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The investigational RNA interference therapeutic, zilebesiran, has shown positive top-line results in the KARDIA-2 phase 2 study for the treatment of hypertension when added to standard-of-care antihypertensive medications.

Zilebesiran, in development by Alnylam and Roche for the treatment of hypertension in high–unmet need populations, is one of the new generation of gene silencing agents. It inhibits the synthesis of angiotensinogen, the most upstream precursor in the renin-angiotensin-aldosterone system, leading to reductions in the vasoconstrictor angiotensin II.

According to a press release from Alnylam, the KARDIA-2 study met its primary endpoint, showing that a single dose of zilebesiran given by subcutaneous injection resulted in clinically and statistically significant additive placebo-adjusted reductions in 24-hour mean systolic blood pressure, assessed by ambulatory blood pressure monitoring, at month 3. 

These findings were reported to be consistent across three independent patient cohorts receiving the standardized background therapies of either a thiazide-like diuretic (indapamide), calcium channel blocker (amlodipine), or angiotensin receptor blocker (olmesartan).

Zilebesiran was also said to show an encouraging safety and tolerability profile when added to standard-of-care antihypertensive medications.

Full study results will be presented as a late-breaking clinical trial at the 2024 American College of Cardiology Annual Scientific Session on April 7.

Zilebesiran previously showed positive results in the KARDIA-1 phase 2 study, reported late last year. 

The KARDIA-2 study involved 672 adults with hypertension who were first randomly assigned into three different cohorts to receive open-label therapy with olmesartan, amlodipine, or indapamide as their protocol-specified background antihypertensive medication during a run-in period of at least 4 weeks.

They were then randomly assigned 1:1 to receive 600-mg zilebesiran or placebo in addition to their protocol-specified background antihypertensive medication for 6 months.

The primary endpoint is the change from baseline in mean systolic blood pressure at month 3 assessed by ambulatory blood pressure monitoring. Additional endpoints include the change in 24-hour mean systolic blood pressure after 6 months of treatment assessed by ambulatory blood pressure monitoring, change in office systolic blood pressure at month 3 and month 6, and change in diastolic blood pressure measured by ambulatory blood pressure monitoring and office blood pressure at month 3 and month 6. 

Alnylam and Roche today also announced the initiation of the global KARDIA-3 phase 2 study, a randomized placebo-controlled study designed to evaluate the efficacy and safety of zilebesiran used as an add-on therapy in adult patients with high cardiovascular risk and uncontrolled hypertension despite treatment with two to four standard-of-care antihypertensive medications. 

Approximately 1 in 3 adults are living with hypertension worldwide, with up to 80% of individuals remaining uncontrolled despite the availability of several classes of oral antihypertensive treatments, Alnylam noted.

There remains a significant unmet medical need, especially given the poor rates of adherence with existing standard of care with oral antihypertensive medications, resulting in inconsistent blood pressure control and an increased risk for stroke, myocardial infarction, and premature death, the company added.