Alnylam Pharmaceuticals has advanced its RNA interference therapeutic zilebesiran into the pivotal Phase III ZENITH trial, marking a significant milestone in the development of novel hypertension treatments. The drug, developed in partnership with Roche, represents a paradigm shift in blood pressure management by targeting angiotensinogen (AGT), the upstream precursor in the renin-angiotensin-aldosterone system (RAAS), and offering sustained effects with biannual dosing.
Clinical Evidence from Phase II Studies
The KARDIA Phase II program provided compelling evidence for zilebesiran's therapeutic potential. In the KARDIA-3 trial, a single 300 mg dose achieved a 5.0 mmHg reduction in systolic blood pressure (SBP) at three months and maintained a 3.9 mmHg reduction at six months. Patients on diuretics with baseline SBP ≥140 mmHg experienced even greater reductions of 9.2 mmHg at three months, highlighting the drug's efficacy in high-risk populations.
While KARDIA-3 did not meet statistical significance due to multiplicity testing, the clinical meaningfulness of these results, particularly in combination with diuretics, supported the decision to advance to Phase III development. The trial also demonstrated favorable safety data, with no renal, hepatic, or electrolyte disturbances reported.
ZENITH Trial Design and Objectives
The global Phase III ZENITH trial will enroll 11,000 patients with uncontrolled hypertension on two or more antihypertensive medications, including a diuretic. The study will evaluate zilebesiran's efficacy in reducing major adverse cardiovascular events (MACE) over a median follow-up of 2.5 years. This cardiovascular outcomes trial represents a critical test of whether zilebesiran's blood pressure lowering effects translate into meaningful reductions in heart attacks, strokes, and cardiovascular deaths.
Mechanism and Therapeutic Innovation
Zilebesiran utilizes GalNAc-conjugated siRNA technology to selectively silence AGT in hepatocytes, minimizing off-target effects while enabling prolonged therapeutic effects. This upstream targeting of the RAAS pathway differentiates it from existing hypertension therapies and addresses a critical unmet need in chronic disease management: adherence challenges.
The biannual dosing regimen could significantly improve long-term outcomes by reducing the burden of daily medication administration. Current therapies require daily dosing, contributing to suboptimal compliance and persistent cardiovascular risk in the 80% of patients globally who fail to achieve adequate blood pressure control despite existing treatments.
Financial Performance and Market Position
Alnylam's robust financial performance provides a strong foundation for zilebesiran's development. In Q2 2025, the company reported total net product revenues of $672 million, representing a 64% year-over-year increase. The TTR franchise alone generated $544 million in Q2 2025, with full-year 2025 guidance raised to $2,175-$2,275 million.
The global RNAi therapeutics market is projected to grow at a 14.9% CAGR, reaching $5.11 billion by 2034. Within this market, the cardiometabolic and renal disorders segment holds a 31.7% market share and is expected to grow at 18.3% CAGR. The broader hypertension market is projected to reach $30.69 billion by 2030, growing at a CAGR of 3.91%.
Strategic Partnership and Commercial Potential
The collaboration between Alnylam and Roche leverages complementary strengths, with Alnylam providing RNAi expertise and Roche contributing global commercial infrastructure. The partnership includes co-commercialization in the U.S. with shared profits and losses, while Roche retains exclusive rights outside the U.S. Roche's $1.5 billion upfront investment underscores confidence in zilebesiran's commercial viability.
Analysts estimate zilebesiran's U.S. revenue could reach $116 million by 2037, assuming approval and favorable reimbursement. The drug's potential to capture a significant share of the $5.3 billion treatment-resistant hypertension segment positions it as a valuable addition to the cardiovascular therapeutic landscape.
Competitive Landscape and Market Differentiation
Zilebesiran's upstream RAAS targeting and durable efficacy differentiate it from existing hypertension treatments in a competitive market dominated by players like Pfizer and Novartis. Its potential for use alongside diuretics enhances its value proposition, as combination therapies are increasingly favored for their convenience and efficacy.
The drug faces competition from emerging RAAS-targeting therapies like Baxdrostat and TRYVIO, but its biannual dosing frequency and novel RNAi mechanism provide unique advantages. The treatment's ability to reduce pill burden and improve adherence could be a key driver of long-term cardiovascular outcomes.
