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Aprocitentan Reduces BP in Black Adults with Resistant Hypertension and Lowers Proteinuria
Aprocitentan, when added to background therapy of at least 3 antihypertensive agents, led to clinically meaningful and sustained BP reduction in this preplanned subanalysis.
Aprocitentan (Tryvio; Idorsia) demonstrated clinically meaningful and sustained blood pressure (BP) reductions in Black adults with confirmed resistant hypertension when added to a background regimen of at least 3 antihypertensive agents. In addition to lowering BP, the dual endothelin receptor antagonist significantly reduced proteinuria in study participants with elevated urinary albumin-to-creatinine ratio (UACR) at baseline and was safe and well tolerated, including in those with chronic kidney disease (CKD).
The data are the result of a preplanned analysis of the phase 3 PRECISION study, which Idorsia announced today has been published in the journal Hypertension.
In the PRECISION phase 3 clinical trial, (NCT03541174), participants were randomly assigned to receive either aprocitentan 12.5 mg, 25 mg, or placebo once daily during a 4-week double-blind period (part 1), followed by a 32-week single-arm period (part 2) during which all patients received aprocitentan 25 mg. At baseline, included participants had a seated systolic BP (SBP) of 140 mm Hg or greater despite treatment with at least 3 antihypertensive medications from different classes within the year prior to enrollment. More than half of the participants were taking 4 antihypertensive agents, according to the study
The preplanned analysis included 82 PRECISION participants who self-identified as Black. In part 1, the least-squares mean reduction in office SBP at trough level was –11.3 mm Hg (12.5 mg), –11.19 mm Hg (25 mg), and –12.0 mm Hg (placebo). However, 24-hour ambulatory systolic BP monitoring demonstrated dose-dependent decreases at week 4 in aprocitentan-treated participants of –4.0 mm Hg (12.5 mg), –8.6 mm Hg (25 mg), and –0.7 mm Hg (placebo). The BP lowering effect was observed during both day and nighttime monitoring, the authors said. In part 2, the mean systolic BP reduction from baseline continued, reaching 16.4 mm Hg at week 36.
Notably, aprocitentan reduced UACR by approximately 38% (12.5 mg) and 65% (25 mg) at week 4 in patients with micro- or macroalbuminuria, compared to a 13% reduction in the placebo group, reductions in proteinuria that were sustained throughout part 2 of the study.
Safety outcomes were favorable and aprocitentan was well tolerated in Black patients, including those with CKD. Six patients discontinued treatment due to adverse events (AEs), with edema and fluid retention being the most commonly reported AEs during early treatment. No new safety signals emerged during long-term exposure, according to the study
These findings are of particular relevance given the high burden of resistant hypertension among Black individuals, the authors wrote, who experience disproportionately increased cardiovascular risk and lower rates of BP control. The endothelin (ET) system is believed to play a key role in the pathogenesis of resistant hypertension, particularly in populations prone to salt-sensitive and low-renin hypertension, as Black individuals tend to be.
Existing therapies that do not target the endothelin system have demonstrated limited efficacy in this population, according to Keith C. Ferdinand, MD, the Gerald S. Berenson Chair in Preventative Cardiology and professor of medicine at Tulane University School of Medicine. "Now, for the first time, we have an approved treatment targeting the endothelin system that may help fulfill an unmet need in Black patients with resistant hypertension," Ferdinand, coauthor of the analysis, said in an Idorsia press release.
The findings are especially significant in the Black population studied in this analysis. "Black adults with hypertension less often achieve guideline-recommended BP goals, leading to an estimated 400,000 cardiovascular events over 10 years that are preventable if control is achieved. In PRECISION, the effect of aprocitentan for these patients was striking," lead author John M. Flack, MD, MPH, chair of medicine at Southern Illinois University School of Medicine, said in the press statement.
In a separate news release on April 9, Idorsia announced an update to the aprocitentan label, removing the previous Risk Evaluation and Mitigation Strategy (REMS) requirement. The agency determined that the benefits of aprocitentan outweigh the risks, including concerns about embryo-fetal toxicity.3
