Strong results for new drugs to lower blood pressure in resistant hypertension

CHICAGO — Two new drugs show promise in lowering blood pressure (BP) in people with treatment-resistant hypertension, according to research presented at American Heart Association (AHA) Annual Meeting.

The first, the dual endothelin receptor antagonist aprocitentan, works by targeting the endothelin pathway involved in hypertension. It lowered systolic blood pressure after 4 weeks in the phase III, placebo-controlled PRECISION trial in people with resistant hypertension who had not responded to conventional medications, reported Markus Schlaich, MD, of the University of Western Australia, Perth.

Another drug, baxdrostat, reduced blood pressure compared 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 lower blood pressure, but because their novel mechanisms may be better tolerated in many cases,” commented AHA session discussant Suzanne Oparil, MD, of the 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 could be controlled by adding or increasing diuretic therapy, indicating that appropriate diuretic therapy is critical, Schlaich said.

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

Proportionate and PRECISION

PRECISION showed that the 12.5 mg and 25 mg doses of aproxitentan significantly lowered the mean office-based nadir systolic blood pressure at 4 weeks, both outperforming placebo by approximately 5 mmHg.

Furthermore, aprocitentan users who were withdrawn from therapy and placed on placebo for 4 weeks experienced a significant increase in systolic blood pressure, according to Schlaich.

“This study clearly demonstrates that dual antagonism of endothelin with aprocitentan could be a valuable new pharmacological approach to resistant hypertension,” said Oparil.

The phase III trial included more than 700 people with uncontrolled office blood pressure despite taking three or more antihypertensive medications. Eligibility criteria included unmonitored office systolic blood pressure greater than 140 mmHg, and participants had to complete periods of screening, standardized baseline therapy, and placebo 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) for 4 weeks, with standard therapy in the background for all three groups.

All people then received a higher dose of aprocitentan for 32 weeks. After withdrawal of aproxitentan at week 36, they were re-randomized to aproxitentan 25 mg or placebo in the third phase of the trial. Treatment ended at week 48, after which a 30-day safety follow-up period began.

The average age of the cohort was 52, and 60% were men. BP at outpatient follow-up was 138/83 mmHg at baseline.

PRECISION results were published in Lancet.

Baxdrostat in BrightN

Participants in BrigHTN randomized to baxdrostat had significant reductions in mean sitting systolic blood pressure 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 field of resistant hypertension, particularly in patients who produce too much aldosterone,” commented Oparil.

The dose-ranging BrigHTN study included people who had a sitting blood pressure above 130/80 mmHg despite being on antihypertensive medication with at least 70% adherence.

Researchers randomized 274 participants to placebo or three doses of baxdrostat after screening and a run-in period. The average age was 62 years, and more than half of the patients were men. Initial blood pressure was 148/88 mmHg.

Baxdrostat’s aldosterone-lowering mechanism is supported by findings of decreased urinary and serum aldosterone excretion. The drug increased plasma renin activity, Freeman added.

The full report of his group was published in New England Journal of Medicine.