New drug proves effective in phase 2 trials

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Scientists are developing new drugs to treat resistant hypertension. Veejay Villafranca/Bloomberg via Getty Images
  • Uncontrolled high blood pressure, or hypertension, affects millions of people worldwide, putting them at increased risk for serious health problems.
  • Research on a new drug called Baxdrostat has shown that it can significantly reduce blood pressure in people with treatment-resistant hypertension.
  • The results from the phase 2 trial support the idea that some cases of treatment-resistant hypertension may be caused by the hormone aldosterone.

Blood pressure is a simple measurement of blood pushing against the walls of arteries. It consists of two numbers – one representing the systolic pressure when the heart beats and the other the diastolic pressure between heartbeats.

Healthy blood pressure can reach 120 mmHg systolic and 80 mmHg diastolic. Anything consistently above 130 mmHg and 80 mmHg is considered elevated or hypertensive depending on the 2017 US clinical practice guidelines.

The increased pressure not only affects the blood vessels, it also puts a strain on the heart, brain, kidneys and eyes. In the long term, persistent high blood pressure is linked to an increased risk of life-threatening health problems such as stroke and heart disease, two of the leading causes of death in the USA.

New research from CinCor Pharma, Brigham and Women’s Hospital, Harvard Medical School and Queen Mary University of London may offer hope for people with uncontrolled high blood pressure.

The study, published in The New England Journal of Medicineand presented at the American Heart Association Scientific Conference, shows that a new drug called Baxdrostat can significantly reduce blood pressure in people for whom current treatments have not worked.

Hypertension has no symptoms or warning signs, and the only way to know blood pressure levels is to have them tested regularly. Risk factors for high blood pressure include “genetic, age-related, dietary and lifestyle factors,” said Dr Rigved Tadwalkarboard-certified cardiologist at Providence Saint John’s Health Center in California.

The Centers for Disaster Control and Prevention estimated that tens of millions of people in America suffer from hypertension. Of these, an estimated 12% have treatment-resistant hypertension (tRH), which is equivalent to approximately 7.6 millions of people.

“Hypertension can be a difficult condition to treat,” Professor Nilesh Samani, medical director of the British Heart Foundation, said Medical News Today.

Resistant hypertension, on the other hand, is classified as having high blood pressure that persists despite long-term use. This can greatly increase the risk of heart disease and renal failure.

Talk to DTM, Dr. Tadwalkar, who was not involved in the study, explained that tRH is common in clinics.

“About 10% of all people with hypertension have resistant hypertension. As a result, it is frequently seen in clinical settings by both cardiologists and primary care physicians,” he said.

Dr Tadwalkar said the evaluation and treatment of tRH is different from standard hypertension because it is considered “clinically […] belong to a separate category.

Its causes go beyond the usual risk factors associated with standard hypertension. When studying tRH, clinicians consider “predisposing medical conditions, contributing medications, and secondary causes of hypertension.”

To understand if the drug lowered blood pressure, researchers conducted a multicenter phase 2 clinical trial BrigHTN.

Between July 2020 and June 2022, researchers gave a total of 248 people with tRH with a mean blood pressure of 130/80 mmHg a daily dose of 2 mg, 1 mg or 0.5 mg of Baxdrostat or a placebo control. for 12 weeks.

Participants taking a mineralocorticoid receptor antagonist or potassium-sparing diuretic had to stop these agents for a total of 4 weeks before randomization if it was safe to do so. All of the participants who entered the randomization took the new drug in combination with their current blood pressure medications.

People with kidney disease and uncontrolled diabetes were excluded from the trial.

Researchers contacted clinic participants at specific times with a follow-up call one week after the final dose. They took the participants’ blood pressure measurements alongside the levels of Baxdrostat they were taking, and their aldosterone and cortisol blood and urine levels. The researchers also gave the participants electrocardiograms and physical exams.

The researchers noted a drop in blood pressure with the treatment. The highest 2 mg dose of Baxdrostat showed more than a 20 point reduction in systolic blood pressure, an 11 point drop from the placebo control group.

Interestingly, halving the dose to 1mg also reduced blood pressure by more than 8 points compared to placebo.

120 participants reported 232 adverse events during the study. High levels of side effects were reported in the control group (41%), but most were mild. No deaths were reported and no cases of adrenocortical insufficiency, but a few patients had recurrent high potassium levels which were managed by temporary discontinuation of the drug and routine dietary advice.

Baxdrostat stops the body from producing aldosterone, which has been related at tRH. Too much aldosterone increases the amount of salt and water reabsorbed by the kidneys, which increases blood volume and blood pressure.

Author of the study Dr Morris J Brownprofessor of endocrine hypertension at Queen Mary University of London explained to DTM the underlying assumption:

“The reason why patients are resistant to several conventional drugs is that in this set of patients there is a specific cause of hypertension, namely the hormone aldosterone.”

Dr Brown said he thought it was one of the “most exciting parts of the study, especially since it’s not targeted by conventional drugs”.

But could suppressing aldosterone lead to longer-term health issues? Dr. Brown said there would be no harm.

“In most people, physiological levels of aldosterone are already suppressed by excessive salt in the diet. In people with resistant hypertension, aldosterone comes from microscopic clumps of cells in the adrenal gland where specific mutations have led to the production of aldosterone in “automode” – the hormone is produced continuously, regardless of the body’s needs.
— Dr. Morris J. Brown

The researchers showed a dose-related reduction in blood pressure and aldosterone secretion.

They concluded that Baxdrostat inhibits aldosterone synthase, a key enzyme in the production of aldosterone that leads to lower blood pressure in participants with treatment-resistant hypertension.

Dr. Tadwalkar believes a drug like Baxdrostat offers a potential new treatment option for people with resistant hypertension.

“[A] a drug like Baxdrostat is of great potential value in preventing the onset of these [cardiovascular disease, stroke, heart attack, and heart failure] diseases,” he said.

“We finally have a drug that targets the synthesis of a hormone [aldosterone] which we believe is primarily involved in the pathogenesis of resistant hypertension, and this is a huge step forward.
— Dr. Rigved Tadwalkar

The research was also welcomed by Professor Samani, who was not involved in the current study, who said:

“This new type of drug that appears to be safe and effective in lowering blood pressure in some patients with hypertension despite taking other antihypertensive drugs is welcome.”

However, he warned that “[m]Mineral studies are needed to show their long-term benefits.

It is important to note that the trial population was predominantly white (70%), so the results may not translate to the entire population.

“The limitations of this trial are mainly related to the fact that it is a phase 2 study. […]the enrolled population is generally smaller and the length of time that individuals are followed may be shorter,” echoed Dr. Tadwalker, also pointing out that phase 2 trials do not test the drug against current treatments, which would be an important next step.

“At some point, it will also be useful to see how this drug performs in other patient populations, including those with standard hypertension,” he said.

The immediate next step in research is the results of a second phase II trial called HALO, which will study “[p]patients whose hypertension was not controlled by one or two drugs, but did not meet the definition of resistant (HALO patients were not taking diuretics, while 100% of BRIGHTN patients were),” said Dr Brown.

“We need phase 3 [trials]. It will start next year. Realistically, we’re probably looking at 2025 as the first date for the clinic. An interesting question, however, is whether regulators would accept a much smaller program for a separate indication, namely patients with primary hyperaldosteronism,” he added.

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