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An RNAi-based treatment helps control blood pressure for several months in patients who are on standard of care, according to new Phase II trial results. Roche and Alnylam’s zilebesiran is given as a single injection and its long-lasting effects could be a boon, especially in patients whose blood pressure is poorly controlled by standard treatments. Hypertension is the leading cause of cardiovascular disease worldwide.

“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’s chief medical officer Levi Garraway, MD, PhD, said in a release.

These promising results also reinforce the wisdom of Roche’s 2023 deal to co-develop the treatment. That deal involved an upfront cash payment of $310 million to Alnylam, and a full potential deal worth up to $2.8 billion. 

RNA interference (RNAi) is the process of mRNA degradation, which is very specific. There are only a few such drugs approved yet. Zilebesiran targets liver-expressed angiotensinogen (AGT), which is the sole precursor of angiotensin peptides. AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System, a cascade that has a key role in blood pressure regulation and AGT’s inhibition has well-established antihypertensive effects. 

In the KARDIA-2 Phase II trial results released so far, the treatment significantly lowered blood pressure for at least three months. In the 2023 report on KARDIA-I, zilebesiran was associated with consistent and durable blood pressure reduction up to six months after single doses of ≥200 mg.

According to Roche, the full KARDIA-2 data will be presented as a late-breaking clinical trial at the upcoming American College of Cardiology Annual Scientific Session. The KARDIA-2 results build on the Phase II KARDIA-1 data, presented at the congress of the American Heart Association Scientific Sessions in November 2023, and published in JAMA in February 2024.

“We are thrilled that a single dose of zilebesiran achieved clinically significant, additional reductions in systolic blood pressure when administered to patients who are not adequately controlled with commonly prescribed antihypertensives,” said Simon Fox, PhD, Vice President, Zilebesiran Program Lead at Alnylam. 

KARDIA-2 is a global, multicenter study that enrolled 672 adults with hypertension. Patients were first randomized into three different cohorts to receive open-label therapy with olmesartan, amlodipine, or indapamide during a run-in period of at least four weeks. Eligible patients were then randomized 1:1 to receive zilebesiran or placebo in addition to their standard antihypertensive medication for six months.

Alnylam and Roche yesterday also announced the initiation of the global KARDIA-3 (NCT06272487) Phase II study to evaluate the efficacy and safety of zilebesiran 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. 

Uncontrolled hypertension is the chronic elevation of blood pressure, defined by the 2017 ACC/AHA guidelines as ≥130 mmHg systolic blood pressure and ≥80 mmHg diastolic blood pressure. More than one billion people worldwide live with hypertension, with up to 80% of individuals remaining uncontrolled despite the availability of several classes of oral antihypertensive treatments. Inconsistent blood pressure control leads to an increased risk for stroke, heart attack, and premature death. 

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