Lorundrostat Efficacy and Safety in Patients With Uncontrolled Hypertension - Advance-HTN

Mar 29, 2025
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Author/Summarized by Author:
Carlos A Vergara Sanchez, MD
Summary Reviewer:
Fred M. Kusumoto, MD, FACC; R. Scott Wright, MD, FACC
Trial Sponsor:
Mineralys Therapeutics
Date Presented:
03/29/2025
Date Updated:
03/29/2025
Original Posted Date:
03/27/2025
References

Contribution To Literature:

The Advance-HTN trial showed that lorundrostat effectively lowered 24-hour SBP at 12 weeks among patients with uncontrolled and treatment-resistant hypertension vs. placebo.

Description:

The goal of the phase 2b trial was to assess the 24-hour systolic blood pressure (SBP) lowering effect of lorundrostat, a novel aldosterone synthase inhibitor, taken once daily in participants with uncontrolled and treatment-resistant hypertension on a standardized antihypertensive regimen.

Study Design

Participants at 103 U.S. sites with elevated BP despite taking two to five BP-lowering medications at baseline were randomized to one of three groups following a 3-week period of standard BP-lowering medications: placebo, lorundrostat 50 mg daily, or lorundrostat 50 mg daily with the potential to increase to 100 mg daily if BP remained uncontrolled at 4 weeks.

  • Total number of enrollees: 926
  • Total number randomized: 285
  • Duration of follow-up: 12 weeks
  • Mean patient age: 60 years
  • Percentage female: 40%
  • Black or African-American: 53%

Principal Findings:

The primary outcome was change in 24-hour average SBP from baseline (randomization) to week 12. Results showed:

  • Placebo: -7.4 points (mm Hg)
  • Lorundrostat 50 mg: -15.4 points. Placebo adjusted: -7.9 points (-13.3 to -2.6) p=0.001
  • Lorundrostat 50-100 mg: -13.9 points. Placebo adjusted: -6.5 points ( -11.8 to -1.2) p=0.006

Secondary outcomes include:

  • Change in 24-hour average SBP from baseline to week 4: Placebo: -6.2 points vs. lorundrostat 50 mg: -11.5% points. Placebo adjusted: -5.3 points (-8.4 to -2.3 points)
  • Change in office SBP from baseline to week 12 among participants escalated to 100 mg daily (n=19): - 17.5 mm Hg (-30.3 to -4.7 mm Hg) p<0.001
  • Proportion of participants with 24-hour average SBP <125 mm Hg at week 4 in placebo (18%) vs. lorundrostat 50 mg (41%): odds ratio (OR), 3.3 (1.4-7.8) p<0.001 
  • Change in 24-hour average SBP from baseline to week 4 by number of BP medications in standardized regimen (i.e., in patients taking two BP medications), placebo was -5.1 (n=60) vs. lorundrostat (n=117) -11.2, placebo adjusted -6.1 (-10.8 to -1.4) p=0.001. In patients taking three BP medications, placebo adjusted (n=34): - 7.2 points vs. lorundrostat (n=71): - 11.8 points, placebo adjusted result: -4.6 points (-10.6 to 1.5) p=0.06
  • Importantly, in the adverse events, hyperkalemia was notably different in the placebo group (0%), vs. lorundrostat 50 mg (5%) vs. lorundrostat 50-100 mg (7%)

Interpretation:

In patients with uncontrolled hypertension and treatment-resistant hypertension in the Advance-HTN trial, the use of lorundrostat 50 mg and 50-100 mg lowered 24-hour BP at week 12, with higher rates of adverse events at the higher dose.

The trial recruited a diverse population with 40% women and >50% African Americans; the BP effect was achieved irrespective of race, gender, or weight. Higher levels of hyperkalemia and hyponatremia were seen in the lorundrostat group.

The use of a therapy which targets aldosterone production is promising as a new treatment in resistant hypertension if these data are confirmed by subsequent phase 3 clinical trials.

References:

Presented by Dr. Luke Laffin at the American College of Cardiology Annual Scientific Session (ACC.25), Chicago, IL, March 29, 2025.

Clinical Topics: Prevention, Hypertension

Keywords: ACC25, ACC Annual Scientific Session, Antihypertensive Agents, Blood Pressure Monitoring, Ambulatory, Hypertension


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