Aprocitentan: New insights.
Ontology highlight
ABSTRACT:
SUBMITTER: Varzideh F
PROVIDER: S-EPMC9813740 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Aprocitentan: New insights.
Varzideh Fahimeh F Kansakar Urna U Jankauskas Stanislovas S SS Santulli Gaetano G
Frontiers in cardiovascular medicine 20221222
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Project description: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.
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Project description:This study examined the dose-response characteristics of aprocitentan, a dual endothelin A/endothelin B receptor antagonist, in patients with essential hypertension. In a randomized, double-blind, parallel study design, eligible patients with a sitting diastolic blood pressure (BP) of 90-109 mm Hg received aprocitentan 5, 10, 25, or 50 mg, placebo, or lisinopril 20 mg as a positive control once daily for 8 weeks. Multiple automated office BP readings were obtained with patients resting unattended (unattended automated office BP) at baseline, weeks 2, 4, and 8. Ambulatory BP was monitored for 24 hours at baseline and week 8. After a single-blind placebo run-in period, 490 eligible patients were randomized to the double-blind phase, with 409 patients completing 8 weeks of therapy per protocol. Aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office BP from baseline to week 8 (placebo-corrected decreases: 7.05/4.93, 9.90/6.99, and 7.58/4.95 mm Hg, respectively, P≤0.014 versus placebo), compared with an unattended automated office BP reduction of 4.84/3.81 mm Hg with lisinopril 20 mg. For patients with valid ambulatory BP, aprocitentan 10, 25, and 50 mg significantly decreased placebo-corrected 24-hour BP by 3.99/4.04, 4.83/5.89, and 3.67/4.45 mm Hg, respectively. Incidence of adverse events was similar in the aprocitentan groups (22.0%-40.2%) and the placebo group (36.6%). Aprocitentan produced dose-dependent decreases in hemoglobin, hematocrit, albumin, and uric acid, an increase in estimated plasma volume, but no change in weight versus placebo. These findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02603809.
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Project description:PURPOSE OF REVIEW: Resistant hypertension (RH) defined as uncontrolled blood pressure despite the use of a combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses is associated with a substantially increased risk of cardiovascular and renal events. Despite targeting relevant pathophysiological pathways contributing to elevated blood pressure, approximately 10-15% of hypertensive patients remain above recommended blood pressure targets. Further optimization of blood pressure control is particularly challenging in patient populations who frequently present with RH such as elderly and patients with chronic kidney disease, due to the unfavorable safety profile of the recommended fourth-line therapy with mineralocorticoid receptor antagonists. This review explores the potential role of endothelin antagonists as an alternative fourth-line therapy. RECENT FINDINGS: Despite the well-described role of the endothelin pathway in the pathogenesis of hypertension, it is currently not targeted therapeutically. Recently however, main outcome data from the PRECISION study, a randomized placebo-controlled phase 3 trial, in patients with RH on guideline-recommended standardized single-pill background therapy convincingly demonstrated the safety and blood pressure-lowering efficacy of the dual endothelin antagonist Aprocitentan. Findings from the phase 3 PRECISION study could signify a turning point in the utilization of endothelin receptor antagonists as a standard treatment for patients with RH.
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Project description:Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed. Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.
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