Zilebesiran: KARDIA-3 Study

Zilebesiran: KARDIA-3 Study

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 Summary

Abbreviations

AE = adverse event; AGT = angiotensinogen; ASCVD = atherosclerotic cardiovascular disease; CCB = calcium channel blocker; CI = confidence interval; CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular filtration rate; GalNAc = N‑acetyl galactosamine; LS = least-squares; LSMD = least squares mean difference; mRNA = messenger RNA; RAAS = renin-angiotensin-aldosterone system; RNAi = RNA interference; SBP = systolic blood pressure.

 Index

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

 Study Design

The KARDIA‑3 (NCT06272487) study was 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.3,6,7

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 30-44 mL/min/1.73m2.3

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.3,4

The primary endpoint of the study was 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 was the hourly mean daytime/nighttime ambulatory SBP at Month 6. A mixed model for repeated measurements was used for the primary analysis.3 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.3,4

Key study inclusion criteria included3,4:

         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 included6:

      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 1-3.3

Table 1. Cohort A: Patient Demographics and Baseline Characteristics.3

Table 2. Cohort A: Baseline Blood Pressure.3

Table 3. Cohort A: Baseline Antihypertensive Medications.3

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

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

Figure 1. Cohort A: Placebo-Adjusted Change from Baseline in Office SBP at Month 3.3

Cohort A Key Secondary Endpoints

Change from Baseline in Office SBP at Month 6

The LS mean change from baseline in office SBP at Month 6 was -7.9 mmHg in the placebo arm and ‑11.8 mmHg in the zilebesiran 300 mg arm, resulting in a LSMD (95% CI) of ‑3.9 (‑8.5, 0.7) mmHg. In the zilebesiran 600 mg arm, the LS mean change from baseline was -11.5 mmHg, with a LSMD (95% CI) of -3.6 (-8.2, 1.0) mmHg (Figure 2).3

Figure 2. Cohort A: Placebo-Adjusted Change from Baseline in Office SBP at Month 6.3

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

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

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

Figure 3. Cohort A: Placebo-Adjusted Change from Baseline in 24-Hour Mean Ambulatory SBP at Months 3 and 6.3

Additional Secondary and Exploratory Endpoints

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 LS mean 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. The LS mean 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).3

Figure 4. Cohort A: Hourly Mean (Exploratory Endpoint) and Placebo-Adjusted Change from Baseline (Secondary Endpoint) in Mean Daytime/Nighttime Ambulatory SBP at Month 6.3

Subgroup Analyses: Diuretic Treatment

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 LSMD (95% CI) of -6.6 (-13.2, 0.0) mmHg compared with placebo. In the zilebesiran 600 mg arm, the LS mean change from baseline was ‑12.7 mmHg, with a LSMD (95% CI) of ‑5.1 (‑11.8, 1.6) mmHg (Figure 5).3

Post-Hoc Subgroup Analysis: Diuretic Treatment ± Baseline SBP ≥140 mmHg

In a post-hoc subgroup analysis of patients on diuretic treatment with a baseline office SBP ≥140 mmHg the mean change from baseline in office SBP at Month 3 was -12.0 mmHg in the placebo arm and ‑21.3 mmHg in the zilebesiran 300 mg arm, resulting in a LSMD (95% CI) of ‑9.2 (‑17.3, ‑1.2) mmHg. In the zilebesiran 600 mg arm, the mean change from baseline in office SBP was -19.0 mmHg, with a LSMD (95% CI) of -7.0 (-15.3, 1.3) mmHg (Figure 5). At Month 6, the LSMDs (95% CI) in office SBP were ‑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.3

Figure 5. Cohort A: Placebo-Adjusted Change from Baseline in Office SBP at Month 3.3

In this post-hoc analysis, the placebo-adjusted change (95% CI) from baseline in mean daytime ambulatory SBP was -7.9 (-13.8, -2.0) mmHg in the pooled zilebesiran 300 mg and 600 mg arms and the placebo-adjusted change (95% CI) from baseline in mean nighttime ambulatory SBP was -8.6 (‑14.6, ‑2.5) mmHg in the pooled zilebesiran 300 mg and 600 mg arms. The placebo-adjusted change (95% CI) from baseline in 24-hour ambulatory SBP at Month 6 was-8.1 (-13.9, -2.4) mmHg.5

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).3

Table 5. Cohort A: Adverse Events Through Month 6.3

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

References

1.  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

2.  Alnylam Pharmaceuticals. Zilebesiran in patients with hypertension not adequately controlled and with either established cardiovascular disease or high risk for cardiovascular disease (ZENITH). Available from: https://clinicaltrials.gov/study/NCT07181109. Accessed September 1, 2026.

3.  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.

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.  Pagidipati N, Weber M, Saxena M, et al. Zilebesiran in combination with a diuretic in patients with uncontrolled hypertension: a subgroup analysis from the phase 2 KARDIA-3 trial. Presented at: European Society of Cardiology (ESC) Congress; August 28-31, 2026; Munich, Germany.

6.  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.

7.  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 September 1, 2026.

Updated 1 September 2026