Lorundrostat, aprocitentan, baxdrostat
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Executive summary
Three next‑generation antihypertensive agents are emerging as contenders for patients with hard‑to‑control blood pressure: lorundrostat and baxdrostat are selective aldosterone synthase inhibitors (ASIs) that lower aldosterone and have shown meaningful systolic blood pressure (SBP) reductions in late‑stage trials, while aprocitentan (marketed as Tryvio) is a dual endothelin receptor antagonist already approved by the FDA for resistant hypertension and offers an alternative mechanism with a different safety profile [1] [2] [3].
1. What each drug is and how it works
Lorundrostat and baxdrostat both inhibit aldosterone synthase (CYP11B2), reducing aldosterone production to lower blood pressure and potentially address mineralocorticoid‑driven disease, whereas aprocitentan blocks endothelin receptors to counter vasoconstriction and fluid retention driven by the endothelin pathway [1] [4] [3].
2. Where they stand in development and approval
Aprocitentan (Tryvio) received FDA approval in 2024 as the first endothelin receptor antagonist for resistant hypertension and is already positioned as an add‑on option for patients inadequately controlled on standard regimens [2] [5]. Baxdrostat has had positive pivotal data, an NDA accepted under FDA Priority Review and is being advanced by AstraZeneca toward potential 2026 approval, with large global trials ongoing [6] [7]. Lorundrostat completed phase 2 trials showing clinically meaningful BP lowering and is progressing through phase 3 work with planned or ongoing regulatory discussions [8] [9] [10].
3. Efficacy signals — how much blood pressure falls
Phase 2 and emerging phase 3 results show both ASIs reduce SBP by clinically relevant amounts: lorundrostat produced placebo‑adjusted reductions (e.g., 9–15 mmHg by some trial readouts and real‑world launch data), while baxdrostat reported statistically significant seated SBP reductions in BaxHTN and related trials [8] [11] [7]. Aprocitentan produced modest but consistent reductions in resistant hypertension in the PRECISION program, sufficient for regulatory approval [5] [3].
4. Safety tradeoffs and patient selection concerns
ASIs so far have lowered aldosterone without causing cortisol suppression seen with earlier agents, but they carry risks familiar to mineralocorticoid‑pathway modulation—principally hyperkalemia, which was uncommon but observed in trials for both baxdrostat and lorundrostat and may be higher in patients with reduced renal function [4] [12] [5]. Aprocitentan’s approval followed data showing efficacy but with edema as a notable adverse effect, and questions remain about its positioning relative to spironolactone for fourth‑line therapy in patients at high hyperkalemia risk [5] [1].
5. How clinicians might choose among them
Emerging reviews suggest a mechanistic, personalized approach: in patients with evidence of renin‑angiotensin system activation or elevated plasma renin/aldosterone, an ASI such as baxdrostat or lorundrostat may be preferred; in patients without RAS activation or with fluid retention patterns, an endothelin receptor antagonist like aprocitentan could be more appropriate [3]. Real‑world kidney function and hyperkalemia risk will materially affect this calculus given limited long‑term safety data so far [5] [3].
6. Commercial and regulatory dynamics that shape access
Commercial incentives and strategic acquisitions are driving urgency: AstraZeneca paid to acquire baxdrostat and is using a priority review voucher to accelerate filing, while Mineralys (lorundrostat) is racing to file its own ASI, creating a head‑to‑head commercialization contest that will influence pricing, indications sought, and postmarketing evidence generation [13] [7] [6]. Idorsia’s Tryvio approval gives it a first‑mover clinical and market advantage, but projected market share forecasts expect strong competition from ASIs over the coming years [2] [7].
7. Bottom line and unknowns
The evidence base positions lorundrostat and baxdrostat as promising ASIs that appear effective at lowering blood pressure with a tolerable short‑term safety profile, while aprocitentan is already an approved alternative class for resistant hypertension; however, longer‑term outcomes, comparative effectiveness against spironolactone, real‑world hyperkalemia incidence in CKD patients, and head‑to‑head data remain limited in the public record and will determine clinical uptake [3] [5] [6].