Reference: Lancet. 2022 Dec 3;400(10367):1927-1937
Practice Point: There’s a new kid in town for resistant hypertension. You can expect the newly FDA-approved aprocitentan, dosed at 12.5 mg daily, to lower SBP by about 5 mmHg.
EBM Pearl: Phase-three trials required for FDA approval are an essential part of evidence-based medicine and provide data on efficacy (and/or effectiveness), safety, and dosing.
This is a long one, so TL;DR—aprocitentan is a newly FDA-approved drug that reduces mean SBP by about 5 points in patients with uncontrolled blood pressure despite being on at least three antihypertensives.
Endothelin, an enzyme produced by vascular endothelial cells, comes in three isoforms, conveniently labeled 1, 2, and 3. It activates three vascular receptors (less conveniently called A, B1, and B2) to cause vasoconstriction. Drugs blocking this interaction have been studied since the 1990s and have demonstrated effectiveness for pulmonary hypertension and promise for renal disease. In March 2024, the FDA approved an endothelin antagonist that blocks A and B receptors, aprocitentan (Tryvio), as adjunctive management for resistant hypertension. Resistant hypertension, defined as high blood pressure uncontrolled by ≥ 3 agents, occurs in anywhere from 5-30% of people requiring medications. FDA approval of a drug therapy for this common problem is a great metaphorical foot-in-the-door for the manufacturers of this new medication.
We thought it might be worthwhile to review the FDA approval process, particularly for our non-US-based readers. FDA approval is an example of the EBM process, and as good EBM nerds, we try to understand how medicines come to be available at the point of care. The aprocitentan story started in December 2022 when the Lancet published results of this phase 3 trial which used the drug for patients with resistant hypertension. At that point, aprocitentan was still an investigational new drug (IND) and had already undergone phase 1 (testing of a small number of subjects for safety) and phase 2 testing (again, basic testing of only a few subjects to get a general idea of efficacy). This phase 3 trial was cleverly designed to hone in on when and how to use this medicine and to provide a little more grist for the future research mill.
Seven hundred and four adults with resistant hypertension were first placed on a regimen of amlodipine, valsartan, and hydrochlorothiazide (except for those on a beta blocker, who stayed on their beta-blocker) for a 4 to 8 week run-in period. Then, patients were randomized to one of 3 groups: placebo, aprocitentan 12.5 mg daily, or aprocitentan 25 mg daily for 4 weeks. Systolic blood pressure (SBP) was measured at this time point as part of the primary outcome. Following this, all patients received aprocitentan 25 mg daily during a 32-week maintenance phase. Finally, after a second randomization, patients received either placebo or aprocitentan 25 mg daily for an additional 4 weeks and SBP was measured again at this second time point.
At the first 4-week mark, SBP was 3.8 mmHg and 3.7 mmHg lower for patients who received the study drug at 12.5 mg and 25 mg doses, respectively, compared to placebo. Conversely, after the 32-week maintenance phase, withdrawing the drug resulted in a 5.7 mm Hg higher (95% CI 3.7 to 7.9) SBP for those assigned to placebo compared to those continued on the 25 mg aprocitentan.
In addition to these data on efficacy, data on adverse effects and dropout rates collected during the maintenance phase of the trial provided long-term safety information and generated data which helped to move this drug from the IND status to “NDA” (new drug approval) status over the last year, leading up to an approval letter last month. Part of the NDA process (which, in this case, took 14 months) was reviewing this and prior studies. Information about manufacturing, labeling, and marketing were all reviewed before aprocitentan was given an approval letter. The FDA only approved the 12.5 mg dose, given the 25 mg dose didn’t result in substantial benefits over the 12.5 mg dose. Patients with proteinuria and kidney disease were incidentally noted to have a 30% sustained reduction in proteinuria.
So what’s next for aprocitentan now that it has FDA approval? Clearly, we can use this for treatment of resistant hypertension. The FDA will continue to monitor the drug for adverse effects, and there will be plenty of opportunities for new markets (non-resistant hypertension, people with significant kidney disease?) as well as pitfalls (edema was the most commonly noted side effect—will people be more likely to have heart failure?). And of course some clinicians will inevitably prescribe the drug off-label for non-resistant hypertension. FDA approval is a milestone for any developing drug, but is far from the whole story.
For more information, see the topic Resistant Hypertension in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.