Aprocitentan gets FDA nod for uncontrolled HTN

The US Food and Drug Administration (FDA) has approved aprocitentan for the treatment of uncontrolled hypertension (HTN) in adults.

The drug potently inhibits the binding of ET-1 to ET_A and ET_B receptors. It has a low potential for drug-drug interaction, with a mechanism of action that is intended to address the pathophysiology of difficult-to-control HTN.

Aprocitentan is indicated for use in combination with other antihypertensive agents for treatment-resistant HTN. It is the only endothelin receptor antagonist (ERA) approved for HTN so far.

The recommended dose is 12.5 mg once daily, orally, with or without food.

The approval is based on the phase III PRECISION trial results conducted in Europe, North America, Asia, and Australia, which demonstrated the efficacy and safety of aprocitentan. The study involved 730 adults who had systolic blood pressure (BP) of ≥140 mmHg despite treatment with at least three antihypertensive medications, including a diuretic. [Lancet 2022;400:1927-1937]

After 4 weeks of treatment, the least square mean (SE) change in office systolic BP was –15.3 (SE 0.9) mm Hg for aprocitentan 12.5 mg, –15.2 (0.9) mm Hg for aprocitentan 25 mg, and –11.5 (0.9) mm Hg for placebo, for a difference of –3.8 (1.3) mm Hg (97.5 percent confidence interval [CI] –6-8 to –0.8, p=0.0042) and –3.7 (1.3) mm Hg (97.5 percent CI, –6.7 to –0.8; p=0.0046), respectively.

The difference in 24-hr ambulatory systolic BP after adjusting for the change in placebo was –4.2 mm Hg (95 percent CI, –6.2 to –2.1) and –5.9 mm Hg (95 percent CI, –7.9 to –3.8), respectively. These BP reductions were sustained out to 40 weeks and were consistent among subgroups defined by age, sex, race, BMI, baseline urine albumin-to-creatinine ratio, estimated glomerular filtration rate, history of diabetes, and between BP measurement methods.

Aprocitentan was well tolerated. Mild-to-moderate oedema was the most common side effect reported during the trial, occurring in 9.1 percent and 18.4 percent of the patients treated with aprocitentan 12.5 and 25 mg, respectively.

Long wait finally over

Uncontrolled hypertension is a common cause of cardiovascular disease globally. It is the deadliest and costliest chronic disease in the US.

Study investigator Dr Michael Weber from the State University of New York in New York, US, said they had to wait for over 30 years for the approval of an oral anti-hypertensive agent that works on a new therapeutic pathway.

“Aprocitentan provides transformational progress in the field of systemic hypertension,” he said. “It is to be taken as a single oral dose daily and works in combination with other BP-lowering drugs, without any drug-drug interaction, in patients with the burden of uncontrolled hypertension. It is easy for physicians to prescribe and for patients to use.”

Aprocitentan will only be made available through a Risk Evaluation and Mitigation Strategy (REMS) programme, owing to the risk of embryo-foetal toxicity when used by pregnant women.