Aprocitentan: A new development of resistant hypertension

Abstract

As the blood pressure threshold for commencing antihypertensive treatment diminishes, the cohort suffering from resistant hypertension (RH) correspondingly expands. Notwithstanding the availability of known antihypertensive medications, there exists a conspicuous lacuna in therapeutic options specifically intended for the management of RH. Currently, aprocitentan is the sole endothelin receptor antagonist (ERA) under development for addressing this pressing clinical challenge. Aprocitentan (ACT‐132577), deriving its active form as a metabolite of macitentan, demonstrates oral potency as a dual endothelin (ET) receptor antagonist. This compound effectively obstructs the binding of endothelin‐1 (ET‐1) to both ETA and ETB receptors, exhibiting an inhibitory potency ratio of 1:16. Clinical investigation of aprocitentan has advanced to phase 3 trials, yielding promising preliminary outcomes.

1. INTRODUCTION

Per the 2018 American Heart Association (AHA) Statement ¹ on resistant hypertension (RH), a patient is classified as hypertensive if their blood pressure persistently surpasses the targeted level despite the concurrent administration of three antihypertensive agents from distinct classes. These typically encompass a long‐acting calcium channel blocker (CCB), a renin‐angiotensin‐aldosterone system (RAAS) blocker (either an angiotensin‐converting enzyme [ACE] inhibitor or an angiotensin receptor blocker [ARB]), and a diuretic. Each agent must be dispensed at the maximum or maximum‐tolerated dose consistent with the recommended dosage frequency. Furthermore, this definition excludes cases attributable to the white coat effect or irregular antihypertensive medication usage. The term RH also encompasses patients whose blood pressure meets target levels through the utilization of four or more antihypertensive medications, a situation referred to in the literature as “controlled RH”. Broadly, RH refers to hypertension manifesting as either uncontrolled or controlled blood pressure, contingent on the quantity of antihypertensive agents employed.

Regarding the objectives for hypertension control, the 2017 AHA guideline ² reduced the blood pressure threshold for initiating antihypertensive therapy to ≥130/80 mm Hg for adults who have existing cardiovascular disease (CVD) or a 10‐year atherosclerotic CVD risk of ≥10%. Simultaneously, the treatment goal was lowered to <130/80 mm Hg for the majority of individuals. These recommendations significantly influence the diagnostic threshold for RH, resulting in an increased prevalence of RH among the hypertensive population. The query subsequently arises as to the alternatives beyond the known triple or quadruple antihypertensive medications for RH treatment.

Numerous elements such as the central nervous system, renin‐angiotensin‐aldosterone system, vascular factors, and renal and fluid volumes are known to contribute to hypertension pathophysiology, with these elements exerting mutual influences. ³ , ⁴ Given this understanding, the antihypertensive agents currently recognized include CCB, ACEI/ARB, and a diuretic. However, challenges emerge due to intolerances to these drugs, the inability to use ACEI/ARB drugs in patients with severe renal insufficiency, and the presence of RH. The urgent need for new antihypertensive medications becomes apparent. It is worth noting that the endothelin (ET) system, a significant player in hypertension pathophysiology known to be hyperactive under pathological conditions including hypertension, ⁵ , ⁶ , ⁷ has been largely overlooked in managing refractory hypertension.

In 1988, Yanagisawa and coworkers ⁸ unveiled ET‐1, an integral subtype of a 21‐amino acid peptide family, including ET‐1, ET‐2, and ET‐3, involved in numerous cardiovascular diseases. This peptide family operates by binding to two endothelin receptors, ETA and ETB. ⁹ , ¹⁰ By using the search terms “Aprocitentan [Title/Abstract]” and “ACT‐132577[Title/Abstract]”, 46 articles were discovered as of April 5, 2023. A meticulous review of these articles revealed insights into the progress of aprocitentan clinical trials, its interactions with related medications, and the compound's tolerability.

1.1. Aprocitentan: The only drug to enter phase 3 clinical trials in the treatment of RH

As cited in Burnier's review, ¹¹ the utility of endothelin receptor antagonists (ERAs) is often curtailed by their tolerability, with fluid retention, edema, and hepatotoxicity constituting common adverse reactions. Consequently, numerous clinical programs were prematurely discontinued. Presently, aprocitentan is the sole ERA still under development for RH treatment. Macitentan, recognized as an orphan drug employed in the therapy of pulmonary arterial hypertension, metabolizes into the active compound, aprocitentan (ACT‐132577). This metabolite is an orally potent, dual ET receptor antagonist, which inhibits ET‐1 from binding to both ETA/ETB receptors with an inhibitory potency ratio of 1:16. ¹² , ¹³ The clinical examination of aprocitentan has advanced to phase 3 trials, with promising results detailed further in the text.

Schlaich and coworkers ¹⁴ organized a multicenter, blinded, randomized, parallel‐group, phase 3 trial (PRECISION), executed in three consecutive phases across a 48‐week span at facilities in North America, Europe, Asia, and Australia. The trial ran from June 18, 2018 to April 25, 2022, enrolling 730 RH patients (Registered on ClinicalTrials.gov, NCT03541174). The initial phase consisted of a 4‐week, double‐blind, randomized, placebo‐controlled segment, wherein patients were administered either aprocitentan 12.5 mg, aprocitentan 25 mg, or a placebo in a 1:1:1 ratio. The second phase was a 32‐week, single‐blind period, during which all patients received aprocitentan 25 mg. The final phase was a 12‐week, double‐blind, randomized, placebo‐controlled withdrawal segment, wherein patients were again randomly allocated aprocitentan 25 mg or placebo in a 1:1 ratio. The PRECISION trial yielded the following conclusions: The least square mean (SE) shift in office systolic blood pressure at 4 weeks was −15.3 (SE 0.9) mm Hg for aprocitentan 12.5 mg, −15.2 (0.9) mm Hg for aprocitentan 25 mg, and −11.5 (0.9) mm Hg for placebo, rendering a difference versus placebo of −3.8 (1.3) mm Hg (97.5% CI −6.8 to −0.8, p = .0042) and −3.7 (1.3) mm Hg (−6.7 to −0.8; p = .0046), respectively. The corresponding disparity for 24‐h ambulatory systolic blood pressure was −4.2 mm Hg (95% CI −6.2 to −2.1) and −5.9 mm Hg (−7.9 to −3.8). Following 4 weeks of withdrawal, office systolic blood pressure significantly ascended with placebo versus aprocitentan (5.8 mm Hg, 95% CI 3.7 to 7.9, p < .0001). The most recurrent adverse event was mild‐to‐moderate oedema or fluid retention, occurring in 9%, 18%, and 2% of patients receiving aprocitentan 12.5 mg, 25 mg, and placebo during the 4‐week double‐blind phase, respectively.

As highlighted previously, fluid retention, edema, and hepatotoxicity often prompt the cessation of various RH treatment clinical trials. However, a phase III study of aprocitentan revealed a lower incidence of edema. ¹⁴ , ¹⁵ Regarding fluid retention, aprocitentan caused moderate weight gain in healthy patients on a high‐sodium diet, absent significant sodium retention. ¹⁶ Additional clinical trials indicate no worsening hepatotoxicity in patients exhibiting mild to severe liver impairment, suggesting no requirement for aprocitentan dosage adjustment in patients with abnormal liver function (ClinicalTrials.gov NCT04252495 and ClinicalTrials.gov, NCT03165071). ¹⁷ , ¹⁸

1.2. Combination therapy of apocitentan with other antihypertensive agents

Research exploring the effects of aprocitentan in concert with other antihypertensive agents have generated the following insights. Trensz and coworkers ¹⁹ indicated that in spontaneously hypertensive (SHR) and deoxycorticosterone acetate (DOCA)‐salt (low‐renin model) rats, a solitary combined dose of aprocitentan and valsartan exhibited a synergistic effect, yielding a larger reduction in blood pressure than the cumulative effects of the individual drugs. A similar outcome was observed with the combination of aprocitentan and enalapril. In contrast, spironolactone (a mineralocorticoid receptor antagonist [MRA]) that operates downstream of ARB/ACEI, only displayed additive effects when combined with valsartan or enalapril, with no evidence of a synergistic antihypertensive effect. This points to the unique potential of aprocitentan in combination with renin‐angiotensin system blockers. Abbas and coworkers ²⁰ exhibited a significant escalation in hyperkalemia risk upon adding spironolactone to a population‐ and insurance‐based cohort of heart failure patients undergoing ACE/ARB standard therapy. In real‐world practice, the hyperkalemia risk associated with this combination outstrips that recorded in clinical trials. However, Trensz and coworkers ¹⁹ reported that, in contrast to the combination of spironolactone and enalapril, the use of aprocitentan with enalapril did not raise plasma urea or creatinine levels in SHR consuming a low‐salt diet. This again emphasizes the unique potential of aprocitentan combined with the renin‐angiotensin system.

1.3. Interactions with commonly used drugs for cardiovascular disease

Considering that RH patients frequently present with target organ damage, assessing the pharmacokinetics and pharmacodynamics of aprocitentan in conjunction with cardiovascular‐related medications becomes critical for the potential widespread application of aprocitentan.

The metabolism of aprocitentan involves two primary elimination pathways, independent of cytochrome P450 (CYP) enzymes and dependent on uridine 5′‐diphosphate glucuronosyltransferase and chemically hydrolyzed (Figure 1) glycoside action. ²¹ As such, aprocitentan can be administered simultaneously with any cytochrome P450 inhibitor or inducer, with no need for dose adjustment. Current research includes rifampicin (a potent CYP3A4 inducer), ²² warfarin (metabolized predominantly by CYP1A2 (R‐enantiomer) and CYP2C9 (S‐enantiomer)), ²³ and midazolam (proven to be affected by CYP3A inhibitors or inducers to a clinically significant degree). ²⁴ Moreover, aprocitentan exhibited 50% inhibition of the breast cancer resistance protein (BCRP) in vitro. Given that rosuvastatin is a substrate of organic anion‐transporting polypeptide and BCRP transporters, a single‐center, open‐label, single‐sequence, phase 1 study (NCT03245229) demonstrated that rosuvastatin did not influence plasma concentrations of aprocitentan. ²⁵ , ²⁶

FIGURE 1.

Chemical structure of aprocitentan.

1.4. Whether there is a difference in aprocitentan between different races, ages, and sex

To ascertain whether age and sex affect tolerance to aprocitentan, Sidharta and coworkers ²⁷ conducted single and multiple doses of aprocitentan in healthy adults and elderly patients, finding no disparity in age and sex tolerance to aprocitentan. The tolerated dose was established at 100 mg daily for a total of 10 days. Fontes and coworkers ²⁸ found no clinically relevant differences between Japanese and Caucasian patients, and aprocitentan dose levels were as high as 25 mg, without any need for dose adjustment across different ethnic groups.

2. CONCLUSIONS

At present, aprocitentan is the sole drug in phase 3 clinical trials for RH, arguably representing the most promising candidate for clinical application in addressing the current challenges in RH treatment. Nonetheless, the current phase III trial duration is limited to 48 weeks, leaving potential long‐term adverse reactions in patients requiring prolonged use of the drug undetermined. The established safe maximum dose level for aprocitentan is 25 mg, warranting additional clinical data to further corroborate the safety of aprocitentan. Aprocitentan could emerge as a new treatment alternative for RH in the foreseeable future.

AUTHOR CONTRIBUTIONS

Yao Yao: Conceptualization, Data Curation, Writing—Original Draft, Bin Fan: Conceptualization, Data Curation, Writing—Original Draft, Zi‐Xuan Jia: Writing—Original Draft, Bin Yang: Writing—Review & Editing, Project administration, Funding acquisition, Bao Li: Writing—Review & Editing, Project administration, Funding acquisition

CONFLICT OF INTEREST STATEMENT

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service, and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled.

Yao Y, Fan B, Yang B, Jia Z, Li B. Aprocitentan: A new development of resistant hypertension. J Clin Hypertens. 2023;25:587–590. 10.1111/jch.14686

DATA AVAILABILITY STATEMENT

Data openly available in a public repository. The data that support the findings of this study are openly available in PUBMED.