act-132577 and Hypertension

Hypertension is one of the most common disorders encountered, yet pharmacotherapy for resistant hypertension has limited effective options. Aprocitentan is postulated to be a novel antihypertensive. The main goal was to determine the effect of aprocitentan on blood pressure among patients with hypertension. A thorough search of 5 electronic databases, including PubMed Central, PubMed, EMBASE, Springer, and Google Scholar, was carried out. The study included eight articles. With doses exceeding 25 mg, plasma ET-1(endothelin-1) concentrations, which show ETB (Endothelin receptor type B) receptor antagonism, significantly rose. Aprocitentan significantly reduced systolic and diastolic blood pressure with both doses of 10mg and 25mg in patients with hypertension. Further research is warranted to evaluate the efficacy, safety, and long-term outcomes of aprocitentan and its synergistic effect with other antihypertensives.

Topics: Antihypertensive Agents; Blood Pressure; Endothelin Receptor Antagonists; Humans; Hypertension

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.

Topics: Antihypertensive Agents; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension

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.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase III as Topic; Endothelin Receptor Antagonists; Endothelins; Humans; Hypertension; Randomized Controlled Trials as Topic

Endothelin has emerged as a target for therapeutic intervention in systemic hypertension. As a vasoconstrictor, comitogenic agent, linking pulse pressure and vascular remodeling, and mediator of aldosterone and catecholamine release, endothelin is a key player in hypertension and end-organ damage. In 10%-20% of the hypertensive population, the high blood pressure is resistant to administration of antihypertensive drugs of different classes in combination. Because endothelin is not targeted by the current antihypertensive drugs, this may suggest that this resistance is due, in part at least, to a dependence on endothelin. This hypothesis is supported by the observation that this form of hypertension is often salt-sensitive, and that the endothelin system is stimulated by salt. In addition, the endothelin system is activated in subjects at risk of developing resistant hypertension, such as African Americans or patients with obesity or obstructive sleep apnea. Aprocitentan is an investigational, novel, potent, dual endothelin receptor antagonist (ERA) currently in phase 3 development for the treatment of difficult-to-treat hypertension. This article discusses the research that underpinned the discovery of this ERA and the choice of its first clinical indication for patients with forms of hypertension that cannot be well controlled with classical antihypertensive drugs.

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension; Pyrimidines; Receptor, Endothelin A; Sulfonamides

Treatment-resistant hypertension (TRH) is associated with increased cardiovascular risks and progression of chronic kidney disease. The pathophysiology of TRH is multifactorial, including overactivity of the renin-angiotensin-aldosterone system and sympathetic nervous system, endothelial dysfunction, and volume overload. Endothelin-1 is a vasoconstrictive peptide that causes neurohormonal and sympathetic activation, increased aldosterone synthesis and secretion, endothelial dysfunction, vascular hypertrophy and remodeling, and fibrosis. Endothelin-1 acts through 2 receptors, ETA and ETB. Activation of ETA receptors in vascular smooth muscle cells results in vasoconstriction, whereas ETB receptor activation results in vasoconstriction in the vascular smooth muscle cells and vasodilation through nitric oxide release in endothelial cells. Aprocitentan is novel, oral, dual endothelin-receptor antagonist that has demonstrated a more favorable tolerability and safety profile in early clinical trials compared with other endothelin-receptor antagonists studied. Phase 2 trial data support a significant reduction in blood pressure compared to placebo and similar blood pressure reduction compared to a moderately dosed angiotensin-converting enzyme inhibitor in patients with essential hypertension. An ongoing phase 3 randomized clinical trial is evaluating aprocitentan's efficacy and safety in patients with TRH receiving multiple antihypertensives. Additional research is needed to determine aprocitentan's role in therapy, but this agent may be a suitable treatment option for TRH.

Topics: Animals; Antihypertensive Agents; Drug Resistance; Endothelin Receptor Antagonists; Humans; Hypertension; Pyrimidines; Randomized Controlled Trials as Topic; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides

The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel-group Phase 3 study and its three-part design assesses the short-term and sustained long-term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single-tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single-blind placebo run-in period. The 4-week placebo run-in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4-week double-blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32-week single-blind part with aprocitentan 25 mg; and (3) a 12-week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.

Topics: Antihypertensive Agents; Blood Pressure; Double-Blind Method; Humans; Hypertension; Pyrimidines; Single-Blind Method; Sulfonamides

Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension.. PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174.. The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change 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, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference 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). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment.. In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40.. Idorsia Pharmaceuticals and Janssen Biotech.

Topics: Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Endothelin Receptor Antagonists; Humans; Hypertension; Treatment Outcome

Aprocitentan is an orally active, dual endothelin receptor antagonist that may offer a new therapeutic option for the treatment of difficult-to-control hypertension.. To investigate safety, tolerability, mass balance, absorption, distribution, metabolism, and excretion of aprocitentan.. In this single-center, open-label study, a single oral dose of 25 mg containing 3.7 MBq of. Aprocitentan was well tolerated and there were no clinically significant findings for any safety variable. The geometric mean cumulative recovery of radioactivity from urine and feces over 14 days was 77% of the administered radioactive dose, with 52.1% cumulative recovery from urine and 24.8% from feces. Concentrations of total radioactivity in whole blood were markedly lower compared to plasma. In plasma, 94.3% of total radioactivity was aprocitentan. In urine and feces, 5 and 2, respectively (in feces one being aprocitentan) main products were identified. Metabolism data of aprocitentan identified two main elimination pathways, glucosidation to M3 and hydrolysis to M1, representing approximately 25% and 32% of the radioactive dose, respectively.. Based on these metabolism data, aprocitentan can be concomitantly administered without dose adjustment with drugs that are inhibitors or inducers of any metabolizing enzyme, specifically cytochrome P450 enzymes.

Topics: Administration, Oral; Aged; Endothelin Receptor Antagonists; Humans; Hypertension; Male; Middle Aged; Pyrimidines; Sulfonamides

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycated Hemoglobin; Hematocrit; Humans; Hypertension; Male; Middle Aged; Pyrimidines; Serum Albumin; Sulfonamides; Treatment Outcome; Uric Acid

Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug-drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single-center, open-label, single-sequence study. Twenty healthy male subjects received a single dose of 10-mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration-time curve from time 0 to time t and area under the plasma concentration-time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25. Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport.

Topics: Administration, Oral; Adult; Anticholesteremic Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily G, Member 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Drug Tolerance; Endothelin Receptor Antagonists; Healthy Volunteers; Humans; Hypertension; Male; Middle Aged; Neoplasm Proteins; Pyrimidines; Rosuvastatin Calcium; Sulfonamides