Phase 3 Multicenter Study on Lorundrostat Efficacy and Safety in Uncontrolled and Resistant Hypertension

The primary objective of this study is to evaluate the effect of **Lorundrostat** when added to prescribed antihypertensive therapy (AHT) on systolic blood pressure (SBP) in subjects with hypertension. This is clinically relevant as it aims to determine the efficacy of Lorundrostat in managing blood pressure in patients with uncontrolled and resistant hypertension, potentially offering a new therapeutic option for this challenging condition.

Secondary objectives include:

• Assessing the ability of Lorundrostat, when added to prescribed AHT therapy, to achieve SBP control in subjects with hypertension.
• Evaluating the SBP lowering effect of Lorundrostat in subjects with uncontrolled hypertension on two prescribed AHT medications.
• Assessing the SBP lowering effect of Lorundrostat in subjects with resistant uncontrolled hypertension on three or more prescribed AHT medications.
• Evaluating the effect of obesity on the SBP lowering effect of Lorundrostat in subjects with hypertension.
• Assessing the SBP effect of Lorundrostat dose escalation from 50 mg once daily to 100 mg once daily in subjects with hypertension who do not achieve blood pressure control on a Lorundrostat dose of 50 mg once daily.

The clinical trial involves a total of **580 participants** diagnosed with **uncontrolled and resistant hypertension**. The study population includes both male and female subjects, aged 18 years and older, who are capable of providing informed consent. Participants are required to have a history of hypertension lasting at least six months prior to screening and must be on a stable regimen of 2 to 5 antihypertensive medications, including a thiazide or thiazide-like diuretic, unless medically contraindicated. The trial population was selected based on specific criteria, including a body mass index (BMI) of at least 18 kg/m² and an arm circumference of less than 52 centimeters. Participants must also have a serum cortisol level within the range of 3 to 22 µg/dL. Both fertile male subjects and female subjects of childbearing potential, along with their partners, are required to use effective contraception methods throughout the study duration and for 28 days following the last dose of the study drug. The trial includes a vulnerable population, ensuring comprehensive monitoring and ethical considerations throughout the study.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of **Lorundrostat** in subjects with **uncontrolled and resistant hypertension**. The trial is structured as a parallel-arm, multicenter Phase 3 study. The primary objective is to assess the effect of Lorundrostat when added to prescribed antihypertensive therapy on systolic blood pressure (SBP) in the target population. The trial is expected to commence recruitment on March 5, 2024, and conclude by April 30, 2025, with a maximum treatment period of 12 weeks for participants.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, blood pressure levels, and medication history. Following successful screening, participants will be randomized to receive either Lorundrostat or placebo. The study includes a run-in period to stabilize medication regimens, followed by randomization and treatment phases. Key study visits will occur at baseline, Week 6, and Week 12, with primary endpoints assessed at Week 6. Secondary endpoints include changes in SBP at Week 12 and the proportion of subjects achieving target SBP levels.

The expected length of participant involvement is approximately 12 weeks, with conditions for early termination including adverse events, non-compliance with study protocols, or withdrawal of consent. The study will ensure that all participants provide written informed consent and are willing to comply with study instructions and attend all scheduled visits. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Lorundrostat**, an investigational medication, in the form of tablets. **Lorundrostat** is a chemical compound with the active substance name **LORUNDROSTAT**. The pharmaceutical form is a tablet, and it is administered orally. The maximum daily dose is 100 mg, with a total maximum dose of 100 mg over a treatment period of up to 12 weeks. The medication is provided by Mineralys Therapeutics Inc. and is identified by the sponsor product code MLS-101. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental medication, the trial includes the use of **Lorundrostat Placebo Tablets**. These tablets are designed to match the experimental medication in appearance but do not contain the active substance. The placebo is administered orally, following the same dosing schedule as the active medication, to maintain the double-blind nature of the study.

Another non-experimental treatment used in the study is **Synacthen 0.25 mg/ml Injektionslösung**, which contains the active substance **Tetracosactide**. This solution for injection is administered as needed, with a maximum daily dose of 0.25 mg/ml. The product is manufactured by Alfasigma S.P.A. and is used as an auxiliary treatment in the trial. The administration route is via injection, and the treatment period is limited to one day.

The efficacy of Lorundrostat in the treatment of **hypertension** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in automated office blood pressure (AOBP) systolic blood pressure (SBP) at Week 6 in subjects randomized to Lorundrostat 50 mg once daily (QD) compared to those randomized to placebo. Secondary endpoints include the proportion of subjects with AOBP SBP less than 130 mmHg at Week 6, and changes from baseline in AOBP SBP at Week 12 in subjects who escalate to Lorundrostat 100 mg QD, among other comparisons based on the number of antihypertensive therapy (AHT) medications and obesity status.

Measurements of AOBP SBP will be conducted at specified timepoints, including Week 6 and Week 12, using validated automated office blood pressure devices. Data collection will occur at these intervals to ensure accurate assessment of the drug's efficacy. The analysis will compare the results between the Lorundrostat and placebo groups, focusing on the predefined endpoints to determine the treatment's impact on blood pressure control in subjects with uncontrolled and resistant hypertension.