CHICAGO — Two new drugs showed promise for lowering blood pressure (BP) in people with treatment-resistant hypertension, according to research presented at the annual meeting of the American Heart Association (AHA).
The first, the dual endothelin receptor antagonist aprocitentan, works by targeting the endothelin pathway involved in hypertension. It reduced systolic BP after 4 weeks in the placebo-controlled, phase III PRECISION trial of people with resistant hypertension unresponsive to standard medications, reported Markus Schlaich, MD, of the University of Western Australia, Perth.
The second drug, baxdrostat, conferred reductions in BP relative to placebo after 12 weeks of treatment in the BrigHTN study. Baxdrostat reduces aldosterone production by blocking aldosterone synthase, and its Phase III program will begin in 2023, according to Mason Freeman, MD, of CinCor Pharma in Waltham, Massachusetts.
“These agents are exciting not because they reduce pressure, but because their new mechanisms may be better tolerated in many cases,” said Suzanne Oparil, MD, of the University of Alabama at Birmingham, the panelist for the session. OH
Indeed, the main treatment-emergent adverse events associated with aprocitentan were edema and fluid retention at 30 days. These events were managed with the addition or increase of diuretic therapy, Schlaich said, indicating that appropriate diuretic therapy is crucial.
For baxdrostat, the biggest safety concern was any off-target effect on cortisol, which did not appear in BrigHTN. Freeman acknowledged, however, that long-term follow-up will be needed to assess the drug’s benefits and risks.
They measure in PRECISION
PRECISION showed that the 12.5 mg and 25 mg doses of aprocitentan significantly reduced mean office seated systolic blood pressure over 4 weeks, both exceeding placebo by approximately 5 mmHg.
Also, according to Schlaich, aprocitentan users withdrawn from therapy and placed on placebo for 4 weeks saw systolic BP increase significantly.
“This study clearly shows that dual antagonism of endothelin with aprocitentan may be a valuable new pharmacological approach for resistant hypertension,” said Oparil.
The phase III trial included more than 700 people with uncontrolled BP despite taking three or more antihypertensive drugs. Eligibility criteria included unmonitored office systolic blood pressure greater than 140 mmHg, and participants had to undergo periods of screening, standardized background therapy, and placebo use before randomization.
For the first phase of the study, participants were randomized to aprocitentan 12.5 mg (n=243) or 25 mg (n=243) or placebo (n=244) for 4 weeks, with standard therapy in background for the three groups.
All subjects subsequently received 32 weeks of the highest dose of aprocitentan. When aprocitentan was withdrawn at week 36, they were re-randomized to aprocitentan 25 mg or placebo in the third phase of the study. Treatment ended at week 48, after which the 30-day safety follow-up period began.
The cohort had a mean age of 52 and 60% were male. BP at ambulatory follow-up was 138/83 mmHg at baseline.
The PRECISION results were published in The Lancet.
Baxdrostat to BrigHTN
BrigHTN participants who were randomized to baxdrostat had significant reductions in mean sitting systolic BP at 12 weeks, with the 2 mg dose lowering it by an average of 11 mmHg compared to placebo, Freeman reported at the AHA.
This drug “appears to have a bright future in the area of ​​resistant hypertension, especially patients who produce too much aldosterone,” commented Oparil.
The dose BrigHTN study included people who had a sitting blood pressure above 130/80 mmHg despite being on antihypertensives with at least 70% adherence.
The researchers randomized 274 participants to placebo or three doses of baxdrostat after screening and baseline periods. The median age was 62 years and more than half of the patients were male. Initial BP was 148/88 mmHg.
The aldosterone-lowering mechanism of Baxdrostat was supported by the findings of urinary aldosterone excretion and reduced serum aldosterone. The drug increased plasma renin activity, Freeman added.
His group’s full report was published in the New England Journal of Medicine.
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Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. keep going
disclosures
Schlaich reported institutional grants and/or personal honoraria from Medtronic, Abbot, ReCor Medical, Merck, Servier Laboratories; and served as president of the High Blood Pressure Research Council of Australia and a member of the scientific committee of the International Society of Hypertension.
Freeman is an employee of CinCor Pharma and receives stock-based compensation.
Oparil disclosed links to Preventric Diagnostics, CinCor Pharma, Bayer, Idorsia Pharmaceuticals and George Medicine Pty Limited.