FDA approves once-daily oral antihypertensive Aprocitentan for uncontrolled BP

The announcement by Idorsia Pharmaceuticals makes aprocitentan the first endothelin receptor antagonist for treating high blood pressure (BP).

Lowering BP reduces the risk of fatal and non-fatal cardiovascular (CV) events, primarily myocardial infarctions and strokes. The recommended dosage of TRYVIO is 12.5 mg orally once daily, with or without food.

It is believed that some patients may respond better to the drug's novel mechanism as aprocitentan is a dual endothelin receptor antagonist that works differently than conventional diuretics, calcium channel blockers, renin-angiotensin-aldosterone system antagonists, and beta-blockers used for BP lowering.

Aprocitentan is an endothelin receptor antagonist that inhibits the binding of endothelin (ET)-1 to ETA and ETB receptors. The effects of ET-1 have similarities with the pathophysiology of hypertension, and ET-1 is a major driver of aldosterone production.

"Until the approval of Aprocitentan, no systemic antihypertensive medications targeted the ET pathway, stated the company's press release.

The approval was based on Aprocitentan's evaluation as a monotherapy in a Phase 2 study in hypertension patients and as an add-on therapy in a Phase 3 study called PRECISION in patients with confirmed resistant hypertension. In the PRECISION trial, aprocitentan was well tolerated and superior to placebo in BP lowering at week 4, with a sustained effect at week 40.

"Early on, we realized that endothelin was involved in patients with hypertension, especially in those remaining uncontrolled despite other anti-hypertensive drugs. Since the endothelin pathway was not yet tackled in these patients, we selected aprocitentan, an endothelin receptor antagonist with the ideal properties for use in this condition," Martine Clozel, MD and Chief Scientific Officer of Idorsia commented.

"We were delighted when we saw the efficacy and safety data with TRYVIO, even on top of multiple antihypertensives, in patients whose hypertension is not adequately controlled. Recognizing its potential with today’s FDA approval is great news for prescribers and patients.”

“Today, we cannot reduce blood pressure below recommended levels in at least 10% of the hypertensive patients we treat. As well, it is often patients at high risk of adverse cardiovascular outcomes and typically with comorbidities who pose this challenge. We have had to wait for over 30 years to see the approval of an oral anti-hypertensive agent that works on a new therapeutic pathway, so TRYVIO provides transformational progress in the field of systemic hypertension, said Michael A. Weber, MD, Professor of Medicine, Division of Cardiovascular Medicine State University of New York, and an investigator in the PRECISION study.

"It is taken as a single daily oral dose that works in combination with whatever other drugs are being prescribed and without drug-drug interactions in patients with the burden of uncontrolled hypertension. TRYVIO is easy for physicians to prescribe and easy for patients to use."

In the PRECISION study, both 12.5 mg and 25 mg doses of aprocitentan lowered systolic blood pressure in patients starting at a systolic BP of 140 mm Hg or higher by approximately 4 mm Hg over placebo at week 4, with a sustained effect at week 40.

Trial participants were then given the 25 mg dose for eight months and re-randomized in the third phase of the study to this higher dose of aprocitentan or placebo. Aprocitentan users withdrawn from therapy and placed on a placebo for four weeks saw systolic BP rebound.