Large reductions in blood pressure with baxdrostat: the phase II BrigHTN study

Large reductions in blood pressure with baxdrostat: the phase II BrigHTN study

The drug inhibits the enzyme that creates aldosterone and has been impressive when added to other drugs for resistant hypertension.

CHICAGO, IL—An investigational aldosterone synthase inhibitor successfully lowers blood pressure in patients with treatment-resistant hypertension, a new study shows.

In those with a mean blood pressure of 130/80 mm Hg despite taking at least three antihypertensive medications, including a diuretic, patients treated with baxdrostat 2 mg (CinCor Pharma) had a greater than 20 mm Hg reduction in systolic blood pressure. When adjusted for the reduction seen in the placebo group, the mean reduction in systolic blood pressure was 11.0 mm Hg, the researchers report.

Senior investigator Morris J. Brown, MD (Queen Mary University of London, England), said he was impressed by the magnitude of the reduction seen in this trial, which was presented today during the final late clinical trial session at the American Heart Association Scientific Meetings 2022. and simultaneously published in New England Journal of Medicine.

Putting the results into context, Brown stated an A meta-analysis of 42 trials in 11,000 patients which looked at blood pressure reduction with diuretics, ACE inhibitors/ARBs, beta-blockers, and calcium channel blockers. “No other study has had a double-digit drop in placebo-controlled systolic blood pressure, despite the fact that our mean baseline blood pressure is not very high,” Brown told TCTMD.

Baxdrostat is the first candidate in a new class of drugs that inhibits the enzyme that makes aldosterone instead of blocking the mineralocorticoid receptor, which is how spironolactone works.

“The challenge in developing this class of drugs is that the enzyme that makes aldosterone and the enzyme that makes cortisol are 93% identical,” Brown said. “Therefore, it was difficult to develop a drug that would stop the production of aldosterone without affecting cortisol. There have been other examples of drugs that have gone down this route but failed because cortisol levels dropped.”

For example, one drug in development, osilodrostat (Isturisa; Novartis), is now used to treat Cushing’s disease or hypercortisolism. Still, researchers are optimistic baxdrostat may succeed where others have failed. Brown noted that preclinical and Phase I studies have shown that baxdrostat has very high selectivity for aldosterone synthase compared to the enzyme required for cortisol synthase.

Positive findings of phase II

BrighHTN enrolled 248 patients randomized to placebo or baxdrostat 0.5 mg, 1 mg, or 2 mg. All patients were treated with a diuretic, 91% to 96% were treated with either an ACE inhibitor or an ARB, and 64% to 70% were treated with a calcium channel blocker. The use of beta-blockers ranged from 52% to 68% in the four treatment groups. Baseline blood pressure in the sitting position was approximately 148/88 mm Hg.

Both the 1 mg and 2 mg doses of baxdrostat resulted in significant reductions in systolic blood pressure compared to placebo.

Change in blood pressure compared to the initial value

Placebo

Bakhdrostat

0.5 mg

Bakhdrostat

1 mg

Bakhdrostat

2 mg

Systolic pressure, mm Hg

-9.4

-12.1

-17.5*

-20.3**

Diastolic pressure, mm Hg

-9.2

-8.6

– 11.8

– 14.2

* P = 0.003 compared to placebo; ** P < 0.001 compared to placebo

For TCTMD, Brown said that treating hypertension is one of the therapeutic success stories in medicine, but that there are approximately 5% to 10% of patients who do not reach their goals despite treatment with optimal medical therapy.

“What has been shown, and I think our study strongly supports this, is that resistant hypertension overlaps with primary aldosteronism, which occurs when the adrenal cells that produce aldosterone go into automatic mode and just throw it out even though the body already has enough salt, ” He said. “Resistant hypertension is driven by an excess of salt and water in the circulatory system, which does not respond to any of the conventional classes of drugs.”

Data from Prevention and treatment of hypertension with therapy based on algorithm-2 (PATHWAY-2) study supports this hypothesis. In PATHWAY-2, researchers have previously shown that spironolactone is the most effective add-on drug for patients with resistant hypertension. That study, along with this one, suggests that resistant hypertension is resistant because of aldosterone, Brown said.

“That makes it a natural target for this drug,” he said.

Pharmacokinetic testing

As part of the study, the researchers also measured plasma baxdrostat levels, serum and urine aldosterone, and serum cortisol activity. The reduction in aldosterone levels at the end of the study ranged from 3.0 ng/dL with the 0.5 mg dose to 4.9 ng/dL with the 2 mg dose. 24-hour urinary aldosterone levels decreased with all three drug doses, but serum cortisol levels remained unchanged.

The drug was well tolerated, with no reported side effects, Brown said. At the 2 mg dose, there was one case of hyponatremia and two patients with elevated potassium levels. In total, there were six patients with hyperkalemia, with potassium levels ranging from 6.0 to 6.3 mmol/L in three individuals and from 5.5 to 5.9 mmol/L in the other three. Four of the six patients temporarily discontinued treatment but were able to continue taking baxdrostat and complete the study.

One of the main problems with spironolactone, Brown said, is an increase in potassium levels, so that’s a side effect researchers have been watching for. However, he noted that there are genetic models that suggest that inhibiting aldosterone synthase will not lead to the same problems. However, larger studies are needed to assess the drug’s safety.

“With an aldosterone enzyme inhibitor, compared to a receptor blocker, quite a few factors suggest that it should be a cleaner drug,” Brown said. “The enzyme is only produced by a very small fringe of cells in the adrenal glands – it’s not made anywhere else in the body – so you wouldn’t expect off-target effects.”

Researchers are also evaluating baxdrostat in 249 patients with uncontrolled hypertension who take one or more antihypertensive drugs. The study has completed randomization and top results are expected soon. Baxdrostat was initially developed by Roche, but after they stopped developing cardiovascular and metabolic drugs, the company licensed the drug to CinCor Pharma.

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