Roche and Alnylam Announce Positive Phase 2 Results for Zilebesiran, a Twice-Yearly RNAi Therapy for Hypertension

On September 7, Roche and Alnylam jointly announced that the Phase II KARDIA-1 study of the investigational RNAi therapy Zilebesiran, which targets liver-expressed angiotensinogen (AGT), met its primary endpoint.

KARDIA-1 is a randomized, double-blind, placebo-controlled, multicenter global clinical trial designed to evaluate the efficacy and safety of Zilebesiran as a monotherapy for adult patients with mild to moderate hypertension. The study enrolled 394 adult patients, covering a diverse population of hypertensive patients, some of whom were untreated, while others were on stable treatment with one or more antihypertensive drugs (after a washout period).

The study showed that by the third month, the 24-hour mean systolic blood pressure (SBP) reduction with Zilebesiran reached clinically significant levels, with reductions of over 15 mmHg in both the 300mg and 600mg dose groups (p<0.0001). The study also met key secondary endpoints, showing sustained SBP reductions for up to six months, supporting quarterly or semi-annual dosing. Additionally, the study demonstrated that Zilebesiran effectively and durably reduced serum AGT levels for six months, while also showing encouraging safety and tolerability.

On July 24, Roche and Alnylam reached a collaboration on Zilebesiran, with a total transaction value of up to $2.8 billion, including a $310 million upfront payment. In the U.S. market, Roche and Alnylam will jointly handle commercialization and equally share rights. Outside the U.S., Roche will be responsible for commercialization, and Alnylam will receive sales royalties.

The KARDIA research program also includes the Phase II KARDIA-2 study, which involves the combination of Zilebesiran with one of three standard antihypertensive drugs. Enrollment for this study was completed in June 2023. Preliminary results from KARDIA-2 are expected to be announced in early 2024.

"These early results suggest that taking Zilebesiran once a quarter or once every six months has the potential to achieve a sustained reduction in blood pressure," said Levi Garraway, M.D., Chief Medical Officer and Head of Global Product Development at Roche. "Furthermore, these data highlight the potential of this investigational drug to bring about a transformative impact for many patients with uncontrolled hypertension."

Hypertension is an increasingly severe global health crisis, causing approximately 10 million deaths worldwide each year. About one in every three adults globally suffers from hypertension. Despite the availability of various oral antihypertensive medications, up to 80% of patients still have uncontrolled conditions, increasing their risk of cardiovascular, cerebrovascular, and kidney diseases.

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