Executive Summary / Key Takeaways

• Mineralys Therapeutics is advancing lorundrostat, a highly selective aldosterone synthase inhibitor (ASI), targeting the significant unmet need in uncontrolled and resistant hypertension by addressing dysregulated aldosterone, a key driver in approximately 30% of hypertensive patients.
• Positive top-line results from two pivotal trials, Launch-HTN and Advance-HTN, demonstrated clinically meaningful and statistically significant systolic blood pressure reductions (e.g., 9.1 mmHg placebo-adjusted in Launch-HTN at Week 6, 7.9 mmHg placebo-adjusted in Advance-HTN at Week 12) with a favorable safety profile, including low rates of confirmed hyperkalemia.
• Lorundrostat's technological differentiation lies in its high selectivity for aldosterone synthase (374-fold vs. cortisol synthase) and a 10-12 hour half-life, aiming to reduce aldosterone levels directly while minimizing off-target effects and providing 24-hour coverage, potentially offering a better benefit-risk profile than mineralocorticoid receptor antagonists (MRAs).
• The company is preparing for a pre-NDA meeting with the FDA in Q4 2025, leveraging the comprehensive data package from its pivotal and exploratory trials (including anticipated Q2 2025 Explore-CKD data), positioning lorundrostat for potential approval in the large and underserved hypertension market.
• A recent public offering significantly strengthened the balance sheet, with cash, cash equivalents, and investments totaling $343.0 million as of March 31, 2025, expected to fund operations into 2027, supporting clinical development, regulatory activities, pre-commercialization efforts, and partnering strategies.

The Challenge of Uncontrolled Hypertension and Mineralys' Targeted Approach

Hypertension, or sustained elevated blood pressure, remains a pervasive health crisis, affecting approximately 120 million individuals in the United States alone. Despite the availability of numerous medications, over half of these patients fail to reach recommended blood pressure goals, leaving them at significantly increased risk of cardiovascular events like heart attack and stroke. Patients whose hypertension persists despite taking two or more medications face 1.8 times greater mortality risk from cardiovascular disease and 2.5 times greater risk from stroke. This underscores a critical unmet medical need, particularly for those with uncontrolled or resistant hypertension.

Mineralys Therapeutics is a clinical-stage biopharmaceutical company founded in 2019 with a strategic focus on addressing diseases driven by dysregulated aldosterone. The company's lead product candidate, lorundrostat, is a proprietary, orally administered, highly selective aldosterone synthase inhibitor (ASI). Unlike traditional therapies that may target broader pathways, lorundrostat is designed to directly inhibit the enzyme responsible for aldosterone production, aiming to normalize levels of this hormone which plays a key role in driving hypertension in about 30% of patients. This targeted approach forms the core of Mineralys' strategy to provide a differentiated and potentially more effective treatment option.

The company's journey began with business planning and capital raising, culminating in a pivotal license agreement with Mitsubishi Tanabe Pharmaceutical Company in July 2020. This agreement granted Mineralys exclusive worldwide rights to lorundrostat, providing the foundational asset for its development pipeline. Since then, Mineralys has dedicated its resources to advancing lorundrostat through preclinical and clinical stages, supported by significant capital raises, including its initial public offering in February 2023 and subsequent financings.

Technological Edge: Selectivity and Mechanism

At the heart of Mineralys' investment thesis is the technological differentiation of lorundrostat. As an aldosterone synthase inhibitor, it represents a distinct pharmacological approach compared to mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone. While MRAs block the effect of aldosterone at the mineralocorticoid receptor, ASIs aim to reduce the production of aldosterone itself. This upstream intervention is hypothesized to mitigate aldosterone's effects not only at the MR but also potentially through other pathways involved in fibrosis, inflammation, and oxidative stress.

Lorundrostat boasts high selectivity for aldosterone synthase (CYP11B2) over cortisol synthase (CYP11B1), demonstrated by a 374-fold selectivity in vitro. This high selectivity is crucial for minimizing off-target effects related to cortisol suppression, a potential concern with less selective inhibitors. The drug also exhibits an observed half-life of 10-12 hours, which management believes is ideal for providing 24-hour blood pressure control while allowing for a window that recapitulates normal circadian rhythm of aldosterone. Clinical data has shown lorundrostat can achieve a 40-70% reduction in plasma aldosterone concentration in hypertensive subjects.

This technological profile is intended to translate into a favorable benefit-risk profile compared to existing therapies. While MRAs are known to cause androgenic side effects like gynecomastia and fertility issues due to MR blockade, ASI's mechanism of action is expected to avoid these. Furthermore, management suggests that while MRAs can lead to hyperkalemia as doses are pushed for efficacy, ASIs like lorundrostat may have a more modest impact on potassium levels, potentially offering a better trade-off between efficacy and this key safety concern.

Clinical Validation and Expanding Horizons

Mineralys' strategic execution is best evidenced by the progression and results of its clinical program. The Phase 2 Target-HTN trial provided initial proof-of-concept, demonstrating statistically significant and clinically meaningful blood pressure reductions. Building on this, the company launched its pivotal program in 2023, comprising the Advance-HTN and Launch-HTN trials, designed to meet regulatory requirements for a New Drug Application (NDA).

The Advance-HTN trial enrolled 285 subjects with confirmed uncontrolled or resistant hypertension, utilizing a rigorous design with standardized background therapy and 24-hour ambulatory blood pressure monitoring (ABPM), considered the gold standard for blood pressure measurement. This trial specifically targeted a high-risk population often managed by specialists. Top-line results announced in March 2025 showed the 50 mg QD dose achieved a highly statistically significant 7.9 mmHg placebo-adjusted reduction in 24-hour ABPM at week 12, with a 15.4 mmHg absolute reduction.

The Launch-HTN trial, a larger Phase 3 study enrolling 1,083 subjects, evaluated lorundrostat in a "real-world setting." Patients remained on their existing 2-5 antihypertensive medications, and efficacy was measured using automated office blood pressure (AOBP). This trial met its primary endpoint, with the 50 mg QD dose demonstrating a clinically meaningful and statistically significant 9.1 mmHg placebo-adjusted reduction in AOBP at Week 6, which was sustained with an 11.7 mmHg placebo-adjusted reduction at Week 12.

Both pivotal trials reported a favorable safety and tolerability profile. While modest, on-target increases in serum potassium were observed, the incidence of confirmed hyperkalemia (> 6.0 mmol/L) was low (0.6% in Launch-HTN 50mg arm vs. 0.4% placebo; 2.1% in Advance-HTN 50mg arm). No cortisol suppression was observed, and discontinuation rates due to adverse events were low. These results are crucial for positioning lorundrostat as a viable and potentially superior option in the third-line or later treatment setting for hypertension.

Beyond core hypertension, Mineralys is exploring lorundrostat's potential in adjacent cardiorenal metabolic conditions where dysregulated aldosterone plays a role. The Explore-CKD Phase 2 trial, which completed enrollment in Q1 2025 and is expected to report top-line data in Q2 2025, evaluates lorundrostat in hypertensive patients with Stage 2-3b CKD and albuminuria already on ACE/ARB and SGLT2 inhibitor therapy. Positive top-line results announced in June 2025 showed the trial met its primary endpoint with a 7.5 mmHg placebo-adjusted SBP reduction at 4 weeks (p=0.0024) and a clinically meaningful 31% reduction in UACR (p<0.0001), along with a favorable safety profile (5% confirmed hyperkalemia > 6.0 mmol/L). The Explore-OSA Phase 2 trial, initiated in Q1 2025, investigates lorundrostat in overweight/obese hypertensive patients with moderate-to-severe obstructive sleep apnea, a condition strongly linked to resistant nocturnal hypertension. These exploratory programs highlight the potential to expand lorundrostat's applicability and market opportunity.

Competitive Landscape and Market Positioning

The hypertension market is large and includes numerous established players offering various classes of medications, including ACE inhibitors, ARBs, calcium channel blockers, diuretics, and MRAs. Major pharmaceutical companies like Novartis (NVS), Pfizer (PFE), Merck (MRK), and AstraZeneca (AZN) have significant market presence with diversified cardiovascular portfolios. Newer approaches like renal denervation and drugs like aprocitentan also represent competitive factors, showing 4-6 mmHg BP reductions in trials.

Mineralys positions lorundrostat as a differentiated therapy addressing the specific pathology of dysregulated aldosterone. While MRAs are available, their use is limited by side effects and hyperkalemia concerns, particularly at higher doses. Management believes lorundrostat's ASI mechanism and favorable safety profile, as demonstrated in pivotal trials, offer a better benefit-risk proposition. The double-digit systolic BP reductions observed in Launch-HTN and Advance-HTN compare favorably to the typical 5 mmHg further reduction seen when adding generic third or fourth-line agents.

Compared to large pharmaceutical companies, Mineralys is a clinical-stage entity with no revenue, incurring significant operating losses ($42.2 million net loss in Q1 2025 vs. $31.5 million in Q1 2024).

Its R&D expenses are substantial ($37.9 million in Q1 2025 vs. $30.8 million in Q1 2024) as it funds clinical trials and prepares for potential commercialization. In contrast, companies like Novartis, Pfizer, Merck, and AstraZeneca are multi-billion dollar enterprises with established revenue streams, positive margins (e.g., NVS TTM Net Margin 23%, PFE 13%, MRK 27%, AZN 13%), and extensive global commercial infrastructures.

Mineralys' competitive advantage lies in its potentially best-in-class ASI technology and the robust clinical data generated in specific, high-unmet-need populations (uncontrolled and resistant hypertension, CKD, OSA). Survey data indicating 95% physician likelihood to prescribe lorundrostat in third/fourth line if approved suggests potential for rapid uptake. However, the company faces the challenge of building market share against deeply entrenched competitors with vast resources and established relationships. Its strategy includes targeting specific physician segments (e.g., the 47,000 prescribers accounting for 50% of third-line+ volume) and pursuing partnerships for global reach and potentially enhanced U.S. commercialization.

Financial Health and Outlook

As a clinical-stage biotechnology company, Mineralys' financial performance is characterized by significant R&D investment and operating losses. For the three months ended March 31, 2025, the company reported a net loss of $42.2 million, an increase from $31.5 million in the same period of 2024. This increase was primarily driven by higher R&D expenses related to advancing the pivotal program and increased general and administrative costs to support operations and public company requirements.

Liquidity is a critical factor for companies at this stage. Mineralys has historically funded its operations through equity and debt financings, raising approximately $700.0 million in gross proceeds since inception through May 8, 2025. A significant recent event was the public offering in March 2025, which generated net proceeds of approximately $188.7 million. This financing substantially bolstered the company's cash position. As of March 31, 2025, Mineralys held cash, cash equivalents, and investments totaling $343.0 million, a significant increase from $198.2 million at the end of 2024.

Management has guided that this cash position is expected to be sufficient to fund operations into 2027. This runway provides the company with the necessary resources to advance lorundrostat through the regulatory submission process and prepare for potential commercialization, as well as continue exploring its potential in adjacent indications. The company expects operating expenses and losses to increase as it expands clinical activities, builds manufacturing capabilities, prepares for launch, and grows its organizational structure. Future funding needs will depend on the timing and success of regulatory approval, the costs of commercialization, and potential partnership arrangements.

Risks and Considerations

Investing in a clinical-stage biotechnology company like Mineralys involves significant risks. The successful development and regulatory approval of lorundrostat are not guaranteed. While pivotal trial results were positive, the FDA's review process is rigorous, and there is no assurance that the data package will be deemed sufficient for approval. The timing and cost of clinical trials can be unpredictable, and unexpected safety findings could emerge in ongoing or future studies.

Competition in the hypertension market is intense, and even if approved, lorundrostat must demonstrate clear value to gain market acceptance, secure favorable reimbursement from payers, and capture market share against established therapies and newer entrants. Manufacturing at commercial scale and managing supply chain complexities also pose potential challenges.

Furthermore, the company's ability to fund future operations beyond the current cash runway will depend on its ability to raise additional capital through equity, debt, or strategic collaborations. Adverse macroeconomic conditions, including inflation and volatility in financial markets, could make future fundraising more difficult or dilutive. The on-target effect of hyperkalemia, while manageable according to management and clinical advisors, particularly in CKD patients, remains a safety consideration that will require monitoring and management in clinical practice.

Conclusion

Mineralys Therapeutics presents a compelling investment narrative centered on lorundrostat, a differentiated aldosterone synthase inhibitor targeting the substantial unmet need in uncontrolled and resistant hypertension. The positive outcomes from the pivotal Launch-HTN and Advance-HTN trials provide strong clinical validation for lorundrostat's efficacy and safety profile, positioning it as a potentially transformative treatment option in a market segment inadequately addressed by current therapies, particularly MRAs.

The company's technological advantage, rooted in lorundrostat's selectivity and mechanism of action, appears to translate into tangible clinical benefits. With a clear path towards a pre-NDA meeting in Q4 2025 and a strengthened balance sheet providing funding into 2027, Mineralys is well-positioned to advance lorundrostat towards potential regulatory approval and commercialization. While significant risks inherent in biotechnology development and market competition remain, the clinical data generated to date, coupled with the strategic focus on a well-defined patient population and exploration of adjacent opportunities, underpins the investment thesis for MLYS as it seeks to unlock value by bringing a novel, targeted therapy to patients with difficult-to-treat hypertension.