JERAYGO (aprocitentan) recommended for approval in Europe for the treatment of resistant hypertension - Seite 2

The positive CHMP opinion is supported by a comprehensive clinical and non-clinical development program. Aprocitentan was evaluated as a monotherapy in a Phase 2 study in patients with hypertension,¹¹ and as an add-on therapy in a Phase 3 study called PRECISION in patients with confirmed resistant hypertension.¹² In the Phase 3 registration study, PRECISION, aprocitentan showed statistically significant and clinically meaningful reduction in blood pressure (BP) which was maintained for up to 48 weeks when added to a combination of background antihypertensive therapies in patients with resistant hypertension. In PRECISION, aprocitentan was generally well tolerated with no major safety concerns. The most frequent adverse event with aprocitentan was mild-to-moderate edema/fluid retention.

The team at Idorsia has been working on the research and development of endothelin receptor antagonists for more than 30 years, successfully bringing three other molecules from this class to patients in different indications. Endothelin (ET)-1, via its receptors (ET_A and ET_B), mediates a variety of effects such as vasoconstriction, fibrosis, cell proliferation, inflammation, aldosterone production⁷ and is upregulated in hypertension. Aprocitentan is a dual ERA that inhibits the binding of ET-1 to ET_A and ET_B receptors and hence the effects mediated by these receptors.⁵ The effects of ET-1 bear many similarities with the pathophysiology of hypertension,^6,8 and the resistance to other antihypertensive drugs in some patients (often with risk factors such as obesity, sleep apnea, older age, kidney failure, type 2 diabetes, and African Americans), can be explained by an endothelin-dependent hypertension⁸. This is now confirmed by the efficacy of aprocitentan in the PRECISION study.

About the Phase 3 PRECISION study (NCT03541174)¹²
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.