Alnylam's Zilebesiran Shows Positive Results in Phase II Study, Enters Phase III Trials with Roche

Alnylam Pharmaceuticals and Roche reported positive results from a mid-stage study of zilebesiran, an investigational RNAi therapeutic, for treating uncontrolled hypertension and high cardiovascular risk. The study met its primary endpoint of reducing systolic blood pressure at month 3 with a single 300 mg dose. The treatment also showed clinically meaningful reductions in 24-hour mean ambulatory systolic blood pressure at three and six months. The companies plan to initiate a global phase III cardiovascular outcomes trial to evaluate the candidate's potential to reduce the risk of major adverse cardiovascular events.

Roche (OTCQX: RHHBY) and Alnylam have announced plans to advance zilebesiran into a Phase III cardiovascular outcomes trial (CVOT) for uncontrolled hypertension treatment. The decision follows comprehensive Phase II KARDIA program results, particularly KARDIA-3, which demonstrated clinically meaningful blood pressure reductions [1].

The KARDIA-3 study showed that zilebesiran (300mg) achieved placebo-adjusted systolic blood pressure reductions of -5.0 mmHg at month three and -3.9 mmHg at month six. Notably, patients on diuretics with baseline BP 140 mmHg showed stronger results of -9.2mmHg and -8.3mmHg at three and six months, respectively [1]. The upcoming ZENITH Phase III trial will enroll approximately 11,000 patients, evaluating zilebesiran's effectiveness in reducing cardiovascular events in high-risk patients on multiple antihypertensives.

The KARDIA-3 study aimed to define the patient population to be investigated in the Phase III CV outcomes trial. Results of KARDIA-3 showed that a single dose of zilebesiran (300 mg every six months, subcutaneous injection) resulted in clinically meaningful placebo-adjusted reductions of office systolic blood pressure (SBP) in all comers at the month three primary endpoint (-5.0 mmHg; p=0.0431) with sustained benefits out to month six (-3.9 mmHg; 95% CI: [-8.5, 0.7]). There were no additional benefits of the 600 mg dose at month three (-3.3 mmHg; p=0.1830) or month six (-3.6 mmHg; 95% CI: [-8.2, 1.0]). The overall KARDIA-3 study did not meet the pre-specified definition for statistical significance, but it met the aim of identifying the patient population that could potentially benefit the most from zilebesiran and showed encouraging safety and clinically meaningful placebo adjusted reductions in blood pressure [1].

The ZENITH trial will be a CVOT enrolling approximately 11,000 patients and evaluating zilebesiran (300 mg) every six months compared to placebo in patients with uncontrolled hypertension with either established CV disease or at high risk for CV disease on two or more antihypertensives, one being a diuretic. The primary objective will be to assess the impact of zilebesiran on reducing the risk of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or heart failure (HF) events (hospitalisation for HF or urgent HF visit), compared to placebo [1].

Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of hypertension to reduce cardiovascular risk in high unmet need populations. It targets angiotensinogen (AGT), the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a role in blood pressure (BP) regulation. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein, and ultimately, in the vasoconstrictor angiotensin (Ang) II [1].

Hypertension is the primary cause of and number one modifiable risk factor for cardiovascular disease. An estimated one in three adults, over 1,2 billion people worldwide, have hypertension and despite the wide availability of antihypertensives, up to 80% of them do not achieve adequate blood pressure control [1]. Poor adherence to daily oral therapies is an important contributor to poor blood pressure control and CV outcomes. An effective long-acting therapy that provides continuous control of blood pressure may help to reduce the burden of uncontrolled hypertension.

The ZENITH Phase III trial has been submitted to global regulators and is expected to be initiated by the end of 2025. With its growing cardiometabolic portfolio and strong diagnostic expertise, Roche is advancing transformative standards of care to improve the lives of people living with cardiometabolic diseases as well as reducing the significant burden on healthcare systems and society [1].

References:
[1] https://www.stocktitan.net/news/RHHBY/roche-and-alnylam-advance-zilebesiran-into-global-phase-iii-a64odjes3xk0.html