ACC.24 – In KARDIA-2, a single dose of zilebesiran in combination with a standard-of care antihypertensive reduced ambulatory and office SBP from baseline to month 3 in patients with uncontrolled hypertension. Sustained reductions were maintained to month 6, when other rescue hypertensives were permitted. 

This summary is based on the presentation of Akshav Desai, MD (Boston, MA, US) at the ACC.24 Scientific Session - Zilebesiran in Combination With a Standard-of-care Antihypertensive in Patients With Inadequately Controlled Hypertension: Primary Results From the Phase 2 Kardia-2 Study.

Introduction and methods

Treatment with zilebesiran, a RNAi therapeutic targeting hepatic angiotensinogen synthesis, led to sustained reductions in systolic BP (SBP) at 6 months in patients with mild-to-moderate hypertension in KARDIA-1. The goal of the phase 2 KARDIA-2 trial was to evaluate the efficacy and safety of zilebesiran as an add-on antihypertensive in patients with uncontrolled hypertension.

In KARDIA-2, a total of 1500 patients (aged 18-75 years) with untreated hypertension who had seated office SBP of ≥155-180 mmHg or treated hypertension with 1-2 antihypertensives and seated office SBP of ≥145-180 mmHg were enrolled. Patients first entered an open-label run-in period (≥ 4 weeks), were they were randomly assigned in a 4:7:10 ratio to indapamide 2.5 mg daily, amlodipine 5 mg daily or olmesartan 40 mg daily. After the run in period, patients with a mean ambulatory SBP of ≥130-160 mmHg despite a ≥80% adherence to the protocol-specified background antihypertensive therapy entered a 6-month double blind study period. A total of 672 patients entered this double-blind study period and were randomized to a single dose of zilebesiran 600 mg subcutaneous or placebo, on top of the protocol-specified background antihypertensive therapy (indapamide cohort: n=130, amlodipine cohort: n=241, and olmesartan cohort: n=301). Rescue medication from month 3 to month 6 were permitted.

The primary endpoint was the change from baseline to month 3 in 24-h mean ambulatory SBP. For the primary endpoint, the following number of patients were analyzed in respectively the placebo and zilebesiran arms: 56 and 53 patients in the indapamide cohort, 100 and 99 patients in the amlodipine cohort, and 120 and 117 patients in the olmesartan cohort.

Main results

• Zilebesiran reduced 24-h mean ambulatory SBP from baseline to month 3 in all treatment cohorts compared with placebo. Least-squares mean (LSM) differences were -12.1 mmHg (95%CI: -16.5 to -7.6; P<0.001), -9.7 mmHg (95%CI: -12.9 to -6.6; P<0.001), and -4.0 mmHg (95%CI; -7.6 to -0.3; P=0.036) in, respectively, the indapamide, amlodipine, and olmesartan cohorts.
• Zilebesiran also lowered office SBP from baseline to month 3 in all treatment cohorts compared with placebo (LSM differences were -18.5 mmHg [95%: -22.8 to -14.2; P=0.001], -10.2 mmHg [95%CI: -13.5 to -6.9; P<0.001] and -7.0 mmHg [95%CI: -10.4 to -3.6; P<0.001] in, respectively, the indapamide, amlodipine, and olmesartan cohorts.).
• Placebo-corrected differences in ambulatory SBP were sustained from baseline to month 6 in the indapamide and amlodipine cohorts despite add-on antihypertensive therapy, but not in the olmesartan cohort. LSM differences in mean ambulatory SBP were -11.0 mmHg (95%CI: -14.6 to -7.3; P<0.001), -7.9 mmHg (95%CI: -10.6 to -5.3; P<0.001), and -1.6 mmHg (95%CI: -4.4 to -1.2; P=0.26) in the indapamide, amlodipine, and olmesartan cohorts, respectively.
• Placebo-corrected differences in office SBP were sustained from baseline to month 6 in all cohorts. LSM differences in office SBP were -13.6 mmHg (95%CI: -16.9 to -10.3; P<0.001), -8.6 mmHg (95%CI: -10.9 to -6.3; P<0.001), and -4.6 mmHg (95%CI: -6.8to -2.4; P<0.001) in the indapamide, amlodipine, and olmesartan cohorts, respectively.
• There were no deaths or adverse events leading to study discontinuation. Increased rates of mild hyperkalemia, hypotension, and eGFR decline ≥30% were detected in the zilebesiran arms compared with the placebo arms, but most of these episodes were non-serious, transient, and resolved without any intervention.

Conclusion

In KARDIA-2, treatment with a single subcutaneous dose of zilebesiran 600 mg versus placebo reduced 24-h mean ambulatory and office SBP from baseline to month 3 when added to a diuretic, calcium channel blocker or maximum-dose angiotensinogen receptor blocker.

According to Akshav Desai, “the results do appear to support the potential for combining biannual dosing of zilebesiran with standard-of care antihypertensives to achieve additive blood pressure reductions”.

- Our reporting is based on the information provided at the ACC.24 Scientific Session -