Aprocitentan

Aprocitentan is a once-daily, orally active, dual endothelin receptor antagonist, which potently inhibits the binding of ET-1 to ET_A and ET_B receptors. Aprocitentan has a half-life of approximately 41 hours and a low drug–drug interaction potential, which is particularly important for patients who are typically being treated for several other problems.

In a Phase 2 dose-response study, patients with hypertension received monotherapy with four doses of aprocitentan or placebo (lisinopril was used as a positive control) for eight weeks, using a randomized, double-blind study design. There was a clear dose response on both diastolic and systolic blood pressure, with clinically relevant effects observed at 10 mg, 25 mg, and 50 mg, with no additional effect at 50 mg. The effect of aprocitentan was shown to cover a 24-hour period. The overall incidence of adverse events observed in the aprocitentan groups (ranging from 22.0% to 40.2%) was similar to that seen in the placebo group (36.6%). Overall, the most common events were hypertension, headache, and nasopharyngitis.

The data from the preclinical and clinical program gave Idorsia the confidence to embark on a large registration study, PRECISION, in patients with resistant hypertension.

PRECISION was a multicenter, blinded, randomized, parallel-group, Phase 3 study, which was performed in hospitals or research centers in Europe, North America, Asia, and Australia. Patients were eligible for randomization if their sitting systolic blood pressure (SBP) was 140 mm Hg or higher despite taking standardized 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, randomized, and placebo-controlled part, in which 730 patients were randomized to aprocitentan 12.5 mg (n=243), aprocitentan 25 mg (n=243), or placebo (n=244) in a 1:1:1 ratio; Part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg (n=704); and Part 3 was a 12-week double-blind, randomized, and placebo-controlled withdrawal part, in which patients were re-randomized to aprocitentan 25 mg (n=307) or placebo (n=307) in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office SBP from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes.

At baseline, 69.2% of patients were obese or severely obese, 54.1% had diabetes, 22.2% had stage 3-4 chronic kidney disease and 19.6% had congestive heart failure. At screening, 63% of all patients who were randomly assigned were prescribed four or more antihypertensive drugs.

Detailed results were published by Schlaich MP, et al. in The Lancet and presented as a Late-Breaking Science presentation during the American Heart Association (AHA) Scientific Sessions in November 2022.

• Schlaich MP, et al. Lancet. 2022

On April 25, 2024, the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), adopted a positive opinion for the use of JERAYGO™ (aprocitentan) for the treatment of resistant hypertension in adult patients in combination with at least three antihypertensive medicinal products. The CHMP has adopted a positive opinion for the use of 12.5 mg JERAYGO orally once daily. The dose can be increased to 25 mg once daily for patients tolerating the 12.5 mg dose and in need of tighter blood pressure control.

Detailed recommendations for the use of JERAYGO will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorization has been granted by the European Commission, expected in approximately two months.

European Commission marketing authorization through the centralized procedure is valid in all European Union Member States, as well as the European Economic Area countries Iceland, Liechtenstein and Norway, and Northern Ireland under the Northern Ireland Protocol.