Zilebesiran: KARDIA-1 Study
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The safety and efficacy of zilebesiran are currently being investigated in clinical studies and have not been evaluated by FDA or any health authority.
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Summary
KARDIA-1 was a phase 2 study to evaluate the safety and efficacy of zilebesiran dosing regimens for adults with mild to moderate hypertension. Statistically significant decreases in both 24‑hour mean ambulatory SBP and office SBP measures were observed across all zilebesiran regimens studied through Months 3 and 6.1 AEs occurring in >5% of patients treated with zilebesiran were ISRs (6%, n=19/302) and hyperkalemia (5%, n=16/302), which were mild to moderate in severity and transient in nature.1 |
Study Design – Patient Demographics & Baseline Characteristics – Primary Endpoint – Secondary Endpoints – Exploratory Endpoint – Abbreviations – References
The KARDIA-1 study (NCT04936035) was a phase 2, randomized, double-blind, placebo-controlled, dose-ranging multicenter study to evaluate the efficacy and safety of zilebesiran in patients aged 18-75 years with mild-to-moderate hypertension (N=394). Patients included in the study had a daytime mean SBP ≥135 mmHg and ≤160 mmHg (evaluated through ABPM) without antihypertensive medication.1
Study participants were randomized to receive subcutaneous administration of either zilebesiran (150 mg q6m, 300 mg q6m, 300 mg q3m, or 600 mg q6m) or placebo for the first 6 months of the 12‑month double‑blind period. Prior to randomization, a washout period of ≥2 weeks, or 4 weeks for long-acting hypertensives (eg, long-acting diuretics or calcium channel blockers), was required for patients previously taking antihypertensive medications.1–3
At month 6, participants randomized to placebo were re-randomized to 1 of the 4 initial dosing regimens until the end of the 12-month double-blind treatment period. Participants originally randomized to zilebesiran regimens remained on their originally assigned treatment arm through the remainder of the study.2 Patients could receive rescue antihypertensives at the discretion of the Investigator between months 3 and 5 and after month 6. Washout of rescue antihypertensives was required between months 5 and 6. Blood pressure measures were censored while patients were on or within 2 weeks after stopping a rescue antihypertensive.3
The primary endpoint was the change from baseline in 24-hour mean ambulatory SBP at month 3.1
Secondary endpoints assessed include1:
Change from baseline at month 3 in office SBP
Change from baseline at month 6 in 24-hour mean SBP, assessed by ABPM
Change from baseline at month 6 in office SBP
Proportion of patients with 24-hour mean SBP <130 mmHg and/or reduction of ≥20 mmHg from baseline without additional antihypertensive medications at month 6
Change from baseline at month 6 in 24-hour mean DBP
Change from baseline at month 6 in office DBP
Change from baseline at month 6 in serum AGT
Change from baseline at month 6 in daytime and nighttime BP
Analyses were also conducted to assess the consistency of the zilebesiran treatment effect in various prespecified subgroups by the following baseline characteristics: age (<65 or ≥65 years), sex, race (Black or other), baseline 24-hour mean ambulatory SBP (<145 or ≥145 mmHg), and eGFR (<60 or ≥60 mL/min/1.73m2).1
Exploratory endpoints of the study evaluated the effect of zilebesiran over time on other measures of blood pressure reduction, such as the percentage of patients requiring rescue antihypertensives.1,2
Patient Demographics & Baseline Characteristics
A total of 394 patients were randomized, with 377 patients included in the full analysis set. The baseline characteristics by treatment assignment are summarized in Table 1.1
Table 1. Baseline Demographics and Disease Characteristics in KARDIA-1.1,a
Characteristic | Zilebesiran | Placebo (n=75) | |||
150 mg q6m (n=78) | 300 mg q6m (n=73) | 300 mg q3m (n=75) | 600 mg q6m (n=76) | ||
Mean age, years (SD) | 55.5 (10.6) | 56.4 (10.3) | 57.7 (10.6) | 57.4 (10.2) | 56.8 (11.2) |
Male sex, n (%) | 39 (50) | 44 (60) | 45 (60) | 45 (59) | 37 (49) |
Race, n (%)b |
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American Indian or Alaska Native | 1(1) | 0 | 0 | 0 | 0 |
Asian | 4 (5) | 2 (3) | 7 (9) | 5 (7) | 5 (7) |
Black or African American | 20 (26) | 17 (23) | 19 (25) | 19 (25) | 18 (24) |
Native Hawaiian or Pacific Islander | 0 | 0 | 1 (1) | 0 | 0 |
White | 53 (68) | 54 (74) | 48 (64) | 52 (68) | 52 (69) |
Ethnicity, n (%)b |
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Hispanic or Latino | 19 (24) | 16 (22) | 10 (13) | 20 (26) | 9 (12) |
BMI ≥30, n (%) | 46 (59) | 46 (63) | 40 (53) | 45 (59) | 37 (49) |
Type 2 diabetes, n (%)c | 14 (18) | 11 (15) | 17 (23) | 16 (21) | 10 (13) |
Receiving ≥1 hypertensive agent before study enrollment, n (%)d | 43 (55) | 55 (75) | 57 (76) | 63 (83) | 55 (73) |
24-hour ambulatory SBP/DBP, mean (SD), mmHg | 140.6 (8.5)/ 81.7 (8.3) | 142.5 (8.8)/ 82.3 (8.7) | 141.6 (7.7)/ 82.0 (8.6) | 143.1 (9)/ 81.4 (8.3) | 141.1 (7.9)/ 81.7 (7.8) |
Office SBP/DBP, mean (SD), mmHg | 142.0 (10.9)/ 87.4 (9.6) | 143.0 (11.3)/ 88.8 (8.8) | 140.0 (11.0)/ 85.3 (9.1) | 140.8 (10.6)/ 85.6 (8.8) | 143.1 (13.3)/ 87.9 (10.5) |
eGFR, mean (SD), mL/min/1.73m2 | 81.7 (16.5) | 82.0 (14.5) | 80.2 (18.3) | 81.9 (19.4) | 78.7 (21.0) |
eGFR ≥60 mL/min/1.73m2, n (%) | 68 (87) | 70 (96) | 69 (92) | 68 (90) | 64 (85) |
Serum AGT concentration, mean (SD), ng/mL | 22.1 (5.9) | 23.2 (7.8) | 20.8 (4.9) | 21.7 (5.9) | 23.9 (10.9) |
Abbreviations: AGT = angiotensinogen; BMI = body mass index; BP = blood pressure; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; q3m = every 3 months; q6m = every 6 months; SBP = systolic blood pressure; SD = standard deviation. aAll randomized patients who received any amount of study drug. Patients enrolled at sites in Ukraine (n = 16) were excluded from the analysis populations. bRace and ethnicity were self-reported from patient to the investigator in closed categories. For ethnicity, categories were Hispanic or Latino, not Hispanic or Latino, not reported, or unknown. For race, categories were American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, other (please specify), or not reported. cPatients who met the study inclusion criteria with at least 1 of the following: medical history of type 2 diabetes, glycated hemoglobin A1c >7% before first study drug dose, or taking diabetes medication before first study drug dose. dSafety analysis set included all patients who received any amount of study drug, grouped according to the treatment actually received. | |||||
Change in 24-Hour Mean Ambulatory SBP at Month 3
At month 3, the LSM differences in the change from baseline in 24-hour mean ambulatory SBP between zilebesiran and placebo were −14.1 mmHg (95% CI, −19.2 to −9.0; P<0.001) for zilebesiran 150 mg every 6 months; −16.7 mmHg (95% CI, −21.2 to −12.3; P<0.001) for zilebesiran 300 mg every 3 months or every 6 months; and −15.7 mmHg (95% CI, −20.8 to −10.6; P<0.001) for zilebesiran 600 mg every 6 months (Figure 1).1
Figure 1. 24-Hour Mean Ambulatory SBP (Full Analysis Set).1,a
Abbreviations: IQR = interquartile range; mo = month; no = number; SBP = systolic blood pressure.
aThe full analysis set included all randomized patients who received any amount of study drug, analyzed according to randomized treatment. Box plots demonstrate median (thick horizontal line), mean (circle), IQR (box top and bottom), highest and lowest values within 1.5x IQR (whiskers), and more extreme values (diamonds). For the efficacy analyses of endpoints assessed at month 3, the zilebesiran 300 mg and 600 mg groups were combined because both had received the same zilebesiran dose.
From Bakris et al.1
Systolic Blood Pressure
The changes from baseline in office SBP at months 3 and 6 and in 24-hour mean ambulatory SBP at month 6 are summarized in Table 2.1
Table 2. Change from Baseline to Month 3 or 6 in 24-Hour Mean Ambulatory and Office SBP (Full Analysis Set).1,a
Outcome | Zilebesiran | Placebo (n=75) | ||||
150 mg q6m (n=78) | 300 mg q6m (n=73) | 300 mg q3m (n=75) | 300 mg q6m or q3m (n=148) | 600 mg q6m (n=76) | ||
Office SBP at month 3, mean (SD), mmHg | 131.8 (13.6) [n=68] | − | − | 129.1 (13.8) [n=134] | 131.1 (15.9) [n=64] | 141.4 (12.6) [n=60] |
LSM change from baseline (95% CI), mmHg | -9.7 (-12.6 to ‑6.8) | − | − | -12.1 (‑14.2 to ‑10.0) [n=133] | -9.2 (-12.1 to ‑6.2) | -0.1 (-3.2 to 3.0) |
LSMD vs placebo (95% CI), mmHgb | -9.6 (‑13.8 to ‑5.3) | − | − | ‑12.0 (‑15.7 to ‑8.3) [n=133] | -9.1 (-13.4 to ‑4.8) | − |
P-value | <0.001 | − | − | <0.001 | <0.001 | − |
Ambulatory SBP at month 6, mean (SD), mmHg | 134.4 (15.0) [n=62] | 132.2 (13.8) [n=68] | 131.6 (12.2) [n=60] | − | 131.7 (16.8) [n=63] | 144.6 (15.0) [n=54] |
LSM change from baseline (95% CI), mmHg | -6.5 (-9.7 to -3.3) | -9.9 (-13.0 to ‑6.8) | -9.5 (-12.8 to ‑6.3) | − | -9.6 (-12.8 to ‑6.4) | 4.6 (1.2 to 8.0) |
LSMD vs placebo (95% CI) , mmHgb | -11.1 (-15.8 to ‑6.4) | -14.5 (-19.1 to ‑9.9) | -14.1 (-18.9 to ‑9.4) | − | -14.2 (-18.9 to ‑9.5) | − |
P-value | <0.001 | <0.001 | <0.001 | − | <0.001 | − |
Office SBP at month 6, mean (SD), mmHg | 133.7 (13.6) [n=65] | 131.2 (16.1) [n=68] | 127.4 (14.5) [n=58] | − | 128.9 (15.6) [n=62] | 140.6 (12.4) [n=57] |
LSM change from baseline (95% CI), mmHg | -8.2 (-11.5 to ‑4.8) | -11.1 (-14.4 to ‑7.8) | -12.8 (‑16.3 to ‑9.2) [n=57] | − | -10.8 (‑14.2 to ‑7.4) | -0.6 (‑4.2 to 2.9) |
LSMD vs placebo (95% CI), mmHgb | -7.5 (‑12.4 to ‑2.7) | -10.5 (-15.3 to ‑5.7) | -12.1 (-17.2 to ‑7.1) [n=57] | − | ‑10.2 (‑15.1 to ‑5.3) | − |
P-value | 0.003 | <0.001 | <0.001 | − | <0.001 | − |
Abbreviations: CI = confidence interval; LSM = least-squares mean; LSMD = least-squares mean difference; q3m = every 3 months; q6m = every 6 months; SBP = systolic blood pressure; SD = standard deviation. aAll randomized patients who received any amount of study drug, analyzed according to randomized treatment. bMixed model for repeated measures adjusted for race and corresponding baseline SBP. | ||||||
At months 3 and 6, reductions from baseline SBP were consistent for each hour of the 24-hour diurnal cycle in zilebesiran-treated patients and were greater in magnitude than placebo across all zilebesiran regimens studied.1
Subgroup Analyses of SBP
At month 3, the ambulatory SBP reductions were generally consistent across subgroups (Figure 2).4 A variation in SBP reduction was observed in the race subgroup, in which Black patients experienced lower SBP reduction compared to patients of all other races. A post hoc analysis of the subgroup defined by baseline PRC identified that this racial variation was largely attributed to the low baseline PRC in Black patients (median of 5.2 mIU/L) compared to the PRC level (median of 13.5 mIU/L) in patients of all other races. Patients with higher baseline PRC had greater mean reductions across both 24-hour mean ambulatory SBP and office SBP measures (Table 3).4
Figure 2. LSMD (95% CI) for Zilebesiran (All Doses Combined) vs Placebo.4
- Change from Baseline to Month 3 in 24-Hour Mean Ambulatory SBP
- Change from Baseline to Month 3 in Mean Office SBP
Abbreviations: ABPM = ambulatory blood pressure monitoring; BL = baseline; CI = confidence interval; eGFR = estimated glomerular filtration rate; hr = hours; LSMD = least-squares mean difference; PRC = plasma renin concentration; SBP = systolic blood pressure.
a24-hour mean SBP assessed by ABPM.
bBaseline PRC above or below median (11mIU/L).
From Saxena et al.4
Table 3. LSM Change from Baseline to Month 3 in SBP by PRC and Race Subgroups.4,a
Race | Baseline PRC Above or Below Median (11 mIU/L) | Zilebesiran (all doses combined) | |
24-hour Mean Ambulatory SBP (SE) | Office SBP (SE) | ||
Black Median PRC: 5.2 mIU/L | ≤ 11 mIU/L (n=52) | -0.7 (2.1) | -2.7 (2.0) |
>11 mIU/L (n=17) | -12.1 (3.0) | -13.4 (2.5) | |
All other races Median PRC: 13.5 mIU/L | ≤11 mIU/L (n=96) | -8.3 (1.2) | -10.9 (1.2) |
>11 mIU/L (n=129) | -12.6 (1.1) | -13.7 (1.1) | |
Abbreviations: LSM = least-squares mean; PRC = plasma renin concentration; SBP = systolic blood pressure; SE = standard error.
aPlacebo data not presented owing to small sample size.
Diastolic Blood Pressure
The changes from baseline in 24-hour mean ambulatory DBP and office DBP at months 3 and 6 were consistent with the observed changes in SBP and are summarized in Table 4.1,3
Table 4. Change from Baseline to Month 3 or 6 in 24-Hour Mean Ambulatory and Office DBP (Full Analysis Set).3,a
Outcome | Zilebesiran | Placebo (n=75) | ||||
150 mg q6m (n=78) | 300 mg q6m (n=73) | 300 mg q3m (n=75) | 300 mg q6m or q3m (n=148) | 600 mg q6m (n=76) | ||
Ambulatory DBP at month 3, mean (SD), mmHg | 76.7 (10.6) [n=68] | − | − | 76.1 (9.3) [n=137] | 75.4 (8.2) [=65] | 84.8 (9.3) [n=60] |
LSM change from baseline (95% CI), mmHg | -4.5 (-6.1 to -2.9) | − | − | -5.7 (-6.8 to -4.5) | -5.8 (-7.4 to -4.1) | 3.5 (1.8 to 5.2) |
LSMD vs placebo (95% CI), mmHg | -8.0 (-10.3 to -5.6) | − | − | -9.2 (-11.2 to -7.1) | -9.2 (-11.6 to -6.8) | − |
Office DBP at month 3, mean (SD), mmHg | 81.6 (10.0) [n=68] | − | − | 79.8 (9.5) [n=134] | 80.0 (9.6) [n=64] | 86.8 (8.5) [n=60] |
LSM change from baseline (95% CI), mmHg | -5.3 (-7.2 to -3.4) | − | − | -7.0 (-8.4 to -5.7) [n=133] | -5.4 (-7.3 to -3.5) | -0.6 (-2.6 to 1.3) |
LSMD vs placebo (95% CI), mmHg | -4.7 (-7.4 to -2.0) | − | − | -6.4 (-8.8 to -4.0) [n=133] | -4.7 (-7.5 to -2.0) | − |
Ambulatory DBP at month 6, mean (SD), mmHg | 76.8 (11.5) [n=62] | 75.9 (8.9) [n=68] | 75.6 (9.4) [n=60] | − | 74.2 (9.5) [n=63] | 83.1 (10.9) [n=54] |
LSM change from baseline (95% CI), mmHg | -4.8 (-6.6 to -3.0) | -6.1 (-7.9 to -4.4) | -6.3 (-8.1 to -4.5) | − | -6.3 (-8.0 to -4.5) | 2.2 (0.3 to 4.1) |
LSMD vs placebo (95% CI), mmHg | -7.0 (-9.6 to -4.3) | -8.3 (-10.9 to -5.7) | -8.5 (-11.1 to -5.8) | − | -8.4 (-11.0 to -5.8) | − |
Office DBP at month 6, mean (SD), mmHg | 83.2 (11.0) [n=65] | 81.3 (11.3) [n=68] | 77.6 (10.1) [n=58] | − | 79.8 (12.1) [n=62] | 86.1 (11.1) [n=57] |
LSM change from baseline (95% CI), mmHg | -4.1 (-6.3 to -1.8) | -6.8 (-9.0 to -4.6) | -8.2 (-10.5 to -5.8) [n=57] | − | -5.0 (-7.3 to -2.8) | -1.2 (-3.6 to 1.2) |
LSMD vs placebo (95% CI), mmHg | -2.9 (-6.1 to 0.4) | -5.6 (-8.8 to -2.4) | -7.0 (-10.3 to -3.6) [n=57] | − | -3.8 (-7.1 to -0.6) | − |
Abbreviations: CI = confidence interval; DBP = diastolic blood pressure; LSM = least-squares mean; LSMD = least-squares mean difference; q3m = every 3 months; q6m = every 6 months; SD = standard deviation. aAll randomized patients who received any amount of study drug, analyzed according to randomized treatment. | ||||||
Serum Angiotensinogen
The change from baseline to months 3 and 6 in serum AGT was greater in patients receiving any dose of zilebesiran compared with those who received placebo (Figure 3). After single 300 mg or 600 mg doses of zilebesiran, a decrease greater than 90% in serum AGT was observed and persisted to month 6.1,3
Figure 3. Mean Percent Change from Baseline in Serum AGT.3,a
Abbreviations: AGT = angiotensinogen; BL = baseline; CI = confidence interval
aData points are staggered for visualization.
From Bakris et al.3
Patients Requiring Rescue Antihypertensives
During the 6-month double-blind treatment period, a higher percentage of patients in the placebo arm required rescue antihypertensives (52.0%) compared to patients in the zilebesiran arms (20.5%–32.1%). In all study arms, the most frequently prescribed classes of rescue antihypertensives were calcium channel blockers and diuretics.1
Drug-related AEs reported in >5% of patients treated with zilebesiran included ISRs (n=19/302, 6.3%) and hyperkalemia (n=16/302, 5.3%); all of these events were mild to moderate in severity and transient in nature (Table 5). Serious AEs were reported in 5 patients (6.7%) in the placebo group and 11 patients (3.6%) in the zilebesiran groups, none of which were considered related to the study drug. There were 3 patients with drug-related AEs leading to dose interruption and 4 patients with drug-related AEs leading to discontinuation (orthostatic hypotension [n=2], BP elevation [n=1], and injection site reaction [n=1]).1
Among the treatment-emergent AEs of clinical interest, 1 event of AKI was reported in the zilebesiran 300 mg every 3 months arm, which was considered unrelated to zilebesiran. There were no serious hepatic AEs, and the majority of LFT elevations were transient and resolved while receiving treatment. Hypotension AEs were mild or moderate in severity and transient in nature, with one event in zilebesiran 300 mg every 3 months group requiring treatment with normal saline. Hyperkalemia AEs were mild and did not lead to acute kidney injury or study drug discontinuation.1
Table 5. Summary of AEs During the 6-Month Double-Blind Treatment Period.1,a
AE, n (%) | Zilebesiran | Zilebesiran Total (N=302) | Placebo (n=75) | |||
150 mg q6m (n=78) | 300 mg q6m (n=73) | 300 mg q3m (n=75) | 600 mg q6m (n=76) | |||
At least 1 AE | 45 (58) | 44 (60) | 46 (61) | 49 (64) | 184 (61) | 38 (51) |
Related to study drugb | 12 (15) | 12 (16) | 14 (19) | 13 (17) | 51 (17) | 6 (8) |
At least 1 SAEc | 0 | 1 (1) | 4 (5) | 6 (8) | 11 (4) | 5 (7) |
Related to study drugb | 0 | 0 | 0 | 0 | 0 | 0 |
At least 1 study drug-related AE leading to study drug interruptionb,d | 1 (1) | 0 | 1 (1) | 1 (1) | 3 (1) | 0 |
At least 1 study drug-related AE leading to study drug discontinuationb,e | 1 (1) | 1 (1) | 1 (1) | 1 (1) | 4 (1) | 0 |
Death | 0 | 0 | 1 (1) | 0 | 1 (<1) | 0 |
Study drug-related AEs occurring in at least 5% of patientsb | ||||||
Hyperkalemia | 4 (5) | 3 (4) | 4 (5) | 5 (7) | 16 (5) | 1 (1) |
ISR | 3 (4) | 4 (5) | 8 (11) | 4 (5) | 19 (6) | 0 |
Additional treatment-emergent AE of clinical interest (any relatedness) | ||||||
Potential hypotensionf | 6 (8) | 6 (8) | 5 (7) | 7 (9) | 24 (8) | 5 (7) |
Hyperkalemiag | 5 (6) | 4 (5) | 5 (7) | 5 (7) | 19 (6) | 2 (3) |
Hypotensionh | 3 (4) | 3 (4) | 3 (4) | 4 (5) | 13 (4) | 1 (1) |
Hepatic AEi | 2 (3) | 2 (3) | 4 (5) | 1 (1) | 9 (3) | 1 (1) |
Acute kidney failurej | 1 (1) | 1 (1) | 1 (1) | 1 (1) | 4 (1) | 0 |
Abbreviations: AE = adverse event; AKI = acute kidney injury; BP = blood pressure; ISR = injection site reaction; MedDRA = Medical Dictionary for Regulatory Activities; q3M = every 3 months; q6M = every 6 months; SAE = serious adverse event; SMQ = Standardized MedDRA Query. aAEs are defined per MedDRA terminology. bRelated to study drug indicates a reasonable possibility that the event may have been caused by the study drug as evaluated by the investigator. c Included AEs that were life-threatening, required hospitalization, prolonged existing hospitalization, or resulted in disability, birth defect, or death. dStudy drug interruption refers to a pause of further study drug dosing (including placebo dosing) with potential to resume. eStudy drug discontinuation is the stopping of further study drug dosing (including placebo dosing) without potential to resume. fInclude decreased blood pressure, hypotension, orthostatic hypotension, dizziness, syncope, and orthostasis. gInclude hyperkalemia, increased serum potassium, and abnormal serum potassium. hInclude additional terms of decreased blood pressure, hypotension, and orthostatic hypotension. iInclude AEs mapped to the standardized MedDRA query drug-related hepatic disorders, both narrow and broad terms. Terms include but are not limited to alanine aminotransferase increased; aspartate aminotransferase increased; serum alkaline phosphatase increased; serum bilirubin increased; gamma-glutamyltransferase increased; liver function test abnormal; liver function test increased; and transaminases increased. jAcute kidney failure includes events of increased serum creatinine, increased blood urea, decreased glomerular filtration rate, and acute kidney injury. | ||||||
ABPM = ambulatory blood pressure monitoring; AE = adverse event; AGT = angiotensinogen; AKI = acute kidney injury; BL = baseline; BMI = body mass index; BP = blood pressure; CI = confidence interval; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; ISR = injection site reaction; LSM = least-squares mean; LSMD = least‑squares mean difference; MedDRA = Medical Dictionary for Regulatory Activities; mo = month; no = number; PRC = plasma renin concentration; q3m = every 3 months; q6m = every 6 months; RNAi = RNA interference; SAE = serious adverse event; SBP = systolic blood pressure; SD = standard deviation; SE = standard error; SMQ = Standardized MedDRA Query.
Updated 14 July 2025
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MED-ALL-AGT-2400013 3.0 Approved through Jul 2027 |
