No change in placebo-corrected SBP after 8 weeks with aldosterone synthase inhibitor

HALO: Results From a Phase 2, Double-blind, Placebo-controlled Trial Evaluating the Efficacy and Safety of Baxdrostat in Patients With Uncontrolled Hypertension

Presented at the ACC.23/WCC by: Prof. Deepak Bhatt, MD - New York, NY, USA

Introduction and methods

Early phase 1 studies have shown that the highly selective aldosterone synthase inhibitor baxdrostat resulted in a sustained, dose-dependent reduction of plasma aldosterone by >70%. The phase 2 trial BrigHTN demonstrated that baxdrostat reduced SBP by 11 mHg more than placebo in patients with treatment-resistant hypertension.

In the HALO trial -a double-blinded phase 2 study- the efficacy and safety of baxdrostat was examined in patients with uncontrolled hypertension.

Patients on a stable regimen of an ACEi or ARB, an ACEi/ARB plus a thiazide diuretic, or an ACEi/ARB plus a calcium channel blocker with a mean seated SBP ≥140 mmHg were included. Those with seated SBP ≥180 mmHg, BMI >50 kg/m2, or eGFR <30 mL/min/1.73 m2 were excluded. After screening and a run-in phase, 249 patients were randomized in a 1:1:1:1 ratio to baxdrostat 0.5 mg, baxdrostat 1 mg, baxdrostat 2 mg, or placebo on a background of antihypertensive medication.

The primary endpoint was change in mean seated SBP from baseline to 8 weeks of treatment.

Main results

Primary and secondary endpoints

• Change in SBP was -16.6 mmHg in the placebo group, and -17.0, -16.0 and -19.8 mmHg in the 0.5 mg, 1 mg and 2 mg groups, respectively (change in placebo-corrected SBP was -0.5 mmHg, 0.6 mmHg and -3.2 mmHg for the 0.5, 1 and 2 mg groups). Therefore, the primary endpoint was not met at any baxdrostat dose.
• There was no significant difference in placebo-corrected DBP change for any baxdrostat dose (change in DBP at 8 weeks was -5.9 mmHg in the placebo group, and -5.8 mmHg, -5.0 mmHg, and -5.4 mmHg in the 0.5 mg, 1 and 2 mg groups, respectively.
• Percentage of patients achieving a seated SBP response <130 mmHg at 8 weeks was not different between the groups (56.3%, 57.1%, 53.7% and 71.7% in the placebo and 0.5, 1, 2 mg baxdrostat groups, respectively).
• Baxdrostat reduced serum aldosterone levels (significant lowering with all doses), and increased renin activity (significant finding with 1 mg baxdrostat).

Safety

• There were 2 serious adverse events in the baxdrostat groups and none in the placebo group.
• There were 14 adverse events in the placebo group, 18 in the 0.5 mg group, 19 in the 1 mg group and 14 in the 2 mg group, of which 4 in the placebo group, 4 in the 0.5 mg group, 6 in the 1 mg group and 6 in the 2 mg group were drug-related.
• There were few adverse events of special interest (hyperkalemia, hyponatremia, and hypotension).

Post-hoc analysis

• 20 patients in the 2 mg arm had baxdrostat levels <0.2 ng/mL, suggesting non-adherence.
• There was a discordance with dosing records by pill-count, which showed >95% adherence in all groups.
• There was a placebo-corrected change in SBP of -7.9 mmHg for the 2 mg baxdrostat group, when only adherent patients were included (P<0.01).

Conclusion

The primary endpoint of placebo-corrected change in mean seated SBP with baxdrostat in patients with uncontrolled hypertension in the HALO trial was not achieved. In general, baxdrostat appeared to have a favorable safety profile and was well tolerated. There was a large effect on SBP lowering by placebo in this study.

When only adherent patients were included, a significant lowering of mean seated SBP was observed with 2 mg baxdrostat, which needs to be further investigated in future trials.

• Our reporting is based on the information provided at the ACC.23/WCC -

Watch a video on the HALO trial