AstraZeneca’s first-in-class aldosterone synthase inhibitor has received FDA approval for treating hypertension in combination with other antihypertensive medications. The approval, based on Phase III BaxHTN trial results showing statistically significant reductions in systolic blood pressure, offers a novel therapeutic mechanism for approximately 50 percent of US hypertension patients who remain uncontrolled on existing treatments.
AstraZeneca’s Baxfendy (baxdrostat) has received US Food and Drug Administration (FDA) approval as the first aldosterone synthase inhibitor (ASI) for treating hypertension in combination with other antihypertensive medications in adults with inadequate blood pressure control.
The approval addresses a significant unmet clinical need, with approximately 50 percent of US patients with hypertension already taking multiple antihypertensive medications continuing to experience persistently elevated blood pressure—a leading risk factor for cardiovascular disease and premature death.
Phase III trial demonstrates clinically meaningful efficacy
The regulatory decision was based on positive results from the BaxHTN Phase III trial, published in the New England Journal of Medicine, which demonstrated statistically significant and clinically meaningful reductions in seated systolic blood pressure (SBP). At week 12, Baxfendy 2mg achieved an absolute reduction from baseline of 15.7 mmHg (95% confidence interval [CI], -17.6 to -13.7) and a placebo-adjusted reduction of 9.8 mmHg (95% CI, -12.6 to -7.0; p<0.001). The 1mg dose produced an absolute reduction of 14.5 mmHg (95% CI, -16.5 to -12.5) and a placebo-adjusted reduction of 8.7 mmHg (95% CI, -11.5 to -5.8; p<0.001).
Results were consistent across both uncontrolled and treatment-resistant hypertension subgroups, with Baxfendy demonstrating a generally well-tolerated safety profile with no unanticipated findings.
Novel mechanism targets aldosterone production
Baxfendy represents a first-in-class, highly selective and potent oral small molecule that inhibits aldosterone synthase, an enzyme encoded by the CYP11B2 gene responsible for aldosterone synthesis in the adrenal gland. The agent specifically targets aldosterone production—a hormone that elevates blood pressure through sodium and water retention and contributes to heart and kidney complications.
In clinical trials, Baxfendy significantly lowered aldosterone levels without affecting cortisol levels across a wide dose range, offering a differentiated mechanism from existing antihypertensive therapies.
“We have been waiting for an innovative medication like Baxfendy for hypertension for many years,” said Dr Bryan Williams, Chair of Medicine at University College London and BaxHTN primary investigator. “Its novel way of lowering blood pressure has the potential to transform clinical practice by targeting a root cause of persistently uncontrolled hypertension. Epidemiological data indicate that a 10 mmHg decrease in systolic blood pressure is associated with a roughly 20 percent lower risk of serious cardiovascular events.”
Addressing persistent treatment challenges
Hypertension affects an estimated 1.4 billion people worldwide and represents the most prevalent and significant modifiable cardiovascular risk factor, accounting for more deaths and disability than any other modifiable risk. In the US alone, approximately 23 million patients remain uncontrolled despite treatment with two or more antihypertensive medications.
Elevated aldosterone levels, along with factors including obesity, high salt intake and various genetic or secondary conditions, are strongly associated with poor blood pressure control and progression of heart failure and kidney disease. Observational data from nearly 60,000 patients studied over a median of 9.7 years showed that a 9.5 mmHg increase in SBP was associated with a 30 percent increase in all-cause mortality risk and 41 percent increase in cardiovascular death risk.
“Hypertension remains a staggeringly widespread silent killer and a leading risk factor for stroke, heart attack, kidney damage and dementia,” said John M Clymer, Executive Director, National Forum for Heart Disease & Stroke Prevention. “Tens of millions of people struggle to control their blood pressure despite lifestyle changes and currently available treatments.”
Trial design and endpoints
The BaxHTN Phase III trial enrolled 796 patients randomised 1:1:1 to receive Baxfendy 2mg, 1mg or placebo once daily on top of standard of care during a 12-week double-blind, placebo-controlled period. Standard of care comprised two antihypertensive agents at baseline (one being a diuretic) for uncontrolled hypertension, or three or more agents (including a diuretic) for resistant hypertension.
The primary efficacy endpoint assessed the difference in mean change from baseline in seated SBP at week 12 between baxdrostat-treated participants and placebo. Additional confirmatory secondary endpoints included effects on seated SBP in the resistant hypertension subpopulation, seated diastolic blood pressure at week 12, and proportion of participants achieving seated SBP below 130 mmHg at week 12.
Persistence of efficacy was evaluated during a randomised withdrawal period from week 24 to week 32, with approximately 300 patients on Baxfendy 2mg re-randomised 2:1 to continue treatment or receive placebo for eight weeks. Long-term safety was assessed at 52 weeks compared with a standard of care arm.
Broader development programme
Beyond hypertension, Baxfendy is being investigated in conditions where elevated aldosterone contributes to cardiorenal risk, including as monotherapy for primary aldosteronism and in combination with dapagliflozin for chronic kidney disease with hypertension and heart failure prevention in hypertensive patients.
Additional Phase III data from the Bax24 trial, published in The Lancet, demonstrated statistically significant and clinically meaningful placebo-adjusted reductions in 24-hour ambulatory systolic blood pressure in patients with resistant hypertension.
Ruud Dobber, Executive Vice President, BioPharmaceuticals Business Unit, AstraZeneca, commented: “The approval of Baxfendy offers a much-needed, first-in-class innovation for people living with persistently uncontrolled hypertension who have not responded to or tolerated existing medicines. This is a disease that has seen little therapeutic progress for the past two decades.”
AstraZeneca acquired Baxfendy through its purchase of CinCor Pharma, Inc. in February 2023.
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