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Strong results for two BP-lowering drugs in resistant hypertension

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 held recently (5-7 November).

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

MedPage Today reports that 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 programme will begin in 2023, according to Dr Mason Freeman 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,” said AHA session discussant Dr Suzanne Oparil of the University of Alabama at Birmingham.

Indeed, the main treatment-emergent adverse events associated with aprocitentan were oedema 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 four weeks, both beating placebo by approximately 5 mmHg.

Furthermore, aprocitentan users withdrawn from therapy and placed on placebo for four weeks saw systolic BP rise back up significantly, according to Schlaich.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 more than 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, standardised background therapy, and placebo use before being randomised.

For the first phase of the study, participants were randomised to aprocitentan 12.5 mg (n=243) or 25 mg (n=243) or placebo (n=244) over four 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-randomised 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 The Lancet.

Baxdrostat in BrigHTN

Participants in BrigHTN who were randomised 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 said.

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 randomised to placebo or three doses of baxdrostat after screening and run-in periods. Mean age was 62 years, and more than 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 New England Journal of Medicine.

Study 1 details

Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

Markus Schlaich, Marc Bellet, Michael Weber, Parisa Danaietash, George Bakris, John M Flack, et al.

Published in The Lancet on 7 November 2022

Summary

Background
Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension.

Methods
PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes.

Findings
The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was –15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, –15·2 (0·9) mm Hg for aprocitentan 25 mg, and –11·5 (0·9) mm Hg for placebo, for a difference versus placebo of –3·8 (1·3) mm Hg (97·5% CI –6·8 to –0·8, p=0·0042) and –3·7 (1·3) mm Hg (–6·7 to –0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was –4·2 mm Hg (95% CI –6·2 to –2·1) and –5·9 mm Hg (–7·9 to –3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment.

Interpretation
In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40.

Study 2 details

Phase 2 Trial of Baxdrostat for TreatmentResistant Hypertension

Mason Freeman, Yuan-Di Halvorsen, William Marshall, Mackenzie Pater, Jon Isaacsohn, Catherine Pearce, Brian Murphy, Nicholas Alp, Ajay Srivastava, Deepak Bhatt, Mand Morris Brown, for the BrigHTN Investigators.

Published in the New England Journal of Medicine on 7 November 2022

Abstract

Background
Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalysed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels.

Methods
In this multicentre, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group.

Results
A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of −20.3 mm Hg, −17.5 mm Hg, −12.1 mm Hg, and −9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was −11.0 mm Hg (95% confidence interval [CI], −16.4 to −5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was −8.1 mm Hg (95% CI, −13.5 to −2.8; P=0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to
baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level of 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug.

Conclusions
Patients with treatment-resistant hypertension who received baxdrostat had dose related reductions in blood pressure.

 

NEJM article – Phase 2 Trial of Baxdrostat for TreatmentResistant Hypertension (Open access)

 

The Lancet article – Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial (Open access)

 

MedPage Today article – Strong Showing for Novel BP-Lowering Drugs in Resistant Hypertension (Open access)

 

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New NICE hypertension guidelines a ‘pragmatic compromise’ – The Lancet

 

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