Aprocitentan Significantly Lowers Blood Pressure in Patients with Difficult-to-Control Hypertension

Patients with difficult-to-control hypertension have greater risk of heart attack, stroke, end-stage renal disease, and heart failure.

Aprocitentan was found to significantly lower and maintain blood pressure (BP) for up to 48 weeks when added to standardized combination background antihypertensive therapy in patients with difficult-to-control hypertension (HTN), or resistant hypertension. These data for the investigational, novel dual endothelin receptor antagonist (ERA) were from the phase 3 PRECISION study published in The Lancet.

Hypertension is among the primary causes of cardiovascular disease. Approximately 10% of an estimated 1.3 billion patients with the condition worldwide have difficult-to-control HTN, even when receiving at least 3 antihypertensive medications. Aprocitentan has been found to inhibit the binding of ET-1 to ETA and ETB receptors. Further, it has a low potential for drug-drug interaction and a mechanism of action that is intended to address the pathophysiology of difficult-to-control HTN, according to the study authors.

Previous research indicates that difficult-to-control HTN may be due to a lack of treatments that target all of the underlying mechanisms of HTN, specifically the endothelin (ET) pathway, which is an important role in the development of the condition. Patients with difficult-to-control HTN have greater risk of heart attack, stroke, end-stage renal disease (ESRD), and heart failure.

“The challenge to achieve better BP control in patients with resistant hypertension is at least in part due to the fact that currently available treatment options leave relevant pathophysiologic mechanisms unopposed,” said study investigator Markus Schlaich, MD, FAHA, FESC, ISHF, The University of Western Australia/Royal Perth Hospital, in a press release. “The results of PRECISION demonstrate aprocitentan is a novel and generally well-tolerated potential treatment strategy for resistant hypertension with clinically meaningful and sustained blood pressure lowering effect.”

PRECISION evaluated the short-term and sustained effects of aprocitentan on a group of 730 hypertensive patients with difficult-to-control HTN enrolled in the 3-part study.

In part 1 of the study for the double-blind portion, from baseline through week 4, patients were randomized to receive aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio. For the single-blind part 2 of the study, from weeks 4-36, patients who continued to part 2 received 25 mg aprocitentan. For part 3, the double-blind withdrawal period, from weeks 36-48, patients were re-randomized to receive either aprocitentan 25 mg or placebo in a 1:1 ratio.

The study met the primary efficacy endpoint of change in sitting systolic blood pressure (SBP) as measured by unattended automated office BP, from baseline to week 4. After 4 weeks, aprocitentan was found to significantly lower SBP compared with placebo.

The study also met the secondary efficacy endpoint of a sustained SBP reduction in patients administered aprocitentan compared to placebo between week 36 and week 40. At week 40, SBP increased with placebo compared to aprocitentan 25 mg for a significant difference of +5.8 mmHg.

The treatment effect of aprocitentan was found to be consistent across various prespecified subgroups, including sex, age, body mass index, race, and geographic area. Treatment-emergent adverse events (AEs) during the 4-week double-blind study period were reported in 28% and 37% of the patients treated with 12.5 and 25 mg aprocitentan, respectively, compared with 19% in the placebo group.

The most frequent AE with aprocitentan was mild-to-moderate fluid retention leading to discontinuation in 7 patients during the study. The fluid retention was reported more commonly with aprocitentan than with placebo in a dose-dependent fashion.

“Identifying innovative approaches and novel therapies to help address some of the greatest unmet needs for patients around the world is the cornerstone of our research and development efforts. This is especially true for patients with difficult-to-control hypertension where it is critical that novel pathways are discovered to address a decades old need,” said James List, MD, PhD, global therapeutic area head, Cardiovascular, Metabolism, Retina and Pulmonary Hypertension, Janssen Research & Development, LLC, in the release. “The potential addition of aprocitentan to the armamentarium holds promise for these patients.”

REFERENCE

Late-Breaking Data from Pivotal Phase 3 PRECISION Study Demonstrates Significant and Sustained Effect of Aprocitentan on Lowering Blood Pressure for Patients with Difficult-to-Control Hypertension. Janssen. November 7, 2022. Accessed November 9, 2022.

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