What to Know about the Aprocitentan Approval for Resistant Hypertension, with Michael Weber, MD

For the first time in more than 3 decades, hypertension specialists in the US have welcomed a game-changing oral agent with a new mechanism of action in aprocitentan (Tryvio).

Announced on March 20, 2024, the FDA approval of aprocitentan for treatment of hypertension in those without adequate control in combination with other antihypertensives, the approval made aprocitentan, a dual endothelin receptor, the first and only endothelin receptor to receive such an indication. However, with a new mechanism of action, and an accompanying REMS program, patient and provider education stand as significant hurdles to optimal uptake and benefit.

“Today, we are not able to 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,” explained Michael Weber, MD, professor of Medicine in the Division of Cardiovascular Medicine of the State University of New York. “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.”

Approval of aprocitentan is based on the phase 3 multicenter, blinded, randomized, parallel-group PRECISION trial. A 3-part trial, the study enrolled and randomized 730 patients with treatment-resistant hypertension, which was defined as being on at least 3 antihypertensive drugs at baseline.

• Part 1: 4-week double-blind, randomized, placebo-controlled treatment period, with patients randomized 1:1:1 to aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo
• Part 2: 32-week single-blind part, with all patients receiving aprocitentan 25 mg
• Part 3: 12-week double-blind, randomized, and placebo-controlled withdrawal period, with patients rerandomized to aprocitentan 25 mg or placebo.

Upon analysis, results from part 1 of the trial provided evidence of a least square mean change in office systolic blood pressure of –15.3 (Standard Error [SE], 0.9) mmHg for aprocitentan 12.5 mg, –15.2 (SE, 0.9) mmHg for aprocitentan 25 mg, and –11.5 (SE, 0.9) mmHg for placebo, for differences versus placebo of –3.8 (SE, 1.3) mmHg (97.5% CI, –6.8 to –0.8; P=.0042) and –3.7 (SE, 1.3) mmHg (–6.7 to –0.8; P=.0046), respectively. Further analysis pointed to differences for 24-hour ambulatory systolic blood pressure 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.

Additionally, results from part 3 of the trial indicated office systolic blood pressure significantly increased with placebo relative to aprocitentan (5.8 mmHg, 95% CI 3.7 to 7.9; P< .0001) after the 4 weeks of withdrawal. IN safety analyses, the most frequent adverse event was mild-to-moderate edema or fluid retention, which was observed among 9%, 18%, and 2% of patients receiving aprocitentan 12.5 mg, 25 mg, and placebo, respectively, during part 1 of the trial.

The FDA’s decision to approve aprocitentan represents the culmination of a winding clinical development journey for the agent. The approval comes more than a year after the initial filing of the New Drug Application in December 2022. However, the approval also comes more than half a decade after Johnson & Johnson's Janssen Biotech unit entered a deal with Idorsia to develop and market aprocitentan in May 2017. This relationship would conclude in September 2023 when Idorsia reacquired the worldwide rights to the oral, dual endothelin receptor antagonist back from with Johnson & Johnson's Janssen Biotech unit.

Availability of aprocitentan comes through a REMS program called TRYVIO REMS, citing an increased risk of embryo-fetal toxicity with use. As such, use is not intended for people who are pregnant or currently trying to become pregnant.

To learn more about the significance of the approval, applying the trial criteria and results to real-world populations, and communicating with patients about the new mechanism of action and REMS program, check out our video interview with Weber following the approval.

Relevant disclosures for Weber include Medtronic, ReCor, Ablative Solutions, Verve, Idorsia, Roche, Auxilius, and Abbvie.

References:

1. Campbell P. FDA approves Aprocitentan (Tryvio) for treatment-resistant hypertension. HCP Live. March 20, 2024. Accessed March 25, 2024. https://www.hcplive.com/view/fda-approves-aprocitentan-tryvio-for-treatment-resistant-hypertension.
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 [published correction appears in Lancet. 2023 Jan 28;401(10373):268]. Lancet. 2022;400(10367):1927-1937. doi:10.1016/S0140-6736(22)02034-7