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Zilebesiran Reduces Uncontrolled Hypertension as Addition to Standard of Care in Phase 2 KARDIA-2 Trial
Topline KARDIA-2 findings showed zilebesiran led to clinically and statistically significant reductions in SBP on top of either a diuretic, CCB, or ARB.
Zilebesiran, the investigational RNA interference (RNAi) therapeutic for treatment of inadequately controlled hypertension, led to clinically and statistically significant reductions in 24-hour mean systolic blood pressure (SBP) at 3 months when added to common standard of care (SOC) treatments for hypertension.1
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The findings, announced today by codevelopers Alnylam Pharmaceuticals and Roche,1 satisfy the primary endpoint of the phase 2 KARDIA-2 clinical trial, and set the stage for the full results to be presented at the 2024 American College of Cardiology Scientific Session, on April 7.
The additive, placebo-adjusted reductions in mean SBP were measured using ambulatory blood pressure monitoring (ABPM) in 3 independent KARDIA study cohorts, each of which received standardized background treatment with either a thiazide-like diuretic (indapamide), a calcium channel blocker (amlodipine) or an angiotensin receptor blocker (olmesartan). Safety and tolerability findings with zileabesiran as an addition to SOC therapy were “encouraging,” the companies reported.
Roche and Alnylam also said that these mid-stage findings support the every-6-month treatment regimen that was established as effective in the phase 1 KARDIA-1 study.2 In that trial in the same population studied in KARDIA-2, treatment with single subcutaneous doses of zilebesiran was associated with dose-dependent reductions in serum angiotensinogen (AGT) and 24-hour ambulatory BP that were sustained for 24 weeks.2
“These KARDIA-2 results, showing durable additional levels of blood pressure reduction on top of what is achieved by standard of care first-line antihypertensives with an encouraging safety profile, reinforce our confidence in zilebesiran’s differentiated profile,” Simon Fox, PhD, vice president and zilebesiran program lead at Alnylam said in the company announcement.1
“These KARDIA-2 results, showing durable additional levels of blood pressure reduction on top of what is achieved by standard of care first-line antihypertensives with an encouraging safety profile, reinforce our confidence in zilebesiran’s differentiated profile."
The RNAi therapeutic targets liver-expressed angiotensinogen (AGT), the most upstream precursor in the renin-angiotensin-aldosterone system, (RAAS) a cascade with a well-recognized role in regulation of blood pressure (RAAS inhibition is a standard antihypertension mechanism). Through its inhibition of hepatic AGT synthesis, zilebesiran may lead to enduring reductions in AGT protein and ultimately, reductions in the vasoconstrictor angiotensin II, according to the codevelopers.
KARDIA-2
KARDIA-2 evaluated the efficacy and safety of zilebesiran added to standard-of-care antihypertensive treatment in 672 adults with mild-to-moderate hypertension that remained uncontrolled despite SOC therapy. Study participants were first randomized into 3 cohorts to receive open-label treatment with olmesartan, amlodipine or indapamide during run in period of at least 4 weeks. Those eligible after the run-in period were randomly assigned in 1:1 ratio to receive 600 mg zilebesiran or placebo in addition to the protocol-specified background antihypertensive medication for 6 months.
The study’s primary endpoint was the change from baseline in mean SBP at month 3, assessed by 24-hour ABPM. Secondary end points included change in 24-hour mean SBP after 6 months measured by ABPM, change in office SBP at months 3 and 6, and change in diastolic blood pressure measured by ABPM and office blood pressure at months 3 and 6.
The companies also announced the initiation of the global, phase 2 KARDIA-3 study, designed to evaluate the efficacy and safety of zilebesiran as an add-on therapy for adults with high cardiovascular risk and uncontrolled hypertension despite SOC antihypertensive treatment.
Investigators will enroll 2 cohorts in KARDIA-3: cohort A will comprise participants with estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.72m2 and cohort B will enroll adults with eGFR 30 to <45 mL/min/1.73m2. After screening, all eligible participants will be assigned randomly to receive either zilebesiran (300 or 600 mg) or placebo in cohort A, or zilebesiran (150, 300, or 600 mg) or placebo in cohort B, for a 6-month, double-blind treatment period.
The primary endpoint for KARDIA-3 is change from baseline at month 3 in mean seated office SBP. Other endpoints will include the change from baseline at month 3 in 24-hour mean SBP assessed by ABPM, change from baseline at month 6 in mean seated office SBP, and 24-hour SBP assessed by ABPM. Safety will be assessed during a 6-month follow-up period following the treatment period.
