FDA Clears Phase 2 Trial of Lorundrostat for Obstructive Sleep Apnea and Hypertension

Jon Congleton

According to an announcement from Mineralys Therapeutics, the FDA has approved the company’s investigational new drug (IND) application for a phase 2 trial assessing the efficacy of lorundrostat in patients with moderate-to-severe obstructive sleep apnea (OSA) and hypertension. The study, a placebo-controlled, crossover trial, is expected to include 40 individuals with mild-to-moderate OSA and begin in the first quarter of 2025.¹

The study will test whether lorundrostat, taken at 50 mg once daily in the evening, may alleviate the severity of upper airway obstruction and reduce nocturnal hypertension. Investigators will use absolute change in the frequency of apnea-hypopnea episodes as the primary outcome, with secondary objectives that include quantifying blood pressure (BP) during the night using a continuous BP monitor without the benefit of continuous positive airway pressure (CPAP). Other standard patient reported outcomes, specific to OSA, will also be reported.

Hypertension is the leading contributor to cardiovascular morbidity and mortality worldwide, and the majority of individuals in the United States with hypertension have inadequately controlled BP. Lorundrostat, an orally administered, highly selective aldosterone synthase inhibitor, is being developed for a number of conditions, including OSA, uncontrolled hypertension (uHTN), resistant hypertension (rHTN), and chronic kidney disease (CKD). The agent is specifically designed to lower aldosterone levels by inhibiting CYP11B2, the enzyme that regulates its production.

"We are pleased to announce the OSA clinical development program for lorundrostat. This program aligns with our strategy to develop lorundrostat in conditions driven by dysregulated aldosterone, with poor cardiovascular outcomes and few treatment options," Jon Congleton, chief executive officer at Mineralys, said in a statement.¹ "We believe suppression of aldosterone production by lorundrostat has the potential to reduce the nocturnal hypertension driving adverse cardiovascular outcomes. In addition, lorundrostat is anticipated to reduce the severity of upper airway obstruction and associated OSA symptoms such as daytime sleepiness and cognitive impairment.”

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Lorundrostat has shown to be an effective medication at lowering BP, as demonstrated in the pivotal Target-HTN randomized clinical trial (NCT05001945). Published in JAMA Network, the dose-ranging study comprised of 200 participants with uHTN who were taking 2 or more antihypertensive medications. The initial cohort, comprised of 163 participants, randomly assigned patients to placebo or 1 of 5 dosages of lorundrostat (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomly assigned in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily.²

The initial cohort included patients with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) while the subsequent cohort included those with PRA greater than 1.0 ng/mL/h. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic BP of –14.1, –13.2, –6.9, and –4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic BP in individuals who received twice daily doses of 25 mg and 12.5 mg of lorundrostat were –10.1 and –13.8 mm Hg, respectively.

All told, over the 8-week treatment period, the least-squares mean difference between placebo and treatment in systolic BP was –9.6 mm Hg (90% CI, –15.8 to –3.4 mm Hg; P = .01) for the 50-mg once-daily dose and –7.8 (90% CI, –14.1 to –1.5 mm Hg; P = .04) for 100 mg daily. In participants without suppressed PRA, a 100 mg once-daily dose of lorundrostat reduced systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), comparable to the reduction observed in participants with suppressed PRA receiving the same dosage. Notably, in terms of safety, 6 participants (3.6%) had serum potassium levels above 6.0 mmol/L during the trial.

"Obstructive sleep apnea carries significant physiological and psychological impacts on health. Along with trouble sleeping, excessive daytime sleepiness and snoring from repetitive upper airway closure, patients frequently experience significant surges in blood pressure overnight contributing to the daytime hypertension that most are struggling to control," Reena Mehra, MD, MS, director of the Sleep Disorders Research Program at Cleveland Clinic Lerner College of Medicine, said in a statement.¹ "We designed the OSA trial in collaboration with a group of thought leaders in sleep apnea treatment in order to incorporate state-of-the-art technology, register sites with expertise in sleep medicine, and pinpoint the right participants to ensure high-quality data that are reflective of real-world unmet needs facing these patients. I look forward to conducting this innovative trial with Mineralys and our academic partners over the coming months."

In October 2024, Mineralys announced it completed enrollment for its Launch-HTN trial (NCT06153693) ahead of schedule. Launch-HTN is the second of 2 trials under the planned pivotal program evaluating the efficacy and safety of lorundrostat for the treatment of uHTN or rHTN. The global, randomized, double-blinded, placebo-controlled study testing 3 different arms of lorundrostat, is expected to be completed earlier than anticipated, with topline data to be announced in the first half of 2025.³

REFERENCES
1. Mineralys Therapeutics Announces Phase 2 Clinical Trial of Lorundrostat for Obstructive Sleep Apnea in Patients with Hypertension. News release. Mineralys. January 8, 2025. Accessed January 10, 2025. https://www.globenewswire.com/news-release/2025/01/08/3006229/0/en/Mineralys-Therapeutics-Announces-Phase-2-Clinical-Trial-of-Lorundrostat-for-Obstructive-Sleep-Apnea-in-Patients-with-Hypertension.html
2. Laffin LJ, Rodman D, Luther JM, et al. Aldosterone synthase inhibition with lorundrostat for uncontrolled hypertension: the Target-HTN randomized clinical trial. JAMA Network Open. 2023;330(12):1140-1150. doi:10.1001/jama.2023.16029
3. Mineralys Therapeutics Completes Enrollment Ahead of Schedule in Launch-HTN, the Second Pivotal Trial of Lorundrostat for the Treatment of Hypertension. News release. Mineralys Therapeutics. October 30, 2024. Accessed January 10, 2025. https://ir.mineralystx.com/news-events/press-releases/detail/51/mineralys-therapeutics-completes-enrollment-ahead-of