FDA Approves Aprocitentan (Tryvio) for Treatment-Resistant Hypertension

Credit: US Food and Drug Administration

The US Food and Drug Administration has approved aprocitentan (Tryvio) for treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs.

Announced by Idorsia Ltd. on March 20, 2024, the FDA’s decision was based on data from the phase 3 PRECISION trial indicating the agent could prove useful in the management of resistant hypertension, but pointed to worrisome rates of edema and fluid retention. The decision comes more than a year after initial filing of the New Drug Application in December 2022 and just more than 6 months after Idorsia reacquired the world-wide rights to the oral, dual endothelin receptor antagonist back from with Johnson & Johnson's Janssen Biotech unit in September 2023.^1,2,3

"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 of the State University of New York.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.”

A multicenter, blinded, randomized, parallel-group trial, PRECISION enrolled patients with a seated systolic blood pressure of 140 mmHg or higher despite taking standardized background therapy consisting of at least 3 antihypertensive drugs, including a diuretic. From centers across Europe, North America, Asia, and Australia, investigators randomized 730 individuals in the trial, which leveraged a 3-part design.⁴

Part 1 was a 4-week double-blind, randomized, placebo-controlled treatment period. During this period, participants were randomized to aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio. Part 2 was a 32-week single-blind part, with all patients receiving aprocitentan 25 mg. Part 3 was a 12-week double-blind, randomized, and placebo-controlled withdrawal period, where patients were rerandomized in a 1:1 ratio to aprocitentan 25 mg or placebo.⁴

Of the 730 who underwent randomization, 704 completed part 1 of the study, 613 completed part 2, and 577 completed part 3. 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.

Results from part 1 of the trial pointed to 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.

Results, which were published in The Lancet in November 2022, also highlighted respective differences for 24-hour ambulatory systolic blood pressure, which were –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. Analysis of results following completion of part 3 revealed 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.

Safety analyses of the trial suggested the most frequent adverse event was mild-to-moderate edema or fluid retention. Overall, fluid retention was observed among 9%, 18%, and 2% for patients receiving aprocitentan 12.5 mg, 25 mg, and placebo, respectively, during part 1 of the trial. Results indicated fluid retention contributed to discontinuation of 7 patients receiving aprocitentan.

Beyond its clinical development program, aprocitentan has also made headlines related to the ownership of its development and marketing rights in the last decade. Idorsia entered an agreement for Johnson & Johnson's Janssen Biotech unit to develop and market aprocitentan and any derivative compounds in December 2017 following the results of positive phase 2 data in May 2017.

This agreement would last nearly 6 years before Johnson & Johnson's Janssen Biotech unit would be returning its rights to the agent to Idorsia, with Idorsia agreeing to pay Janssen a conditional consideration up to a total cap of 306 million Swiss francs—approximately $344 million USD. The same day Idorsia announced it would be reacquiring the global rights to aprocitentan, the company also disclosed the FDA review process would be extended up to 3 months as the company needed to provide additional Risk Evaluation and Mitigation Strategy (REMS) materials to support a streamlined REMS for aprocitentan.^3,4

According to their release announcing the approval, the recommended dosage of aprocitentan is 12.5 mg and Idorsia expects aprocitentan to be available during the second half of 2024.¹

“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. ^{Idorsia Ltd. Idorsia. March 20, 2024. Accessed March 20, 2024. https://www.idorsia.com/media/news/news-archive/media-release-details?id=3195250.}
2. ^{Idorsia. Idorsia submits a New Drug Application to the US FDA for aprocitentan for the treatment of patients with difficult-to-control hypertension. Idorsia. December 20, 2022. Accessed March 19, 2024. https://www.idorsia.com/investors/news-and-events/media-releases/media-release-details?id=2898685.}
3. ^{Idorsia. Idorsia reacquires the world-wide rights to aprocitentan. Idorsia. September 6, 2023. Accessed March 19, 2024. https://www.idorsia.com/investors/news-and-events/media-releases/media-release-details?id=3073952.}
4. ^{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}
5. ^{Idorsia. Idorsia announces collaboration with Janssen Biotech on aprocitentan (ACT-132577). Idorsia. December 4, 2017. Accessed March 19, 2024. https://www.idorsia.com/media/news-details?newsId=1381336.}