Phase II KARDIA-2 Trial Data Show Zilebesiran Achieves Clinically Significant Drop in Systolic Blood Pressure

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Zilebesiran achieved the primary endpoint of the Phase II KARDIA-2 study (NCT05103332) evaluating Roche’s and Alnylam’s novel RNA interference therapeutic agent in the treatment of hypertension. The addition of zilebesiran to standard of care treatment for mild to moderate hypertension produced a clinically and statistically significant decrease in systolic blood pressure (SBP) after three months with an encouraging safety and tolerability profile, according to the study.¹

“With twice-yearly dosing in combination with standard of care medication, zilebesiran has strong potential to sustain lower blood pressure and reduce the risk of stroke, heart attack and death that can result from inadequate treatment,” Roche Chief Medical Officer and Head of Global Product Development, Levi Garraway, MD, PhD, said in a press release. “We look forward to continuing the zilebesiran Phase II study program with Alnylam as we seek to provide transformative impact for millions of people living with uncontrolled hypertension.”¹

According to the World Health Organization (WHO), approximately 1.28 billion adults from 30 to 79 years of age have hypertension worldwide, of whom an estimated 46% are unaware they have the condition and 42% are diagnosed and treated. Just 21% of adults with the condition are projected to have it under control, as hypertension is a significant cause of premature mortality with an estimated 10 million deaths worldwide each year.^1,2

The subcutaneously administered zilebesiran targets angiotensinogen (AGT), which is the most upstream precursor in Renin-Angiotensin-Aldosterone System. This plays a significant role in regulating blood pressure and inhibiting this action has demonstrated antihypertensive effects.

The randomized, double-blind, placebo-controlled KARDIA-2 trial is analyzing the efficacy and safety of zilebesiran added to a standard of care in 672 adults with mild-to-moderate hypertension. Patients enrolled in the trial were randomly assigned to three different cohorts to receive open-label treatment with olmesartan, amlodipine, or indapamide as a protocol-specified background hypertension treatment during a run-in period lasting at least four weeks. After this point, patients were randomly assigned 1:1 to receive zilebesiran 600 mg or placebo plus their protocol-specified background hypertension treatment for six months.¹

The results of the trial will be presented at the upcoming 2024 American College of Cardiology Annual Scientific Session from April 6-8, 2024. These results follow positive findings from the Phase II KARDIA-1 (NCT04936035) trial published in JAMA in February 2024.

In KARDIA-1, zilebesiran produced a clinically significant decrease in 24-hour mean SBP after three months, which translated to a placebo-subtracted decrease greater than 15 mmHg at both the 300 and 600 mg doses. Zilebesiran also achieved the key secondary endpoints of consistent and sustained decreases in SBP at six months, which supports quarterly or biannual dosing, according to Roche. Further, zilebesiran produced a potent and durable drop in serum AGT levels through six months with an encouraging safety and tolerability profile.³

“These early results indicate the potential for zilebesiran to achieve sustained blood pressure reduction with quarterly or biannual dosing,” Garraway said in a prior press release. “Also, these data underscore the potential of this investigational medicine to provide transformative impact for many people living with uncontrolled hypertension.”³

References

1. Roche and Alnylam report positive topline results from the Phase II KARDIA-2 study in people with hypertension, demonstrating clinically significant blood pressure reductions with zilebesiran when added to standard of care. Roche. News release. March 5, 2024. Accessed March 6, 2024. https://www.roche.com/media/releases/med-cor-2024-03-05

2. World Health Organization. Hypertension. Webpage. Updated March 16, 2023. Accessed March 6, 2024. https://www.who.int/news-room/fact-sheets/detail/hypertension#:~:text=Overview,get%20your%20blood%20pressure%20checked.

3. 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 March 6, 2024. https://www.roche.com/media/releases/med-cor-2023-09-07