Highlights
- Lorundrostat achieved significant blood pressure reduction compared to placebo in adults with uncontrolled and treatment-resistant hypertension.
- The drug’s safety profile was generally favorable, with treatment-emergent adverse events mostly mild or moderate.
- Lorundrostat targets dysregulated aldosterone synthesis, a key pathway in resistant hypertension, representing a novel therapeutic class.
- This large, multi-country phase 3 trial provides robust evidence supporting lorundrostat as an adjunct to standard antihypertensive regimens.
Study Background and Disease Burden
Hypertension remains a leading cause of cardiovascular morbidity and mortality worldwide, affecting over 1.2 billion adults and contributing significantly to stroke, myocardial infarction, and chronic kidney disease. Despite the availability of numerous antihypertensive agents, a substantial proportion of patients—estimated at 10-20%—have uncontrolled blood pressure (BP). Of particular concern are those with treatment-resistant hypertension, defined as BP remaining above goal despite the use of three or more antihypertensive drugs, including a diuretic, at optimal doses. Dysregulated aldosterone production is increasingly recognized as a central mechanism in this population, driving sodium retention, vascular inflammation, and fibrosis. Novel pharmacologic strategies targeting aldosterone synthesis may thus address a critical unmet need.
Study Design
The Launch-HTN trial was a multicenter, phase 3, randomized, double-blind, placebo-controlled study conducted across 159 sites in 13 countries from November 2023 to September 2024. Eligible adults (n=1,083) had uncontrolled hypertension—defined as systolic BP ≥130 mm Hg despite 2–5 antihypertensive agents—and included a substantial subset with treatment-resistant hypertension. Participants were randomized in a 1:2:1 ratio to one of three arms:
- 50 mg/day lorundrostat for 6 weeks, with escalation to 100 mg/day for 6 weeks if prespecified criteria were met (n=270);
- 50 mg/day lorundrostat for 12 weeks (n=541);
- Daily placebo for 12 weeks (n=272).
Escalation criteria included sustained systolic BP ≥130 mm Hg, potassium ≤4.8 mmol/L, sodium ≥135 mmol/L, and eGFR >45 mL/min/1.73 m² with less than 25% decline. The primary endpoint was the change in automated office systolic BP at week 6 for 50 mg lorundrostat versus placebo. Key secondary endpoints included adverse events of special interest (hyperkalemia, hyponatremia, and reduction in kidney function), overall safety, and treatment discontinuations.
Key Findings
Baseline characteristics reflected a high-risk, diverse population: mean age was 61.6 years, 46.9% were female, 28.7% Black or African American, 67.7% White, and 63.3% had obesity (BMI ≥30). At randomization, 39.9% were on two antihypertensive agents, while 60.1% were on three or more.
In the pooled 50 mg lorundrostat group (n=808), the least-squares mean reduction in office systolic BP at week 6 was -16.9 mm Hg (95% CI, -19.0 to -14.9) compared to -7.9 mm Hg (95% CI, -11.5 to -4.2) for placebo, yielding a statistically and clinically significant difference of -9.1 mm Hg (95% CI, -13.3 to -4.9; P<.001). This magnitude of effect is notable, given the trial’s population had persistent hypertension despite multi-drug therapy.
Adverse events of special interest were more frequent in the lorundrostat arms. Specifically, treatment discontinuation rates due to hyperkalemia, hyponatremia, or reduced kidney function remained low: 0.37% for hyperkalemia and hyponatremia, and 0–0.56% for kidney function events, depending on dosing. Overall, 49.9% of participants experienced treatment-emergent AEs, predominantly mild or moderate.
A detailed breakdown:
- Hyponatremia, hyperkalemia, and eGFR reduction were more common with lorundrostat but led to discontinuation in only 1–3 participants per group.
- No new safety signals emerged regarding serious adverse renal or electrolyte disturbances.
- Most AEs were manageable and did not necessitate withdrawal.
These findings support both the efficacy and the tolerability of lorundrostat as an adjunct in difficult-to-treat hypertension.
Expert Commentary
The Launch-HTN trial establishes lorundrostat as an effective and generally safe therapeutic option for patients with uncontrolled and treatment-resistant hypertension. The observed BP reduction is on par with or superior to those seen with currently available mineralocorticoid receptor antagonists (MRAs) but with a distinct mechanism—direct inhibition of aldosterone synthase—and potentially less off-target hormonal disruption. This is particularly salient for patients who are intolerant of MRAs or who have persistent aldosterone-driven hypertension.
However, the safety profile, while acceptable, warrants ongoing vigilance, especially given the increased rates of hyperkalemia and hyponatremia. Routine laboratory monitoring remains essential, particularly in populations with compromised renal function or baseline electrolyte abnormalities. The broad international, multi-ethnic patient representation enhances the generalizability of the findings, though real-world effectiveness and long-term outcomes remain to be established.
Mechanistically, lorundrostat’s direct suppression of aldosterone synthesis may also have beneficial effects on cardiac and renal remodeling, though these endpoints were not addressed in this trial and merit future study.
Conclusion
Lorundrostat, as evidenced by the Launch-HTN phase 3 trial, offers a novel, efficacious, and generally safe option for patients with uncontrolled and treatment-resistant hypertension. Its addition to existing antihypertensive regimens resulted in significant incremental BP reductions and a manageable safety profile. These findings have the potential to influence clinical practice guidelines and address a prominent gap for patients with persistent hypertension despite multidrug therapy. Further studies will be needed to evaluate long-term outcomes, cost-effectiveness, and comparative effectiveness versus other aldosterone-targeting agents.
References
1. Saxena M, Laffin L, Borghi C, Fernandez Fernandez B, Ghali JK, Kopjar B, Polu K, Roger SD, Slingsby BT, Strutz F, Vogt L, Weir MR, Rodman D; Launch-HTN Investigators. Lorundrostat in Participants With Uncontrolled Hypertension and Treatment-Resistant Hypertension: The Launch-HTN Randomized Clinical Trial. JAMA. 2025 Aug 5;334(5):409-418. doi: 10.1001/jama.2025.9413. PMID: 40587141; PMCID: PMC12210145.
2. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104.
3. Carey RM, Calhoun DA, Bakris GL, et al. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension. 2018;72(5):e53-e90.
Great information