Lorundrostat Efficacy and Safety in Patients with Uncontrolled Hypertension (ADVANCE-HTN)

Authors, Journal, Affiliations, Type, DOI

• Authors: Luke J. Laffin, Branko Kopjar, Carrie Melgaard, Kathy Wolski, Jessica Ibbitson, Shivani Bhikam, Matthew R. Weir, Elizabeth O. Ofili, Reena Mehra, James M. Luther, Debbie L. Cohen, Ashish Sarraju, Michael J. Wilkinson, John M. Flack, David Rodman, Steven E. Nissen, for the Advance-HTN Investigators
• Journal: N Engl J Med 2025;392:1813-23. Published April 23, 2025.
• Affiliations: Cleveland Clinic Foundation (Laffin, Sarraju, Nissen); Mineralys Therapeutics, Radnor PA (Ibbitson, Bhikam, Rodman); University of Maryland (Weir); Morehouse School of Medicine (Ofili); University of Washington (Kopjar, Mehra); Vanderbilt University (Luther); University of Pennsylvania (Cohen); UC San Diego (Wilkinson); Southern Illinois University (Flack)
• Type: Phase 2b, multicenter, double-blind, randomized, placebo-controlled trial; 103 US sites
• DOI: https://doi.org/10.1056/NEJMoa2501440
• Funding: Mineralys Therapeutics; statistical confirmation by C5Research (Cleveland Clinic)

Overview

ADVANCE-HTN randomized 285 participants with uncontrolled/treatment-resistant hypertension — confirmed by 24-hour ambulatory BP monitoring after a standardized antihypertensive regimen — to placebo, lorundrostat 50 mg stable dose, or lorundrostat 50 mg with dose-adjustment to 100 mg. At 12 weeks, the 50 mg stable dose achieved a placebo-adjusted reduction of −7.9 mmHg in 24-hour average ambulatory SBP (P=0.001) and the dose-adjustment arm −6.5 mmHg (P=0.006). The trial enrolled 53% Black participants, reflecting the real-world burden of resistant hypertension. Key safety signals were hyperkalemia (K >6.0 mmol/L: 5–7% vs 0% placebo) and a reversible eGFR decline (13–15%), consistent with the RAAS class effect.

Keywords

Lorundrostat, aldosterone synthase inhibitor, uncontrolled hypertension, treatment-resistant hypertension, ambulatory blood pressure monitoring, CYP11B2, renin-angiotensin-aldosterone system, hyperkalemia, MATE1 renal transporter

Key Takeaways

Background

• Uncontrolled hypertension remains a leading cause of CVD complications and death despite multidrug regimens; only 23% of US hypertensive adults achieve BP control.
• Among patients with treatment-resistant hypertension, aldosterone dysregulation (relative to sodium status) is increasingly recognised as a driver of persistent BP elevation.
• Aldosterone promotes sodium retention, volume expansion, and vascular remodeling, all contributing to sustained hypertension and end-organ damage.
• MRAs have limitations: compensatory aldosterone level rise (counter-regulation), off-target antiandrogenic effects (steroidal MRAs), and acceptability concerns.
• Lorundrostat is a highly selective CYP11B2 inhibitor that reduces aldosterone production while sparing cortisol synthesis, potentially offering better selectivity and fewer off-target effects than MRAs.

Methods

• Phase 2b, multicenter, prospective, double-blind, randomized, placebo-controlled; 103 US sites; March 2023 – October 2024
• Enrolled adults on 2–5 antihypertensive medications with office BP 140–180/65–110 mmHg (or DBP 90–110 mmHg regardless of SBP)
• Key exclusion criteria: eGFR <45 ml/min/1.73m², serum K >5.0 mmol/L, serum Na <135 mmol/L
• All participants switched to standardized regimen for 3 weeks: olmesartan 40 mg + indapamide 2.5 mg or HCTZ 25 mg ± amlodipine 10 mg (3-drug arm if on ≥3 prior medications)
• After 3-week run-in with single-blind placebo, 24-hour ABPM performed; participants with 24h SBP 130–180 mmHg or DBP >80 mmHg randomized in 1:1:1 to:
  • Placebo (n=94)
  • Lorundrostat 50 mg stable dose for 12 weeks (n=94)
  • Lorundrostat 50 mg dose-adjustment (→100 mg at week 4 if office SBP ≥130 mmHg + biomarker criteria met) (n=94)
• Primary endpoint: placebo-adjusted change in 24-hour average SBP from baseline to week 12 (ANCOVA; two-sided alpha 0.025 for each lorundrostat group)
• Key secondary: placebo-adjusted change in 24h average SBP at week 4 (combined lorundrostat groups; 95% CI)
• 2617 screened; 926 on standardized regimen; 285 randomized (high screen-out = large proportion of apparent resistance explained by suboptimal prior regimen/white-coat effect)

Results — Primary Endpoint

• Least-squares mean change in 24h SBP at 12 weeks:
  • Placebo: −7.4 mmHg (97.5% CI −11.4 to −3.4)
  • Stable-dose 50 mg: −15.4 mmHg (97.5% CI −19.0 to −11.8); placebo-adjusted −7.9 mmHg (97.5% CI −13.3 to −2.6; P=0.001)
  • Dose-adjustment: −13.9 mmHg (97.5% CI −17.6 to −10.3); placebo-adjusted −6.5 mmHg (97.5% CI −11.8 to −1.2; P=0.006)
• Stable-dose 50 mg appears to be the optimal dose: comparable BP reduction to dose-adjustment but lower adverse event rate.

Results — Secondary and Exploratory Endpoints

• Week 4 combined lorundrostat (n=188): placebo-adjusted −5.3 mmHg (95% CI −8.4 to −2.3; P<0.001)
• SBP <125 at week 4: 41% (lorundrostat) vs 18% (placebo); OR 3.3 (98.75% CI 1.4–7.8; P<0.001)
• 100 mg uptitration subgroup (n=19): mean office BP change from baseline to week 12: −17.5 mmHg (99.58% CI −30.3 to −4.7; P<0.001)
• 2-drug vs 3-drug background: greater placebo-adjusted BP reduction at week 4 with 2-drug standardized regimen (more room for lorundrostat effect)
• BMI: No correlation between BP reduction with lorundrostat and baseline BMI (contrast with earlier dose-finding Target-HTN trial)
• Race (exploratory): Similar SBP reduction in Black and White participants

Safety

• 1 death: arteriosclerosis (dose-adjustment group); deemed unrelated to trial drug
• Hyperkalemia:
  • K 5.6–6.0 mmol/L: 6% stable, 11% dose-adjustment, 3% placebo
  • K >6.0 mmol/L: 5% stable, 7% dose-adjustment, 0% placebo — exacerbated by concurrent ARB (olmesartan)
• eGFR (cystatin C):
  • At 12 weeks: −13% stable dose, −15% dose-adjustment, −3% placebo
  • After 4-week washout: eGFR recovered in lorundrostat groups (no persistent decline)
  • eGFR dip interpreted as hemodynamic (reduced intraglomerular pressure) rather than nephrotoxic
• MATE1 renal transporter interaction (important caveat):
  • Lorundrostat (like cimetidine, trimethoprim) competitively inhibits MATE1 → creatinine secretion reduced → serum creatinine rises WITHOUT a true fall in GFR
  • Cystatin C (not creatinine) is the appropriate eGFR measure during lorundrostat treatment
• No adrenal insufficiency in either lorundrostat group
• Serious adverse events in 16 participants (3 drug-related: 2 stable-dose, 1 dose-adjustment)

Discussion

• 50 mg is the effective and best-tolerated dose; 100 mg offers no meaningfully greater BP reduction with higher adverse event burden
• Large proportion of Black participants (53%) reflects disproportionate burden of treatment-resistant hypertension; Jackson Heart Study data support elevated aldosterone/lower renin activity in Black adults as a mechanistic basis
• Large screen-out (926 on standardized regimen → 285 randomized) confirms that apparent resistance to medication in the general hypertensive population is largely driven by suboptimal regimens or white-coat effect — the standardized regimen + ABPM strategy is key methodological strength
• Baxdrostat comparison (BaxHTN phase 3, NEJM 2025): −8.1–11.0 mmHg reduction in office SBP in resistant HT; note measurement methodology differs (ABPM vs office) making cross-trial comparison indirect
• ASIs may address aldosterone breakthrough that occurs with long-term ACEi/ARB use — a risk factor for renal and CVD progression
• Future potential: HF, CKD (vicadrostat EASi-KIDNEY trial ongoing)
• Phase 3 Launch-HTN trial ongoing (NCT06153693) to evaluate renal function and hard outcomes

Limitations of the Document

• Phase 2b only (not phase 3); modest sample size (n=285)
• Short treatment duration (12 weeks); long-term safety and BP durability unknown
• No active comparator (spironolactone, the current guideline-recommended 4th agent) — entirely placebo-controlled
• Use of ambulatory BP (rather than office BP as in BaxHTN) precludes direct cross-trial comparison of effect size
• Industry-funded (Mineralys Therapeutics)
• US-only sites; generalizability to non-US populations uncertain
• Only 20% of dose-adjustment group required uptitration to 100 mg — arm underpowered to characterize 100 mg dose effect

Key Concepts Mentioned

• concepts/Aldosterone-Synthase-Inhibitors — ADVANCE-HTN establishes lorundrostat phase 2b efficacy and safety; 50 mg optimal dose; MATE1 transporter caveat
• concepts/Blood-Pressure-Target-T2DM — resistant HT population context (this trial excluded poorly controlled DM indirectly via BP eligibility)

Key Entities Mentioned

• entities/Hypertension — resistant hypertension management; lorundrostat as emerging add-on agent

Wiki Pages Updated

• wiki/sources/lorundrostat-advancehtn-nejm-2025.md (created)
• wiki/concepts/Aldosterone-Synthase-Inhibitors.md (updated: ADVANCE-HTN data, MATE1 note, contradiction, source_count 1→2)
• wiki/entities/Hypertension.md (updated: ADVANCE-HTN in resistant HT section and contradictions, source_count 7→8)
• wiki/sourceindex.md (updated)
• wiki/wikiindex.md (updated)