Long-Term Safety, Efficacy, and Tolerability Assessment of Lorundrostat in Hypertension: An Open-Label Extension Study

The primary objective of the study is to evaluate the long-term maintenance of the antihypertensive effect of **lorundrostat** in subjects with **hypertension**. This is clinically relevant as sustained blood pressure control is crucial in reducing the risk of cardiovascular events and organ damage associated with hypertension. Additionally, the study aims to assess the efficacy of lorundrostat through a double-blind, Randomized Treatment Withdrawal substudy, and to explore its efficacy at a starting dose of 25 mg once daily. The study also seeks to explore the efficacy of lorundrostat in improving blood pressure and albuminuria, as well as to investigate its long-term safety and tolerability in the target population.

The clinical trial involves a total of **1030 participants** diagnosed with **hypertension**. The study population includes both male and female subjects, aged 18 years and older, who have completed a previous lorundrostat study and are transitioning to the open-label extension study. Participants are required to have signed written informed consent and must be willing and able to comply with study instructions and attend all scheduled visits. The trial does not include a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified. The selection criteria ensure that participants are capable of providing consent and, if applicable, agree to use acceptable methods of contraception. The trial aims to assess the long-term maintenance of the antihypertensive effect of lorundrostat, its efficacy in improving blood pressure and albuminuria, and its long-term safety and tolerability in subjects with hypertension.

The clinical trial is designed to evaluate the long-term safety, efficacy, and tolerability of **lorundrostat** in subjects with **hypertension**. This study is structured as an open-label extension with a double-blind, randomized treatment withdrawal (RTW) substudy. The trial aims to assess the maintenance of the antihypertensive effect of lorundrostat, its efficacy at a starting dose of 25 mg once daily, and its impact on blood pressure and albuminuria. The trial is expected to conclude by December 31, 2026, with recruitment starting on August 11, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, consent, and prior completion of a related lorundrostat study. The trial will include regular follow-up visits to monitor the drug's effects and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment. The expected duration of participant involvement is up to 52 weeks, with conditions for early termination including non-compliance with study procedures or withdrawal of consent.

The trial employs a randomized, double-blind, controlled design for the RTW substudy, ensuring unbiased assessment of lorundrostat's efficacy. Participants in the RTW substudy will be randomly assigned to either continue lorundrostat or switch to a placebo, with changes in blood pressure being the primary endpoint. The study will also explore secondary endpoints related to albuminuria and other health markers. The trial's methodology is rigorous, with strict adherence to ethical standards and regulatory requirements to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Lorundrostat**, an experimental medication developed by Mineralys Therapeutics Inc. Lorundrostat is provided in the form of a **tablet** and is intended for **oral use**. The active substance in Lorundrostat is chemically derived and is identified as N-(trans-4-acetamidocyclohexyl)-2-{4-[5-(4-methylphenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}acetamide. The maximum daily dose of Lorundrostat is 100 mg, with a total treatment period extending up to 52 weeks. The dosing schedule is designed to ensure participant compliance, with regular monitoring to assess adherence to the prescribed regimen.

In addition to the experimental medication, a **placebo** tablet is utilized in the study to serve as a comparator. The placebo is designed to mimic the appearance of the Lorundrostat tablet but contains no active pharmaceutical ingredients. This allows for the assessment of the efficacy and safety of Lorundrostat in a controlled manner, ensuring that any observed effects can be attributed to the active medication rather than psychological or other non-specific factors.

The study also includes the use of **Synacthen 0.25 mg/ml**, a solution for injection containing the active substance **tetracosactide**, provided by Alfasigma S.P.A. Tetracosactide is a protein-based compound used in the trial as an auxiliary treatment. The solution is administered via injection, with a maximum daily dose of 0.25 mg/ml. The treatment period for Synacthen is limited to a single day, and its administration is carefully monitored to ensure safety and compliance with the study protocol.

The efficacy of **lorundrostat** in the clinical trial will be assessed through several primary endpoints focused on its antihypertensive effects in subjects with hypertension. The primary endpoints include the change from the MLS-101-301 baseline in automated office blood pressure (AOBP) systolic blood pressure (SBP) at MLS-101-901 Week 36 for subjects enrolled in the lorundrostat arms of the previous study, excluding those assigned to the placebo arm of the MLS-101-901 randomized treatment withdrawal (RTW) substudy. Additionally, the change in AOBP SBP from MLS-101-901 Week 12 to Week 16 (RTW Week 4) will be evaluated in subjects participating in the RTW substudy. Another endpoint is the change from baseline to Week 12 in AOBP SBP for various groups from the parent studies, specifically exploring the efficacy of lorundrostat at a starting dose of 25 mg once daily (QD).

Further efficacy assessments will include the change from MLS-101-901 baseline AOBP SBP at Week 12 for subjects initially enrolled in the placebo arm of the MLS-101-301 study, aiming to explore the improvement in blood pressure. The percent change in urine albumin creatinine ratio (UACR) from the MLS-101-901 baseline will also be measured by visit during periods of exposure to lorundrostat for subjects with albuminuria at the parent study baseline, to explore its efficacy in improving albuminuria. These efficacy parameters will be collected and analyzed at specified timepoints, such as Week 12, Week 16, and Week 36, using validated scales and laboratory tests to ensure accurate and reliable data collection.