FDA Approves Aprocitentan (Tryvio) for Treatment-Resistant Hypertension in Landmark Decision

The US Food and Drug Administration (FDA) today approved aprocitentan (Tryvio) as concomitant treatment for hypertension in adults whose blood pressure (BP) is not adequately controlled by other medications.¹

Aprocitentan is the first antihypertensive therapy to be approved in nearly 4 decades that delivers its BP-lowering effect through a novel mechanism of action, according to the news release from manufacturer Idorsia.¹

Hypertension remains above recommended targets for at least 10% of individuals who receive pharmacotherapy, according to the company announcement. "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," PRECISION investigator Michael A. Weber, MD, professor of medicine in the division of cardiovascular medicine at the State University of New York said in the statement.¹ "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.”¹

Aprocitentan is an endothelin receptor antagonist that inhibits binding of endothelin (ET)-1 to ETA and ETB receptors.¹ The effects of ET-1 in the body are similar to the pathophysiology of hypertension, including its role in aldosterone production. Aprocitentan is the first systemic antihypertensive agent to target the ET pathway, according to Idorisa.

The company said the unique therapy will be available in the US in the second half of 2024.¹

Phase 3 PRECISION trial²

The FDA approval was based on the phase 3a multinational, blinded, randomized, parallel-group PRECISION trial² that evaluated aprocitentan in adults with a seated systolic BP (SBP) of 140 mg HH or higher despite treatment with standard of care background therapy comprised of at least 3 antihypertensive drugs, including a diuretic. The 3-part study enrolled 730 participants who were randomly assigned after a 4-week run-in period to receive aprocitentan at either 12.5 mg, 25 mg, or placebo once daily during the initial 4-week double-blind treatment period (part 1). In the second part, all participants entered a single-blind 32-week treatment period during which they received aprocitentan 25 mg once daily. Following the 32 weeks, participants were randomly assigned again to receive either 25 mg aprocitentan or placebo, once daily, during a 12-week double-blind withdrawal period (part 3).²

The trial’s primary and key secondary outcomes of interest were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively.

PRECISION participants had a mean age of 62 years, and more than half (60%) were men.

Findings²

For the first part of the study, Weber and colleagues reported a least square mean (LSM) change in office SBP of –15.3 mm Hg for aprocitentan 12.5 mg, –15.2 mmHg for aprocitentan 25 mg, and –11.5 mm Hg for placebo. Differences vs placebo translated to –3.8 mm Hg (97.5% CI, –6.8 to –0.8; P = .004) and –3.7 mm Hg (–6.7 to –0.8; P =. 005), respectively.

Analysis of differences for 24-hour ambulatory systolic blood pressure found changes from baseline of –4.2 mmHg (95% CI –6.2 to –2.1) and –5.9 mmHg (–7.9 to –3.8) with aprocitentan 12.5 mg and 25 mg, respectively. Findings from analysis of part 3 demonstrated a significant increase in office SBP for placebo vs aprocitentan (5.8 mm Hg, 95% CI 3.7 to 7.9; P < .001) after the 4 weeks of withdrawal.

The most frequent adverse event reported in the safety analyses of the trial was mild-to-moderate edema or fluid retention, observed among 9%, 18%, and 2% of participants receiving aprocitentan 12.5 mg, 25 mg, and placebo, respectively, during part 1 of the trial. Fluid retention was cited as contributing to study discontinuation by 7 participants receiving the study drug.

Approximately 54% of patients had a medical history of diabetes mellitus, 31% ischemic heart disease, and 20% congestive heart failure. At baseline, 63% of patients reported taking four or more antihypertensive medications.

“The approval of TRYVIO in the US marks another major milestone for Idorsia. With TRYVIO, we've got an innovative medicine with a unique mode of action in systemic hypertension," said Tosh Butt, president and general manager of Idorsia US.1 "The team at Idorsia has a deep understanding and rich history in the field of endothelin receptor antagonism. We are eager to provide physicians and patients with a novel medicine working in a new pathway in uncontrolled hypertension that can provide additional blood pressure control."

References:

1. US FDA approves Idorsia’s once-daily TRYVIO (aprocitentan) – the first and only endothelin receptor antagonist for the treatment of high blood pressure not adequately controlled in combination with other antihypertensives. News release. Idorsia. March 20, 2024. Accessed March 21, 2024. https://www.idorsia.com/media/news/news-archive/media-release-details?id=3195250.

2. Schlaich MP, Bellet M, Weber MA, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. The Lancet. 2022;400(10367):1927-1937. doi:10.1016/S0140-6736(22)02034-7