Zilebesiran: KARDIA-2 Study

Zilebesiran: KARDIA-2 Study

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 Summary

INDEX

Study Design – Patient Demographics & Baseline Characteristics – Primary Endpoint – Secondary Endpoints – Safety – Abbreviations – References

 Study dESIGN

The KARDIA‑2 study (NCT05103332) was a phase 2, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of zilebesiran as an add‑on therapy in patients aged 18 to 75 years with hypertension that was not adequately controlled by a standard-of-care antihypertensive medication.1

The study included an open-label run-in period of at least 4 weeks and a 6-month DB treatment period. Following discontinuation of antihypertensive therapies, eligible patients with a screening eGFR < 45 mL/min/1.73 m2 or urine albumin:creatinine ratio ≥ 300 mg/g were preferentially assigned to the olmesartan run-in cohort. The remaining patients were randomized in a 4:7:10 ratio to receive open‑label treatment of the following antihypertensive agents: indapamide (diuretic) 2.5 mg daily, amlodipine (CCB) 5 mg daily, or olmesartan (ARB) 40 mg daily (20 mg daily for patients with creatinine clearance ≤60 mL/min at screening enrolled outside of the US, consistent with local labeling). After the run-in period, patients in each cohort with 24-hour mean ambulatory SBP between 130 and 160 mmHg and at least 80% adherence to the protocol-specified background therapy were randomized 1:1 to receive a single subcutaneous injection of either zilebesiran 600 mg or placebo as an add-on treatment during the 6-month DB period.1

Patients eligible for the study included those with1:

      An office SBP at screening ≥155 mmHg and ≤180 mmHg for patients with untreated hypertension

      An office SBP at screening ≥145 mmHg and ≤180 mmHg for patients on 1-2 antihypertensive medications

      24‑hour mean SBP >130 mmHg and ≤160 mmHg by ABPM after at least 4 weeks of run‑in on protocol‑specified background antihypertensive medication

Patients excluded from the study included those with1:

      Known secondary hypertension

      Symptomatic orthostatic hypotension

      Serum potassium > 5.0 mmol/L

      eGFR < 30 mL/min/1.73 m2 calculated by the MDRD method

      Symptomatic heart failure

      Type 1, poorly controlled type 2, or newly diagnosed diabetes

The primary endpoint was the difference in the change from baseline at Month 3 in 24‑hour mean ambulatory SBP.1

Secondary endpoints assessed hierarchically in the following order included1:

      Between-group difference in change from baseline at Month 3 in office SBP

      Time-adjusted change from baseline through Month 6 in office SBP and 24-hour mean ambulatory SBP

      Proportion of patients meeting the protocol-defined BP response criterion at Month 6 (defined as 24‑hour mean ambulatory SBP <130 mmHg and/or a reduction from baseline ≥20 mmHg without rescue antihypertensive medication)

Other secondary endpoints included the change from baseline in serum AGT. Safety outcomes included rates of investigator-reported AEs and occurrence of protocol-defined laboratory abnormalities.1

 Patient demographics & BASELINE CHARACTERISTICS

At the end of the run-in period and before dosing of zilebesiran or placebo, the mean (SD) changes in office SBP were -15.5 (15.6) mm Hg with indapamide, -14.7 (15.2) mm Hg with amlodipine, and ‑13.0 (18.0) mm Hg with olmesartan.1

In the overall population, the mean (SD) age was 58.5 (10.3) years, mean (SD) 24-hour ambulatory SBP was 143.4 (8.2) mm Hg, and mean (SD) office BP was 144.5 (12.2) mm Hg. Of the 658 patients, 376 (57.1%) were male, 187 (28.4%) were self-reported as Black or African American, 151 (22.9%) had diabetes, 398 (60.5%) had a BMI ≥30, 66 (10.0%) had eGFR < 60mL/min/1.73 m2, and 77 (11.7%) were previously untreated for hypertension. Of the 581 patients previously treated for hypertension, 304 (46.2%) were treated with 1 antihypertensive treatment, 239 (36.3%) were treated with 2, and 38 (5.8%) were treated with more than 2. The baseline characteristics of patients by each background therapy cohort are shown in Table 1.1

Table 1. Baseline Characteristics by Background Therapy Cohort in KARDIA-2.1,a

 PRIMARY ENDPOINT

Change in 24‑hour Mean Ambulatory SBP at Month 3

At Month 3, treatment with a single subcutaneous dose of zilebesiran 600 mg demonstrated significant reductions in 24‑hour mean ambulatory SBP compared with placebo when added to indapamide, amlodipine, or olmesartan (Figure 1).1

In the indapamide cohort, the LS mean change from baseline in 24-hour mean ambulatory SBP was ‑15.7 (95% CI, -18.9 to -12.6) in the zilebesiran group and -3.7 (95% CI, -6.7 to -0.6) in the placebo group, resulting in a LS mean difference of -12.1 mm Hg (95% CI, -16.5 to -7.6; P<0.001).1

In the amlodipine cohort, the LS mean change from baseline in 24-hour mean ambulatory SBP was ‑10.5 (95% CI, -12.7 to -8.2) in the zilebesiran group and -0.7 (95% CI, -3.0 to 1.5) in the placebo group, resulting in a LS mean difference of -9.7 mm Hg (95% CI, -12.9 to -6.6; P<0.001).1

In the olmesartan cohort, the LS mean change from baseline in 24-hour mean ambulatory SBP was ‑7.7 (95% CI, -10.3 to -5.1) in the zilebesiran group and -3.2 (95% CI, -5.9 to -0.6) in the placebo group, resulting in a LS mean difference of 4.5 mm Hg (95% CI, -8.2 to -0.8; P<0.018) .1

Figure 1. Change in 24‑hour Mean Ambulatory SBP at Month 3.1,a

Figures 2A-2C show the change from baseline to Month 3 in 24‑hour mean ambulatory SBP across predefined subgroups for each cohort.2

Figure 2A. Indapamide Cohort: Change in 24‑hour Mean Ambulatory SBP at Month 3 Subgroup Analysis.2,a

Figure 2B. Amlodipine Cohort: Change in 24‑hour Mean Ambulatory SBP at Month 3 Subgroup Analysis.2,a

Figure 2C. Olmesartan Cohort: Change in 24‑hour Mean Ambulatory SBP at Month 3 Subgroup Analysis.2,a

 SECONDARY ENDPOINTS

Change in Office SBP at Month 3

At Month 3, treatment with a single subcutaneous dose of zilebesiran 600 mg demonstrated significant reductions in office SBP compared with placebo when added to indapamide, amlodipine, or olmesartan (Figure 3).1

In the indapamide cohort, the LS mean change from baseline in office SBP was -19.3 mm Hg (95%  CI, ‑22.3 to ‑16.2) in the zilebesiran group and -0.8 mm Hg (95% CI, -3.8 to 2.3) in the placebo group, resulting in a LS mean difference of -18.5 mm Hg (95% CI, -22.8 to 14.2; p<0.001).1

In the amlodipine cohort, the LS mean change from baseline in office SBP was ‑11.5 (95% CI, -13.8 to ‑9.2) in the zilebesiran group and -1.4 (95% CI, -3.7 to 1.0) in the placebo group, resulting in a LS mean difference of -10.2 mm Hg (95% CI, -13.4 to -6.90; P<0.001).1

In the olmesartan cohort, the LS mean change from baseline in office SBP was ‑9.3 (95% CI, -11.8 to ‑6.9) in the zilebesiran group and -2.6 (95% CI, -5.1 to -0.1) in the placebo group, resulting in a LS mean difference of -6.7 mm Hg (95% CI, -10.2 to -3.3; P<0.001).1

Figure 3. Change in Office SBP at Month 3.1,a

Figures 4A-4C show the change from baseline to Month 3 in office SBP across predefined subgroups for each cohort.2

Figure 4A. Indapamide Cohort: Change in Office SBP at Month 3 Subgroup Analysis.2,a

Figure 4B. Amlodipine Cohort: Change in Office SBP at Month 3 Subgroup Analysis.2,a

Figure 4C. Olmesartan Cohort: Change in Office SBP at Month 3 Subgroup Analysis.2,a

Time-Adjusted Change in Office SBP and 24-hour Mean Ambulatory SBP Through Month 6

The time-adjusted changes from baseline in SBP through Month 6 by treatment cohorts are summarized in Table 2.1

In the indapamide cohort, 25 patients (41.7%) in the placebo group and 9 patients (15.5%) in the zilebesiran group received rescue antihypertensive therapy at Month 6. In the amlodipine cohort, 55 patients (48.7%) in the placebo group and 28 patients (25.2%) in the zilebesiran group received rescue antihypertensive therapy at Month 6. In the olmesartan cohort, 75 patients (54.0%) in the placebo group and 57 patients (42.5%) in the zilebesiran group received rescue antihypertensive therapy at Month 6.1

Table 2. Time-Adjusted Change from Baseline Through Month 6 in SBP.1,a

SBP Response at Month 6 Without Rescue Medication

At Month 6, treatment with zilebesiran resulted in a larger proportion of patients achieving a SBP response without rescue medication. The response criterion was defined as a 24‑hour mean ambulatory SBP <130 mmHg and/or reduction ≥20 mmHg without additional antihypertensives.1

In the indapamide cohort, 34 patients (64.2%) receiving zilebesiran compared with 8 patients (14.0%) receiving placebo met the prespecified BP response criterion at 6 months (OR, 12.4; 95% CI, 4.6 to 33.3; P<0.001).1

In the amlodipine cohort, 41 patients (39.8%) receiving zilebesiran compared with 14 patients (13.7%) receiving placebo met the prespecified BP response criterion at 6 months (OR, 5.1; 95% CI, 2.4 to 10.6; P<0.001).1

In the olmesartan cohort, the between-group difference in time-adjusted change from baseline in ambulatory SBP was not statistically significant through 6 months. Accordingly, by the prespecified testing hierarchy, formal statistical comparisons of the percentage of patients who met BP response criterion are presented for descriptive purposes. Thirty patients (25.9%) receiving zilebesiran compared with 22 patients (17.2%) receiving placebo met the prespecified BP response criterion at 6 months (OR, 1.7; 95% CI, 0.9 to 3.2).1

Change in Serum AGT at Month 6

Figures 5A and 5B show the change in AGT from baseline to Month 6.3 Across all 3 cohorts, the mean (SD) percent changes from baseline in serum AGT levels at Week 2 ranged from ‑87.8% (36.0) to -92.8% (16.0) in patients receiving zilebesiran. At Month 6, the mean (SD) percent changes from baseline in serum AGT levels ranged from -88.2% (41.6) to -94.5% (9.4). No change in serum AGT levels was noted in patients receiving placebo.1

Figure 5A. Change from Baseline to Month 6 in Serum AGT in All Arms.3

Figure 5B. Change from Baseline to Month 6 in Serum AGT in Zilebesiran Arms.3

 SAFETY RESULTS

During the 6‑month double-blind treatment period, a greater percentage of patients receiving zilebesiran than placebo had at least 1 AE. The rate of SAEs was similar between both groups, and there were no deaths reported. Laboratory abnormalities of interest were mild, occurred in the first 3 months, and resolved upon repeat measurement within 1‑2 weeks without intervention (Table 3).1,4 No apparent safety trends were observed by subgroup.2

Table 3. Zilebesiran Safety Summary Over 6 Months.1,a

 Abbreviations

ABPM = ambulatory blood pressure monitoring; AE = adverse event; AGT = angiotensinogen; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ARB = angiotensin receptor blocker; BL = baseline; BMI = body mass index; CCB = calcium channel blocker; CI = confidence interval; DB = double‑blind; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; FDA = Food and Drug Administration; IQR = interquartile range; LS = least squares; LSM = least squares mean; LSMD = least squares mean difference; MDRD = Modification of Diet in Renal Disease; MedDRA = Medical Dictionary for Regulatory Activities; RD = Modification of Diet in Renal Disease; OLE = open‑label extension; OR = odds ratio; RNAi = RNA interference; SAE = serious adverse event; SBP = systolic blood pressure; SD = standard deviation; SE = standard error; ULN = upper limit of the normal.

Updated 24 March 2026

 References

1.  Desai AS, Karns AD, Badariene J, et al. Add-on treatment with zilebesiran for inadequately controlled hypertension: the KARDIA-2 randomized clinical trial. JAMA. 2025. doi:10.1001/jama.2025.6681

2.  Saxena M, Aswad A, Badariene J, et al. Subgroup results from KARDIA-2: Impact of demographic and baseline disease characteristics on zilebesiran response in patients with hypertension uncontrolled by a standard oral antihypertensive. Presented at: European Society of Cardiology (ESC) Congress; August 30 - September 2, 2024; London, UK.

3.  Supplement to: Desai AS, Karns AD, Badariene J, et al. Add-on treatment with zilebesiran for inadequately controlled hypertension: the KARDIA-2 randomized clinical trial. JAMA. 2025:2. doi:10.1001/jama.2025.6681

4.  Bakris GL, Desai AS, Aswad A, et al. Zilebesiran in combination with a standard-of-care antihypertensive in patients with inadequately controlled hypertension: Primary results from the phase 2 KARDIA-2 study. Presented at: American College of Cardiology (ACC) Annual Scientific Session; April 6-8, 2024; Atlanta, GA, USA.