Lorundrostat Stands a Chance Against Obesity-Related Hypertension

Among selected people with uncontrolled hypertension, blood pressure (BP) could be successfully reduced with a highly selective aldosterone synthase inhibitor, a phase II dose-finding trial found.

In hypertensive patients with suppressed renin -- theoretically the group most likely to benefit from reining in aldosterone production -- reductions of automated office systolic BP reached up to 14.1 mm Hg at 8 weeks in those receiving lorundrostat 50 mg or 100 mg once daily, a significant improvement over the placebo arm's 4-mm Hg reduction, reported Steven Nissen, MD, of Cleveland Clinic, and co-investigators of the small Target-HTN trial.

The subgroup with obesity in particular seemed to derive the greatest BP lowering, they stated in JAMA. The findings were presented at the 2023 Hypertension conference, hosted by the American Heart Association.

Notably, even in people without suppressed renin, 100 mg daily lorundrostat decreased systolic BP by 11.4 mm Hg.

"Lorundrostat was well tolerated, and small expected increases in serum potassium and declines in eGFR suggest a favorable safety profile, particularly with a 50-mg once-daily dose. The trial results support further study of lorundrostat as a treatment for uncontrolled hypertension," the authors concluded.

Lorundrostat is among the new antihypertensives in the pipeline being developed to curb the excess aldosterone synthesis that contributes to high BP.

"This development of this drug is important because no new classes of blood pressure lowering drugs have been introduced for many years," Nissen said in a press release. "Blood pressure is difficult to control in some patients particularly those with obesity and diabetes, so new options will be valuable."

Another selective aldosterone synthase inhibitor, baxdrostat, exhibited mixed results for BP lowering when it progressed to phase II study. Some attribute baxdrostat's failure to beat placebo in the recent HALO trial to hiccups in patient adherence to therapy.

A third agent in this class, dexfadrostat, is in early-phase testing.

Unlike a mineralocorticoid receptor antagonist like spironolactone, the more upstream targeting of aldosterone synthase of these drugs may help classical hyperaldosteronism and obesity-associated hypertension without hormonal adverse effects.

"There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism," commented Bryan Williams, MD, of University College London, in an accompanying editorial.

Williams wrote that the two safety outcomes "especially relevant" to this new class are blood cortisol and potassium levels.

In Target-HTN, six people had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation, while no instances of cortisol insufficiency occurred. "The 50-mg once-daily dose of lorundrostat lowered office BP to a similar degree as the 100-mg once daily dose, but resulted in fewer adverse events, including fewer episodes of hyperkalemia," Nissen's group reported.

Serum aldosterone was in fact reduced by lorundrostat across all doses.

"Consistent with its high selectivity for aldosterone synthase, there was no signal of an effect of lorundrostat on cortisol synthesis," Williams remarked, though he cautioned that "[m]ore significant increases in potassium would be expected in patients with more advanced kidney disease."

"While further studies of this drug are needed, these results are encouraging, particularly among patients with obesity-associated hypertension," said study co-author Luke Laffin, MD, also of Cleveland Clinic, in a statement.

The ongoing ADVANCE-HTN pivotal trial is evaluating lorundrostat as an add-on therapy for 300 people with uncontrolled or resistant hypertension. Another larger phase III trial is being planned for reporting in 2025, drug-maker Mineralys Therapeutics announced.

Target-HTN was a phase II trial conducted at 43 sites in the U.S. Prescreening identified people with systolic automated office BP 130 mm Hg or greater while on at least two antihypertensive medications for at least 4 weeks at maximally tolerated doses

An initial cohort of 163 participants with plasma renin activity (PRA) ≤1.0 ng/mL/h and elevated plasma aldosterone (1.0 ng/dL) was enrolled and randomized to placebo or one of five lorundrostat doses (12.5 mg, 50 mg, or 100 mg once daily, or 12.5 mg or 25 mg twice daily).

Subsequent enrollment included 37 participants with PRA greater than 1.0 ng/mL/h, who were randomized 1:6 to placebo or lorundrostat, 100 mg once daily.

Across the randomized patients, mean age was 65.7 and 60% were women. By race, 36% were Black and 48% Hispanic. Nearly half the participants had a BMI over 30.

Average baseline BP was around 140/80 mm Hg. Three or more antihypertensive medications were already being taken by 42%.

Chief among the limitations of the trial was the small sample size for each tested dose of lorundrostat.

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