Zilebesiran Effectively Lowers Blood Pressure in Patients with Uncontrolled Hypertension

George L. Bakris, MD

Credit: American Heart Association

A single dose of zilebesiran was safe and effective in reducing systolic blood pressure among people with mild-to-moderate hypertension, for up to 6 months, according to new findings from the phase 2 KARDIA-1 study.¹

The late-breaking research, presented at the American Heart Association (AHA) Scientific Sessions 2023 in Philadelphia, Pennsylvania, showed those who received single doses of zilebesiran had ≥10 mm Hg reductions, on average, in 24-hour systolic blood pressure, compared to placebo.

“Uncontrolled high blood pressure is a leading cause of death and disease, so there is a need for new treatments that provide sustained blood pressure control over longer periods of time. This will improve outcomes for people with hypertension,” said lead author George L. Bakris, MD, a professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine, in a statement.¹

Uncontrolled hypertension has been linked to an increased risk of heart disease. Per the AHA’s 2023 statistical update, heart disease is continually the primary cause of death in the United States, with approximately half of adults in the US having hypertension.² Zilebesiran is an investigational RNA interference agent targeting angiotensinogen (AGT), a hormone produced predominantly in the liver that contributes to the regulation of blood pressure.¹

The phase 2 KARDIA-1 study is a global, placebo-controlled, randomized, double-blind trial. Investigators assessed the safety and efficacy of zilebesiran among people with mild-to-moderate hypertension (systolic blood pressure, 135-160 mmHg), who are untreated or on stable therapy with ≤2 antihypertensive medications.

A total of 394 patients with an average systolic blood pressure of 142 mmHg were randomized and 377 were ultimately included for analysis. Of this population, 302 patients were randomized to receive one of 4 subcutaneous zilebesiran dosages (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months), and 75 patients received placebo. Patients had an average age of 57 years, 56% were men, and approximately 25% were Black.

In the study, conducted at locations in Canada, Ukraine, the United Kingdom, and the United States, 78% of participants were in the US. The investigative team noted that 16 patients randomized in Ukraine were excluded from the analysis due to challenges with data collection owing to the war in the area.

The 6-month, placebo-controlled treatment period of the phase 2 trial was conducted from July 2021 to June 2023. Over the study period, those who received single doses of zilebesiran had ≥10 mmHg reductions, on average, in 24-hour systolic blood pressure, as well as ≥90% reductions in serum levels of AGT, compared to those who received placebo.

At the 3-month follow-up mark, those who received the 300 mg and 600 mg doses of zilebesiran had an average lowering of ≥15mmHg in 24-hour average systolic blood pressure. After 6 months, individuals receiving zilebesiran were significantly more likely to experience 24-hour average systolic blood pressure reductions of ≥20 mmHg on average without taking additional hypertensive medications.

Those taking zilebesiran were also more likely to achieve 24-hour average systolic blood pressure measurements of ≤130 mmHg at 6 months. Participants in all zilebesiran dosage groups consistently experienced significantly greater reductions in both daytime and nighttime systolic blood pressure.

In terms of safety, the analysis identified low rates of zilebesiran-related adverse events. There were 4 non-serious, related adverse events leading to discontinuation in the zilebesiran groups, including 2 reports of orthostatic hypotension, 1 report of elevated blood pressure, and 1 report of injection site reaction. There were no clinically relevant changes observed in kidney or liver function and no adverse reactions in the placebo group.

Based on these findings, Bakris indicated quarterly or biannual doses of zilebesiran can effectively and safely lower blood pressure in individuals with uncontrolled hypertension. He noted reductions in systolic blood pressure of ≥5mmHg are linked to a reduction in cardiovascular risk.

However, the study was limited to only those with mild-to-moderate hypertension, as well as by the 6-month placebo-controlled period. Bakris and colleagues indicated future research will assess longer-term safety and the impact of zilebesiran on cardiovascular outcomes.

“These results reinforce the potential of zilebesiran to provide sustained blood pressure control, improve adherence to medication via infrequent dosing, and in turn, improve outcomes for people with high blood pressure,” Bakris said.¹

References

1. _{Single dose of zilebesiran safely and effectively lowered blood pressure for six months. American Heart Association. November 11, 2023. Accessed November 12, 2023. https://newsroom.heart.org/news/single-dose-of-zilebesiran-safely-and-effectively-lowered-blood-pressure-for-six-months.}
2. _{Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association [published correction appears in Circulation. 2023 Feb 21;147(8):e622] [published correction appears in Circulation. 2023 Jul 25;148(4):e4]. Circulation. 2023;147(8):e93-e621. doi:10.1161/CIR.0000000000001123}