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CHICAGO -- Two novel drugs showed promise for blood pressure (BP) lowering in people with treatment-resistant hypertension, according to research presented at the American Heart Association (AHA) annual meeting.

The first, dual endothelin receptor antagonist aprocitentan, acts by targeting the endothelin pathway implicated in hypertension. It lowered systolic BP after 4 weeks in the phase III, placebo-controlled PRECISION trial of people with resistant hypertension that did not respond to usual medications, reported Markus Schlaich, MD, of University of Western Australia, Perth.

The second drug, baxdrostat, conferred BP reductions over placebo upon 12 weeks of treatment in the BrigHTN study. Baxdrostat lowers 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 lower pressure, but because their novel mechanisms may be better tolerated in many cases," commented AHA session discussant Suzanne Oparil, MD, of University of Alabama at Birmingham.

Indeed, the main treatment-emergent adverse events associated with aprocitentan were edema and fluid retention within 30 days. These events were manageable with addition or uptitration of diuretic therapy, indicating that adequate diuretic therapy is crucial, Schlaich said.

As for baxdrostat, the biggest safety concern was any off-target effects on cortisol, which did not surface in BrigHTN. Freeman acknowledged that longer-term follow-up will be needed to assess the drug's benefits and risks, however.

Aprocitentan in PRECISION

PRECISION showed that 12.5 mg and 25 mg doses of aprocitentan significantly lowered mean trough sitting office systolic BP by 4 weeks, both beating placebo by approximately 5 mmHg.

Furthermore, aprocitentan users withdrawn from therapy and placed on placebo for 4 weeks saw systolic BP rise back up significantly, according to Schlaich.

"This study clearly shows that dual endothelin antagonism with aprocitentan may be a valuable new pharmacologic approach to resistant hypertension," Oparil said.

The phase III trial included over 700 people with uncontrolled office BP despite being on three or more antihypertensives. Eligibility criteria included unattended sitting office systolic BP exceeding 140 mmHg, and participants had to undergo periods of screening, standardized background therapy, and placebo use before being randomized.

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) over 4 weeks, with standard therapy in the background for all three groups.

All people subsequently were put on 32 weeks of the higher dose of aprocitentan. At withdrawal of aprocitentan 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 averaged 52 years of age, and 60% were men. BP on ambulatory monitoring was 138/83 mmHg at baseline.

PRECISION results were published in .

Baxdrostat in BrigHTN

Participants in BrigHTN who were randomized to baxdrostat had significant reductions in mean seated systolic BP in 12 weeks, with the 2-mg dose lowering it by 11 mmHg on average over placebo, Freeman reported at AHA.

This drug "seems to have a bright future in the area of resistant hypertension, particularly patients producing too much aldosterone," Oparil commented.

The dose-ranging BrigHTN study included people who had seated blood pressures above 130/80 mmHg despite being on antihypertensives with at least 70% adherence.

Investigators had 274 participants randomized to placebo or three doses of baxdrostat after screening and run-in periods. Mean age was 62 years, and over half of the patients were men. Baseline BP was 148/88 mmHg.

Baxdrostat's aldosterone-lowering mechanism was corroborated by findings of reduced urinary aldosterone excretion and serum aldosterone. The drug increased plasma renin activity, Freeman added.

His group's full report was published in the .