Evaluating phase II results of Baxdrostat, an aldosterone synthase inhibitor for hypertension

ABSTRACTIntroduction Hypertension, a global health concern, poses a significant risk for other cardiovascular diseases. While lifestyle modifications and interventions like the Dietary Approaches to Stop Hypertension (DASH) diet offer some respite, their maintenance can be challenging. Recently, the spotlight has turned toward the renin-angiotensin-aldosterone system, a crucial player in the pathophysiology of hypertension. Contrary to other drugs, Baxdrostat, an innovative aldosterone synthase inhibitor (ASI), targets aldosterone synthesis, mitigating negative systemic effects.Areas covered Baxdrostat showcases rapid absorption, high oral bioavailability, and significant selectivity for aldosterone synthase which presents a proactive approach to hypertension management by reducing aldosterone levels. Early trials have demonstrated its potential in lowering blood pressure in resistant hypertension cases. Current clinical trials are also exploring its application in primary aldosteronism and chronic kidney disease, with preliminary findings indicating its promise as a novel antihypertensive agent. This article encapsulates the current state of knowledge regarding Baxdrostat, encompassing its uses, ongoing clinical trials, and potential future clinical applications.Expert opinion Future research endeavors will play a pivotal role in unveiling the effectiveness and safety profile of this novel medication. Thus, positioning baxdrostat as a valuable addition to the armamentarium of antihypertensive agents, especially for patients with complex, multifactorial hypertensive conditions.KEYWORDS: Baxdrostataldosterone synthase inhibitorsCYP11B2Essential hypertensionTreatment-resistant hypertensionPrimary hyperaldosteronismDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsProlonged and untreated hypertension (HTN) can lead to a variety of detrimental effects, from heart failure and myocardial infarction to systemic failure.The renin-angiotensin-aldosterone system is an important system that exacerbates systemic HTN via sodium and fluid retention alongside associated alterations in the functioning of the heart, peripheral vasculature, and kidneys.Aldosterone synthesis inhibition therefore has the potential of decreasing oxidative stress and endothelial dysfunction associated with HTN, causing more endothelial nitric oxide synthesis, release, and vasorelaxation.Baxdrostat is a novel drug, 100 times more selective and potent inhibitor of aldosterone synthase (AS) which reduces aldosterone synthesis and mitigates its negative effects on both receptor-mediated and non-genomic processes.Several phase 1 and 2 clinical trials have produced promising results. Recently, a phase 2 study of baxdrostat in treatment-resistant hypertensive patients produced dose-dependent decrease in aldosterone, systolic, and diastolic blood pressure with no cortisol effect. Baxdrostat’s selectivity and potency give it a comparative advantage over mineralocorticoid antagonists.Some data from phase 2 clinical trials examining the safety and efficacy of baxdrostat (CIN-107) in uncontrolled hypertension, chronic-kidney disease, and primary Aldosteronism have not yet been published. Further study in a phase 3 clinical trial is currently underway.Declarations of InterestsThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresA reviewer on this manuscript has disclosed they have served as a consultant for Boehringer Ingelheim, Bayer, Astra Zeneca (not baxdrfostat), Bristo; Meyers Squib, KBP Biosciences* (*stock options). They are also involved in the US Patent 9931412 for site specific delivery of eplerenone to the myocardium.Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Author contributionAll Co-authors consent to the submission of the manuscript. Everyone equally contributed to the success of the work appended.Co-Author Ayoola Awosika helped with Conceptualization, writing 1st draft and 2nd draft.Co-Author Anand Nikilesh helped with conceptualization and writing 1st draft and 2nd draft.Co-Author Yoonje Cho helped with writing 1st draft and methodology screening.Co-author Adekunle Omole helped with writing 2nd draft and review/editing.Co-Author Uzochukwu Adabanya helped with methodology screening, 2nd draft and review.Finally, all co-authors reviewed the final manuscript for any further correction and additions to ensure integrity of the submission. Then we all approved and consented to final submission.Figure 1. Action of aldosterone synthase inhibitor on renin-angiotensin-aldosterone system.Aldosterone synthase inhibitors decrease blood pressure by inhibiting the physiological increases in sodium and water reabsorption, blood volume and blood pressure resulting from adequate physiological stimuli such as decreased blood volume, blood pressure, renal perfusion sodium chloride delivery and increased sympathetic stimulation.↓ = decrease ↑ = increaseDisplay full sizeFigure 2. Chemical structure: BaxdrostatThis is an original image drawn using graphic designDisplay full sizeAdditional informationFundingThis paper was not funded.