Zilebesiran: KARDIA-3 Study

Zilebesiran: KARDIA-3 Study

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 Summary

Index

Study Design – Patient Demographics and Baseline Characteristics – Efficacy Results – Safety Results – Abbreviations – References

 Study Design

The KARDIA‑3 (NCT06272487) study is a phase 2, randomized, double-blind, placebo-controlled, dose-ranging multicenter study evaluating the efficacy, safety, and optimal dosing of zilebesiran as an add‑on therapy in patients with uncontrolled hypertension and cardiovascular disease or high CV risk, with or without CKD. A key aim of the KARDIA-3 study was to inform the design of a phase 3 CV outcomes study in this population.1,2,5

The KARDIA-3 study included two cohorts (Cohort A or Cohort B). Cohort A included patients with an eGFR ≥45 mL/min/1.73m2 and Cohort B included patients with an eGFR between 30-45 mL/min/1.73m2.1

In Cohort A, 270 participants were randomized (1:1:1) to receive placebo (n=88) or a single subcutaneous injection of zilebesiran 300 mg (n=91) or 600 mg (n=91). In Cohort B, 105 participants were randomized (1:1:1:1) to receive placebo (n=26) or a single subcutaneous injection of zilebesiran 150 mg (n=26), 300 mg (n=27), or 600 mg (n=26). Antihypertensive intensification was permitted during Months 3–6 in both cohorts.1,4

The primary endpoint of the study is to evaluate the change from baseline in mean office SBP at Month 3. Key secondary endpoints include the change from baseline in mean office SBP at Month 6, the change from baseline to Months 3 and 6 in 24-hour mean ambulatory SBP, and the change from baseline in mean daytime and nighttime ambulatory SBP at Month 6. A key exploratory endpoint is the hourly mean daytime/nighttime ambulatory SBP at Month 6. A mixed model for repeated measurements was used for the primary analysis.1 Cohorts A and B were analyzed separately. Cohort B was not powered to evaluate efficacy; results are descriptive only.4

Safety was assessed by the frequency of AEs throughout the 6-month double-blind period in both Cohort A and Cohort B.1,4

Key study inclusion criteria are1,4:

         Adult patients with established CV disease or high CV risk (10-year ASCVD score >15%)

         Uncontrolled hypertension

o     Mean office SBP 140–170 mmHg at screening

o     24‑hour mean ambulatory SBP 130–170 mmHg within 7 days prior to randomization

      Already prescribed 2–4 antihypertensive medications (including a diuretic or CCB)

      Cohort B: eGFR between 30-45 mL/min/1.73m2

Key study exclusion criteria are5:

      Secondary hypertension

      Orthostatic hypertension

      Proteinuria >3 g/day

      Serum potassium >4.8 mEq/L

 Patient Demographics and Baseline Characteristics

Cohort A

Demographics and baseline characteristics of patients in Cohort A are shown in Tables 1-3.1

Table 1. Cohort A: Patient Demographics and Baseline Characteristics.1

Table 2. Cohort A: Baseline Blood Pressure.1

Table 3. Cohort A: Baseline Antihypertensive Medications.1

Cohort B

Demographics and baseline characteristics for patients in Cohort B are provided in Table 4.4

Table 4. Cohort B: Patient Demographics and Baseline Characteristics.4

 Efficacy Results

Cohort A

Primary Endpoint

In Cohort A, the mean change from baseline in office SBP at Month 3 was -7.3 mmHg in the placebo arm, ‑12.3 mmHg in the zilebesiran 300 mg arm, resulting in a least squares means of ‑5.0 (95% CI ‑9.9, ‑0.2; P=0.04) mmHg compared with placebo, and -10.6 mmHg in the zilebesiran 600 mg arm, resulting in a least squares mean of -3.3 (95% CI -8.2, 1.6; P=0.18) mmHg compared with placebo (Figure 1).1

Figure 1. Cohort A: Placebo-Adjusted Change from Baseline in Office SBP at Month 3.1

Cohort A Key Secondary Endpoints

Change from Baseline in Office SBP at Month 6

In Cohort A, the mean change from baseline in office SBP at Month 6 was -7.9 mmHg in the placebo arm, ‑11.8 mmHg in the zilebesiran 300 mg arm, resulting in a least squares means (95% CI) of ‑3.9 (‑8.5, 0.7) mmHg compared with placebo, and -11.5 mmHg in the zilebesiran 600 mg arm, resulting in a least squares mean (95% CI) of -3.6 (-8.2, 1.0) mmHg compared with placebo (Figure 2).1

Figure 2. Cohort A: Placebo-Adjusted Change from Baseline in Office SBP at Month 6.1

Change from Baseline in 24-Hour Mean Ambulatory SBP at Months 3 and 6

In Cohort A, the mean change from baseline in 24-hour mean ambulatory SBP at Month 3 was ‑11.4 mmHg in the placebo arm, -15.0 mmHg in the zilebesiran 300 mg arm, resulting in a least squares mean (95% CI) of -3.6 (-7.7, 0.4) mmHg compared with placebo, and -14.0 mmHg in the zilebesiran 600 mg arm, resulting in a least squares mean (95% CI) of -2.6 (-6.7, 1.6) mmHg compared with placebo (Figure 3).1

In Cohort A, the mean change from baseline in 24-hour mean ambulatory SBP at Month 6 was ‑8.2 mmHg in the placebo arm, -13.6 mmHg in the zilebesiran 300 mg arm, resulting in a least squares mean (95% CI) of -5.5 (-9.4, -1.5) mmHg compared with placebo, and -15.6 mmHg in the zilebesiran 600 mg arm, resulting in a least squares mean (95% CI) of -7.4 (-11.3, -3.4) mmHg compared with placebo (Figure 3).1

Figure 3. Cohort A: Placebo-Adjusted Change from Baseline in 24-Hour Mean Ambulatory SBP at Months 3 and 6.1

Additional Secondary and Exploratory Endpoints

In Cohort A, the ambulatory SBP measured across a 24-hour period over 6 months with the hourly mean daytime/nighttime ambulatory SBP at Month 6 is provided in Figure 4. The change (95% CI) from baseline in mean daytime ambulatory SBP was -4.9 (-8.9, -0.8) mmHg in the zilebesiran 300 mg arm and ‑6.9 (-11.0, -2.8) mmHg in the zilebesiran 600 mg arm, and the change (95% CI) from baseline in mean nighttime ambulatory SBP was -6.6 (‑11.0, ‑2.2) mmHg in the zilebesiran 300 mg arm and ‑8.2 (‑12.6, -3.8) mmHg in the zilebesiran 600 mg arm (Figure 4).1

Figure 4. Cohort A: Hourly Mean (Exploratory Endpoint) and Placebo-Adjusted Change from Baseline (Secondary Endpoint) in Mean Daytime/Nighttime Ambulatory SBP at Month 6.1

Subgroup Analyses: Diuretic Treatment ± Baseline SBP ≥140 mmHg

In a prespecified subgroup analysis of patients on diuretic treatment in Cohort A, the mean change from baseline in office SBP at Month 3 was -7.7 mmHg in the placebo arm, -14.3 mmHg in the zilebesiran 300 mg arm, resulting in a least squares mean (95% CI) of -6.6 (-13.2, 0.0) mmHg compared with placebo, and ‑5.1 mmHg in the zilebesiran 600 mg arm, resulting in a least squares mean (95% CI) of -5.1 (‑11.8, 1.6) mmHg compared with placebo (Figure 5).1

In a post-hoc subgroup analysis of patients on diuretic treatment and with a baseline SBP ≥140 mmHg in Cohort A, the mean change from baseline in office SBP at Month 3 was -12.0 mmHg in the placebo arm, -21.3 mmHg in the zilebesiran 300 mg arm, resulting in a least squares mean (95% CI) of ‑9.2 (‑17.3, ‑1.2) mmHg compared with placebo, and -19.0 mmHg in the zilebesiran 600 mg arm, resulting in a least squares mean (95% CI) of -7.0 (-15.3, 1.3) mmHg compared with placebo (Figure 5). The least squares mean (95% CI) in office SBP was sustained to Month 6: -8.3 (-16.4, -0.2) mmHg in the zilebesiran 300 mg arm and -6.2 (-14.4, 2.0) mmHg in the zilebesiran 600 mg arm compared with placebo.1

Figure 5. Cohort A: Placebo-Adjusted Change from Baseline in Office SBP at Month 3.1

Cohort B

Primary Endpoint

In Cohort B, the mean change from baseline in office SBP at Month 3 was -7.8 mmHg in the placebo arm, ‑13.1 mmHg in the zilebesiran 150 mg arm resulting in a least squares mean (95% CI) of ‑5.4 (‑14.9, 4.1) mmHg compared with placebo, -10.2 mmHg in the zilebesiran 300 mg arm resulting in a least squares mean (95% CI) of -2.4 (-11.7, 6.8) mmHg compared with placebo, and -8.9 in the zilebesiran 600 mg arm  resulting in a least squares mean (95% CI) of -1.1 (-10.5, 8.2) mmHg compared with placebo (Figure 6).4

Figure 6. Cohort B: Placebo-Adjusted Change from Baseline in Office SBP at Month 3.4

 Safety Results

Cohort A

The majority of AEs through Month 6 were mild or moderate in severity. The rates of hyperkalemia, kidney dysfunction, and hypotension were low and consistent with findings from previous zilebesiran studies. Most instances of hyperkalemia or kidney dysfunction were not confirmed by subsequent measurement (Table 5).1

Table 5. Cohort A: Adverse Events Through Month 6.1

Cohort B

Zilebesiran had an acceptable safety profile, with most AEs being mild to moderate and transient. One serious AE (hospitalization for cholecystitis and laparoscopic cholecystectomy) reported in a patient who received zilebesiran 150 mg was considered related by the Investigator, which was later resolved and the patient fully recovered. One death by cardiac arrest on Day 85 was reported in a patient who received zilebesiran 150 mg, which was not considered treatment-related by the Investigator. Additional details are provided in (Table 6).4

Most hyperkalemia events were transient and occurred by Month 2. No hyperkalemia events required hospitalization or dialysis. Most reductions in eGFR were transient and none required hospitalization or dialysis. The 2 events of dizziness and syncope were transient and not serious.4

Table 6. Cohort B: Adverse Events Through Month 6.4

 Abbreviations

ACEi = angiotensin-converting enzyme inhibitor; AE = adverse event; AGT = angiotensinogen; ARB = angiotensin receptor blocker; ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CCB = calcium channel blocker; CI = confidence interval; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; GalNAc = N‑acetyl galactosamine; mRNA = messenger RNA; RNAi = RNA interference; SBP = systolic blood pressure; SD = standard deviation.

Updated 7 January 2026

 References

1.  Pagidipati N, Weber M, Saxena M, et al. KARDIA-3: Zilebesiran as add-on therapy in adults with hypertension who have established cardiovascular disease or are at high cardiovascular risk. Presented at: European Society of Cardiology (ESC) Congress; August 29 - September 1, 2025; Madrid, Spain.

2.  Alnylam Pharmaceuticals: Zilebesiran as add-on therapy in patients with high cardiovascular risk and hypertension not adequately controlled by standard of care antihypertensive medications (KARDIA-3). Available from: https://www.clinicaltrials.gov/study/NCT06272487. Accessed January 24, 2025.

3.  Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N Engl J Med. 2023;389(3):228-238. doi:10.1056/NEJMoa2208391

4.  Pagidipati N, Weber M, Saxena M, et al. KARDIA-3: A randomized trial of zilebesiran versus placebo on top of standard care for patients with hypertension and established cardiovascular disease or high cardiovascular risk with or without chronic kidney disease. Presented at: American Heart Association (AHA) Congress; November 7-10, 2025; New Orleans, LA, USA.

5.  Havasi A, Pagidipati N, Bakris GL, et al. KARDIA-3 study design: Zilebesiran as add-on therapy in patients with high cardiovascular risk and hypertension inadequately controlled by standard of care antihypertensives. Presented at: European Meeting on Hypertension and Cardiovascular Protection (ESH); May 31-June 3, 2024; Berlin, Germany.