Zilebesiran Meets Primary Endpoint in Phase 2 Hypertension Trial

George Bakris, MD
Credit: American Diabetes Association

The phase 2 KARDIA-1 trial has met its primary endpoint, with use of zilebesiran associated with significant reductions in systolic blood pressure at 3 months relative to placebo therapy, according to an announcement from Alnylam Pharmaceuticals.

Announced less than 3 months after phase 1 results were published in the New England Journal of Medicine, results of the phase 2 dose-finding trial suggest use of zilebesiran as a monotherapy could provide significant and meaningful reductions in systolic blood pressure for people with mild-to-moderate hypertension.¹

“As a physician, I believe these KARDIA-1 results, which demonstrate clinically significant reductions in systolic blood pressure of greater than 15 mmHg, along with the ability to achieve durable tonic blood pressure control, provide hope that we may one day have access to a novel therapy with the potential to address the significant unmet needs of patients with uncontrolled hypertension who are at high risk of future cardiovascular events,” said George L. Bakris, MD, director of the American Heart Association Comprehensive Hypertension Center at University of Chicago Medicine.¹

An investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, the cardiology community received its introduction to zilebesiran when data from the phase 1 study was published in the New England Journal of Medicine on July 24, 2023. A 4-part, multicenter, first-in-human trial conducted at 4 sites in the United Kingdom from May 30, 2019, through January 26, 2022, results of this study provided insight into the potential of zilebesiran for lowering blood pressure, with data indicating use could decrease systolic blood pressure by 10 mmHg or more and diastolic blood pressure by 5 mmHg or more in 8 weeks.²

In their September 7, 2023, announcement, Alnylam Pharmaceuticals detailed positive results from the KARDIA-1 phase 2 trial. A randomized, double-blind, placebo-controlled, multi-center global dose-ranging study, KARDIA-1 was launched with the intent of evaluating use of zilebesiran as a monotherapy in adults with mild-to-moderate hypertension.¹

A total of 394 adult patients with untreated hypertension or who were on stable therapy with one or more antihypertensive medications were enrolled in the trial. Patients were randomized to 1 of 5 treatment arms during a 12-month double-blind period and double-blind extension period zilebesiran 150 mg subcutaneously once every 6 months, zilebesiran 300 mg subcutaneously once every 6 months, zilebesiran 300 mg subcutaneously once every 3 months, zilebesiran 600 mg subcutaneously once every 6 months, or placebo therapy.¹

The primary endpoint of interest for the trial was change from baseline in systolic blood pressure at month 3, which was assessed by 24-hour ambulatory blood pressure monitoring (AMBP). The trial also included multiple secondary and exploratory endpoints of interest, such as additional measures of blood pressure reduction at 6 months, time-adjusted change in blood pressure, and change in daytime average and night-time average blood pressure.¹

Topline data from this trial highlighted with the announcement from Alnylam Pharmaceuticals included zilebesiran achieving a dose-dependent, clinically significant reduction in 24-hour mean systolic blood pressure at Month 3, with a placebo-subtracted reduction greater than 15 mmHg (P < .0001) with both 300 mg and 600 mg doses. Additionally, Alnylam Pharmaceuticals pointed out zilebesiran use was associated with a significant change in 24-hour mean systolic blood pressure at month 6 with AMBP, as well as a significant change in office systolic blood pressure at month 3 and month 6, for all zilebesiran arms relative to placebo.¹

“We believe these results further validate the differentiated profile we observed in Phase 1. Moreover, they reinforce the potential for zilebesiran to be a transformative therapy to reduce cardiovascular risk in patients with hypertension and to offer new possibilities in a field of medicine that has seen limited innovation in nearly 20 years,” said Simon Fox, PhD, vice president and zilebesiran program lead at Alnylam.¹

In their announcement of topline results, Alnylam Pharmaceuticals pointed out the KARDIA-2 phase 2 study of zilebesiran is expected to be completed in early 2024. In this trial, zilebesiran will be used in combination with 1 of 3 standard classes of antihypertensive medication in a patient population with mild-to-moderate hypertension.¹

References:

1. Alnylam Reports Positive Topline Results from KARDIA-1 Phase 2 Dose-Ranging Study of Zilebesiran, an Investigational RNAi Therapeutic in Development to Treat Hypertension in Patients at High Cardiovascular Risk. Investor Relations | Alnylam Pharmaceuticals, Inc. September 7, 2023. Accessed September 7, 2023. https://investors.alnylam.com/press-release?id=27706.
2. Campbell P. Zilebesiran, an RNA interference agent, shows promise for hypertension in phase 1 trial. HCP Live. July 24, 2023. Accessed September 7, 2023. https://www.hcplive.com/view/zilbesarian-rna-agent-shows-promise-in-phase-1-trial-for-hypertension.