New data published in the April edition of Hypertension demonstrates that aprocitentan significantly reduces blood pressure and proteinuria in Black patients with resistant hypertension, addressing a critical unmet need in a population disproportionately affected by cardiovascular complications.
The findings come from a preplanned analysis of the Phase 3 PRECISION study, focusing specifically on the 82 Black participants with confirmed resistant hypertension. Aprocitentan, developed by Idorsia Ltd, is a once-daily, orally active, dual endothelin receptor antagonist that represents the first new antihypertensive medication approved in over two decades.
Significant Clinical Benefits in a High-Risk Population
When added to a background regimen of at least three antihypertensive drugs (with more than 50% of patients on four medications), aprocitentan demonstrated dose-dependent decreases in 24-hour ambulatory systolic blood pressure at week 4: -4.0 mm Hg (12.5 mg dose), -8.6 mm Hg (25 mg dose), compared to just -0.7 mm Hg with placebo. The blood pressure-lowering effect continued throughout the 32-week single-arm period, reaching a mean systolic reduction of 16.4 mm Hg at week 36.
Perhaps most notably, aprocitentan reduced urinary albumin-to-creatinine ratio (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. These reductions in proteinuria were sustained throughout the study's duration.
Prof. John M. Flack, MD, MPH, lead author of the publication and Sergio Rabinovich Endowed Chair of Internal Medicine at Southern Illinois University School of Medicine, emphasized the significance of these findings: "The salt-sensitive, low-renin, hypertension often seen in Black patients makes their hypertension difficult to control and increases their cardiovascular risk. In fact, Black adults with hypertension less often achieve the guideline recommended BP goals, leading to an estimated 400,000 strokes, heart attacks and other cardiovascular events that could be prevented over 10 years if blood pressure control could be achieved."
Targeting the Endothelin Pathway
The endothelin (ET) pathway has been implicated in the pathogenesis of hypertension and is particularly activated in patients prone to developing resistant hypertension, such as Black patients. Existing therapies that do not target this pathway have shown limited efficacy in this population.
Prof. Keith C. Ferdinand, MD, from Tulane University School of Medicine and co-author of the publication, noted: "Black individuals frequently present with resistant hypertension and disproportionately increased cardiovascular risk. This is possibly related to the activated endothelin system seen in patients prone to developing resistant hypertension and this may explain why existing therapies that do not target the endothelin system have not shown optimal improvement for Black patients."
Safety Profile and Tolerability
The safety analysis showed that aprocitentan was well tolerated in Black patients, including those with chronic kidney disease. The most commonly reported adverse events during early treatment were edema and fluid retention, with six patients discontinuing treatment due to adverse events. No new safety signals emerged during long-term exposure.
In a significant regulatory development, Idorsia announced on April 9 that the FDA has removed the previous Risk Evaluation and Mitigation Strategy (REMS) requirement from aprocitentan's label, determining that the benefits outweigh the risks, including concerns about embryo-fetal toxicity.
A New Era for Resistant Hypertension Treatment
An accompanying editorial in Hypertension titled "Endothelin Antagonism: A New Era for Resistant Hypertension?" recognizes that aprocitentan represents the first new antihypertensive approved in over two decades and the first via a new pathway in almost four decades.
The editorial authors from the University of Edinburgh conclude: "Given the broad beneficial effects ET receptor antagonism has on a range of cardiovascular risk factors, it may not be long before clinicians reach for these drugs above other, more established antihypertensive medications."
Hypertension affects an estimated 1.3 billion people globally, with approximately 10% having uncontrolled blood pressure despite receiving at least three antihypertensive medications from different classes at optimal doses. Uncontrolled hypertension significantly increases the risk of heart attack, stroke, end-stage renal disease, and death.
Aprocitentan is approved as TRYVIO™ in the US for the treatment of systemic hypertension in combination with other antihypertensives and has been commercially available since October 2024. In the European Union and the UK, it is approved as JERAYGO™ for the treatment of resistant hypertension in combination with other antihypertensives, with marketing authorization applications currently under review in Canada and Switzerland.
The publication of these results marks an important milestone in addressing the disproportionate burden of resistant hypertension in Black patients and offers a promising new treatment option targeting a previously unexploited pathway in hypertension management.
