Mineralys Therapeutics: A Breakthrough in Hypertension Treatment with Lorundrostat

The publication of Mineralys Therapeutics’ Phase 2 Advance-HTN trial results in the New England Journal of Medicine (NEJM) marks a pivotal moment in the fight against uncontrolled and resistant hypertension (uHTN/rHTN). The trial’s robust data for lorundrostat, a novel aldosterone synthase inhibitor, underscores its potential to transform care for millions of patients. This article explores the clinical significance of the trial, the drug’s commercial prospects, and Mineralys’ strategic trajectory.

Trial Results: A Clinical Milestone

The Advance-HTN trial enrolled 285 patients with uHTN/rHTN, a population disproportionately affected by cardiovascular complications. Key findings include:
- Primary Endpoint: Lorundrostat 50 mg reduced 24-hour ambulatory systolic blood pressure (SBP) by 15.4 mmHg (7.9 mmHg placebo-adjusted, p=0.001) at week 12.
- Early Efficacy: By week 4, SBP dropped by 11.5 mmHg (placebo-adjusted 5.3 mmHg), with 41% of patients achieving a 24-hour SBP <125 mmHg versus 18% on placebo.
- Consistency: Efficacy was consistent across demographics, including Black/African American patients (53% of the cohort), who are at higher risk for treatment-resistant hypertension.

The trial’s design, using 24-hour ambulatory BP monitoring (the gold standard), strengthens the clinical relevance of these results.

Clinical Significance: Addressing a Critical Unmet Need

Approximately 15–20 million U.S. adults live with uncontrolled hypertension, and 30% of cases involve dysregulated aldosterone—a hormone linked to sodium retention and vascular stiffness. Existing therapies like ACE inhibitors or diuretics often fail to suppress aldosterone, leaving patients at elevated cardiovascular risk.

Lorundrostat’s mechanism—selectively inhibiting aldosterone synthase (CYP11B2)—targets this pathway directly. The Phase 2 data suggest it could reduce cardiovascular events by lowering SBP to levels associated with significant risk reduction (e.g., a 15.4 mmHg drop aligns with estimates of a ~30% reduction in stroke risk).

Safety Profile: Manageable Risks

While lorundrostat’s on-target effects (e.g., hyperkalemia) are expected, the trial demonstrated manageable safety:
- Hyperkalemia: Confirmed cases (via repeat testing) were 2.1–3.2%, lower than initial reports.
- Discontinuation Rate: Only 2% of patients stopped treatment due to adverse events.
- No Cortisol Suppression: A key safety advantage over non-selective inhibitors like spironolactone, which disrupt cortisol production.

These findings align with earlier Phase 3 Launch-HTN trial results, which showed 0.1% treatment-related serious adverse events, reinforcing lorundrostat’s favorable risk-benefit profile.

Market Potential and Financial Outlook

Mineralys’ pipeline is advancing rapidly:
- Phase 3 Launch-HTN Trial: Met its primary endpoint with a 9.1 mmHg SBP reduction at week 6, supporting an anticipated NDA filing in 2025.
- Diverse Indications: Ongoing trials (Explore-CKD and Explore-OSA) aim to expand lorundrostat’s use to chronic kidney disease and obstructive sleep apnea, markets with $10–15 billion in combined annual sales potential.
- Financial Strength: With $198.2 million in cash as of December 2024, Mineralys can fund operations through early 2026, though further trials or commercialization may require additional capital.

Risks and Challenges

• Regulatory Hurdles: The FDA may request additional data on long-term hyperkalemia management or require post-marketing studies.
• Competitor Landscape: Existing therapies (e.g., SGLT2 inhibitors, ARBs) and emerging aldosterone-targeting drugs could limit market share.
• Commercialization Costs: Building a sales force and securing formulary access will strain resources unless partnerships are formed.

Conclusion: A Compelling Investment Case

The Advance-HTN trial’s publication in NEJM solidifies lorundrostat’s standing as a potential first-in-class therapy for uHTN/rHTN. With a ~30% reduction in SBP in a high-risk population and a manageable safety profile, the drug addresses a critical gap in hypertension management.

Key data points support this thesis:
- Market Size: 15–20 million U.S. patients with uncontrolled hypertension, with global potential exceeding $3 billion annually.
- Clinical Differentiation: Lorundrostat’s 374-fold selectivity for aldosterone synthase over cortisol synthase avoids adrenal suppression, a major drawback of current aldosterone antagonists.
- Financial Resilience: Current cash reserves and the likelihood of NDA submission in 2025 position Mineralys to capitalize on its lead asset.

While risks remain, the combination of strong clinical data, a large addressable market, and a well-funded pipeline makes Mineralys a compelling play on an underinvested area of cardiovascular therapeutics. Investors should watch closely for Phase 3 Launch-HTN data presentations in 2025 and potential partnerships to solidify its commercial future.