Advance-HTN trial.

“The Launch-HTN study evaluating novel drug lorundrostat is one of the largest blood pressure studies in recent times and demonstrates its benefit in lowering blood pressure and its safety in a diverse group of patients whose hypertension is not well controlled,” stated Manish Saxena MBBS, Hypertension Specialist from Barts Health NHS Trust. “Uncontrolled and resistant hypertension remains a global health concern as it continues to be the leading cause of cardiovascular deaths, heart attacks and strokes. Given today’s announcement, lorundrostat could be a good treatment option for millions of patients with high blood pressure."

Mineralys plans to provide additional data from these two pivotal trials at upcoming medical conferences and in peer-reviewed publications.

The ongoing Transform-HTN open-label extension trial allows subjects to continue to receive lorundrostat and generate additional safety and efficacy data.

About Lorundrostat

Lorundrostat is a proprietary, orally administered, highly selective aldosterone synthase inhibitor being developed for the treatment of uHTN and rHTN as well as CKD and OSA. 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.

In a Phase 2, proof-of-concept trial (Target-HTN) in uncontrolled or resistant hypertensive subjects, once-daily lorundrostat demonstrated statistically significant and clinically meaningful blood pressure reduction in both automated office blood pressure measurement and 24-hour ambulatory blood pressure monitoring. 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.