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March 30, 2025
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Key takeaways:
Once-daily lorundrostat safely lowered 24-hour systolic BP compared with placebo in a phase 2 trial.
A dose-escalation strategy did not result in greater BP lowering.
CHICAGO — The investigational aldosterone synthase inhibitor lorundrostat effectively lowered 24-hour BP for adults with well-treated, uncontrolled and “true” treatment-resistant hypertension, according to data from a new phase 2b study.
The ADVANCE-HTN study, presented at the American College of Cardiology Scientific Session, is the second trial to assess the ability of once-daily lorundrostat to safely lower BP for adults with persistently elevated levels despite already taking multiple BP medications.
Once-daily lorundrostat safely lowered 24-hour systolic BP compared with placebo in a phase 2 trial. Image: Adobe Stock
“We know aldosterone plays an outsize role in CVD and in hypertension in general,” Luke J. Laffin, MD, co-director of the Center for Blood Pressure Disorders at Cleveland Clinic, told Healio. “Current therapies that address aldosterone, such as spironolactone and eplerenone, block the receptor for aldosterone. Aldosterone synthase inhibitors inhibit biosynthesis of aldosterone, so you are not making as much aldosterone, and that is the big difference.”
Researchers analyzed data from 285 adults with treatment-resistant hypertension, defined as an automated systolic BP of 140 to 180 mm Hg while taking two to five BP medications. Participants taking two BP medications at enrollment were switched to a standardized BP medication regimen consisting of daily indapamide 2.5 mg and olmesartan 40 mg. Participants taking three to five BP medications were also prescribed daily amlodipine 10 mg.
Luke J. Laffin
“When you think about treatment-resistant hypertension, oftentimes we use the term ‘apparent,’ because we do not have out-of-office BP monitoring, we do not have adherence data and we do not have patients on maximal therapies,” Laffin told Healio. “This trial addressed all three of those issues.”
After a 3-week run-in period, researchers randomly assigned participants to 50 mg of lorundrostat daily (n = 94), 50 mg with the potential to increase to 100 mg daily if BP remained uncontrolled at 4 weeks (n = 94) or placebo (n = 94) for 12 weeks. The mean age of participants was 60 years; 40% were women and more than half were Black.
The primary endpoint was change in 24-hour average systolic BP from baseline compared with placebo. Secondary endpoints included change in office BP, change in home BP and the proportion of participants achieving controlled BP.
At 12 weeks, participants taking the 50-mg dose of lorundrostat had a mean BP decrease of 15.4 mm Hg compared to placebo; however, a dose-escalation strategy from 50 mg to 100 mg did not lead to further lowering of BP. Those in the 50 mg to 100 mg group had an average drop of 13.9 mm Hg. Participants in the placebo group also experienced a mean 7.4 mm Hg decrease in BP. The placebo-adjusted decrease in BP was –7.9 mm Hg for the 50 mg group (P = .001) and –6.5 mm Hg for the 50 mg to 100 mg group (P = .006).
Patients in the 50 mg group were also more likely to achieve a 24-hour average systolic BP of less than 125 mm Hg compared with placebo (OR = 3.3; 95% CI, 1.4-7.8; P < .001).
Researchers observed a higher incidence of hyperkalemia in the two lorundrostat groups; however, the incidence of hyperkalemia greater than 6 mmol/L confirmed via per protocol repeat testing was 2% and 3% in the 50 mg and 50 mg to 100 mg groups, respectively.
“These data suggest that aldosterone synthase inhibitors could be a very effective medicine to lower BP in the future,” Laffin told Healio. “Increasing awareness of the role aldosterone plays and the impact that drugs that specifically address aldosterone is important.”
As Healio previously reported, data from the Target-HTN trial, presented at the American Heart Association Hypertension Scientific Sessions in 2023, demonstrated that lorundrostat was associated with clinically significant reductions in automated office BP for people with uncontrolled hypertension, with the greatest effects in people with concomitant obesity. That data also showed that lorundrostat was safe for people with suppressed renin.
A pivotal phase 3 trial of lorundrostat, Launch-HTN, which includes adults with resistant hypertension and uses office BP data, recently completed but has not yet been peer reviewed, Laffin said.
“That will contribute to the wealth of evidence for regulatory approval for this drug,” Laffin said.
The ADVANCE-HTN findings are slated for upcoming publication in The New England Journal of Medicine, Laffin said.
For more information:
Luke J. Laffin, MD, can be reached at laffinl@ccf.org; X: @ljlaffin.
Perspective
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We need a greater armamentarium of therapies for people with resistant hypertension. When you look at the data, to get patients truly under control — a systolic BP of less than 120 mm Hg and a diastolic BP of less than 80 mm Hg — it takes at least three, if not more, medications to reach that goal. Having a medicine like lorundrostat that may not only be an additional option but may be able to replace other medications for BP control is always a good thing. The key will be not only cost but the adverse event profile. With aldosterone synthase inhibitors, you worry about potassium levels and hyperkalemia. That has been a limitation of these types of therapies, especially for patients with any degree of renal impairment. It’s exciting data, and it will be important see the next phase of data in a larger patient population.
Keith Churchwell, MD, FAHA
Volunteer President, American Heart Association
Associate Clinical Professor of Medicine
Yale School of Medicine
Adjunct Associate Professor of Medicine
Vanderbilt School of Medicine
Disclosures: Churchwell reports no relevant financial disclosures.
Perspective
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The ADVANCE-HTN trial was well done. It utilizes a newer approach for difficult-to-treat and resistant hypertension: The aldosterone synthase inhibitor lorundrostat. Rather than blocking the mineralocorticoid receptor like spironolactone, it disrupts aldosteronism by turning off the biosynthesis. The primary endpoint is one which we consider the gold standard in hypertension: 24-hour BP lowering. It takes away a lot of the clinician or researcher bias, because now you are using a tool to gather a large amount of BP measurements throughout the circadian rhythm. This was a multicenter, prospective, randomized, double-blind and placebo-controlled trial; this was not an outcomes trial, but rather a dose-finding trial. The fact that the investigators standardized background therapy shows these participants were treated appropriately, using a combination of indapamide or hydrochlorothiazide, olmesartan and amlodipine. The investigators should be congratulated because this is a sizeable study for phase 2, with 285 participants, and the demographics were excellent, with 40% women and almost half defined as Black or African American — people with higher rates of difficult-to-treat or resistant hypertension.The primary endpoint was met, so this was a positive study. When you compare the 50 mg and the 50 mg to 100 mg groups with placebo, there was clinically significant BP reduction. One of the difficulties we have with blocking aldosterone is the potential for hyperkalemia. Indeed, that was shown; however, when looking at rates of significant hyperkalemia, it was only 2% in the 50 mg group and 3% in the 50 mg to 100 mg group.The study suggests that the 50 mg dose will be adequate for most patients, as the BP reduction was not significantly different between the two groups. In the future, we look for more data on lorundrostat. Blocking aldosterone at its root, through aldosterone synthase inhibition, may be another means for controlling these difficult-to-treat patients.
Keith C. Ferdinand, MD
Gerald S. Berenson Endowed Chair in Preventive Cardiology
Professor of Medicine, John W. Deming Department of Medicine
Tulane University School of Medicine
Healio | Cardiology Today Editorial Board Member
Disclosures: Ferdinand reports receiving consultant fees from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, Medtronic and Novartis.
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Sources/DisclosuresCollapse
Source:
Laffin L, et al. Joint American College of Cardiology/Journal of the American Medical Association late-breaking clinical trials III. Presented at: American College of Cardiology Scientific Session; March 29-31, 2025; Chicago (hybrid meeting).
Disclosures:
Mineralys Therapeutics funded ADVANCE-HTN. Laffin reports serving on steering committees for Mineralys Therapeutics but did not receive compensation from the company.
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