KARDIA-1 study met its primary and secondary endpoints, and the drug maintained a positive tolerability profile treating high systolic blood pressure.
Zilebesiran (Kardia; 300 and 600 mg) significantly reduced high systolic blood pressure (SBP) in 3 months, which achieved the primary endpoint of the recent phase 2 KARDIA-1 study, according to a Roche press release. Zilebesiran, an investigational RNAi therapeutic that targets liver-expressed angiotensinogen (AGT), also provided a consistent and sustained reduction in high SBP (hypertension) at 6 months, meeting a key primary secondary endpoint.
“These early results indicate the potential for zilebesiran to achieve sustained blood pressure reduction with quarterly or biannual dosing,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, in the press release.
High blood pressure is the primary cause of cardiovascular disease (CVD) worldwide, which puts many at risk for early death. Although 33% of all adults are believed to have hypertension, 80% of them have an uncontrolled condition and worsens their risk of CVD, cerebrovascular and renal disease.
Investigators conducted the phase 2 KARDIA-1 trial to evaluate zilebesiran for hypertension reduction. The primary endpoint was change in SBP from the start of the study to 3 months, assessed by 24-hour ambulatory blood pressure monitoring (ABPM). The key secondary and exploratory endpoints were a reduction in SBP at 6 months, time-adjusted change in blood pressure, and change in average daytime and night-time blood pressure.
The study included a 12-month double blind (DB) period and DB extension period. Investigators enrolled 394 adults with untreated hypertension or treated hypertension (at least 1 anti-hypertensive medication) who were randomized to 1 of 5 arms: 3 arms received subcutaneous zilebesiran once every 6 months at doses of 150 mg, 300 mg, or 600 mg. One arm received a dose of 300 mg once every 3 months, and the last group received placebo.
Zilebesiran reduced 24-hour mean SBP at 3 months. Specifically, the 300 mg and 600 mg doses reduced SBP by more than 15 mmHg (p < 0.0001). All doses of zilebesiran also changed the 24-hour mean SBP as measured by ABPM at 6 months and changed in-office SBP at 3 and 6 months compared to placebo. The new drug also had a positive safety and tolerability profile.
The early effects of hypertension are organ damage and reduced cognitive function, but uncontrolled high blood pressure can cause CVD (stroke, coronary artery disease, heart failure, peripheral artery disease), chronic kidney disease and end-stage renal disease, dementia, and Alzheimer disease.
Treating hypertension is an unmet need, the investigators noted. Zilebesiran functions by inhibiting AGT synthesis in the liver—AGT being an upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS) that regulates blood pressure—which can be very anti-hypertensive. The product, not yet FDA-approved, is being co-developed and co-commercialized by Alnylam and Roche.
Garraway concluded, “these data underscore the potential of this investigational medicine to provide transformative impact for many people living with uncontrolled hypertension."
Roche and Alnylam report positive topline results from Phase 2 study KARDIA-1 of zilebesiran, an investigational RNAi therapeutic in development to treat hypertension in patients at high risk of cardiovascular disease. Roche. News Release. September 7, 2023. Accessed on September 8, 2023. https://www.roche.com/media/releases/med-cor-2023-09-07