Breakthrough Clinical Results

Alnylam Pharmaceuticals announced plans to initiate a Phase 3 cardiovascular outcomes trial (CVOT) for zilebesiran, an investigational RNAi therapeutic, to reduce major adverse cardiovascular events. This decision follows positive Phase 2 KARDIA-3 study results presented at the European Society of Cardiology Congress. Zilebesiran demonstrated clinically meaningful reductions in systolic blood pressure in patients with uncontrolled hypertension and high cardiovascular risk. The Phase 3 ZENITH trial, expected to begin by the end of 2025, will enroll approximately 11,000 patients and evaluate the drug's impact on reducing cardiovascular events compared to a placebo. Zilebesiran targets angiotensinogen, a key component in blood pressure regulation.

Incidence and Prevalence

Global Hypertension Burden: Latest Estimates

Global Prevalence and Mortality

Hypertension is the leading cause of deaths worldwide, contributing to about 30% of all deaths. According to 2022 data, hypertension affects 1.3 billion adults worldwide, making it the most significant risk factor for cardiovascular disease and mortality. The World Health Organization has concluded that hypertension is the major factor responsible for the most deaths worldwide, 12.8% per year or more than seven million.

Hypertension is rated third on the list of factors responsible for the burden of disease during life, as measured by disability-adjusted life-years. It is the biggest single risk factor for global deaths and an important precursor and most common risk factor of heart failure.

Regional Variations

Half of the cases of Cardiovascular Disease (CVD) are estimated in Asia, the world's most populous continent. Hypertension results in more deaths than any other cardiovascular risk factors in the Asian regions. In Asia, the proportion of the elderly population aged 65 years or more is expected to increase from 7.4% in 2015 to 10.9% in 2030, likely increasing hypertension prevalence.

A meta-analysis suggests that the pooled prevalence of hypertension among the general population in high-altitude areas is 33.0% (95% CI: 29.0-38.0%). Tibetan individuals showed a significantly higher pooled prevalence of hypertension compared to non-Tibetan individuals living in the Himalayas and Pamir Mountains (41% vs. 18%).

Ethnic and Regional Disparities

The crude incidence rate of hypertension, per 1000 person-years, was 56.8 for whites, 84.9 for blacks, 65.7 for Hispanics, and 52.2 for Chinese according to the Multi-Ethnic Study of Atherosclerosis. Blacks had a higher incidence of hypertension compared with whites between 45 and 74 years of age but not after age 75 years. Hispanic participants also had a higher incidence of hypertension compared with whites.

In China, a meta-analysis found that the total prevalence of hypertension among older people was 47%. Central China had the highest prevalence at 59% among older populations.

In the US, Filipino adults have persistently higher hypertension prevalence than South Asian, Chinese, Hispanic, and White adults across the adult lifespan. Filipino adults' hypertension prevalence is similar to Black adults, with decade-specific prevalence ranging from 9.7% for ages 30-39 years to 82.1% for ages 70-79 years.

In a South London study, ethnic minorities had raised prevalence rates of hypertension compared to white people. Age and sex standardized prevalence ratios for hypertension were 2.6 (95% CI 2.1 to 3.2) in people of African descent and 1.8 (95% CI 1.4 to 2.3) in those of South Asian origin.

Global Trends and Control

Global disparities in hypertension control are widening with low- and middle-income countries (LMIC) having the fastest growing rates of hypertension and low rates of control. From 1990 to 2019, the prevalence of hypertension controlled to a systolic/diastolic blood pressure ≤140/90 mmHg increased by 3.2% (95% CI: 3.1 to 3.2) annually across 36 countries in the Americas.

The global median consumption rate of all antihypertensives per 1000 inhabitants per day increased from 184.78 Standard Units in 2010 to 325.6 Standard Units in 2021, with high-income countries consistently having the highest rates.

Study Design Parameters

Study Design Parameters and Endpoints in Key Hypertension Trials

Study Designs

Randomized controlled trials (RCTs) are the predominant design for evaluating hypertension treatments, with double-blinded methodology being standard. Follow-up periods range from 6 months minimum to long-term studies of up to 25 years for projecting outcomes. Sample sizes vary widely from smaller studies (160 patients) to large trials involving 65,733 participants with a mean age of 66 years.

Multicenter studies are common, allowing for diverse patient populations including high-risk diverse populations with 54% black and Hispanic individuals. Phase II and III trials evaluate efficacy, with dose-ranging studies determining optimal medication dosages.

A typical design includes a placebo run-in phase (e.g., 2-week) followed by randomization to treatment arms. For example, one trial compared DOX-GITS with doxazosin standard (DOX-S) in a 9-week double-blind, parallel trial with 310 hypertensive patients.

Patient Populations

Studies often include specific subgroups: - Elderly patients (≥65 years) - Patients with diabetes - Overweight or obese patients - Patients with isolated systolic hypertension - Different racial groups with special focus on black patients - Patients with varying hypertension severity

Exclusion criteria typically include proven secondary hypertension.

Primary Endpoints

Key primary endpoints include: - All-cause mortality/death - Fatal and non-fatal stroke - Fatal and non-fatal myocardial infarction (MI) - Fatal and non-fatal congestive heart failure (CHF) requiring hospitalization - Total cardiovascular (CV) events - End-stage renal failure (ESRF) - Blood pressure reduction from baseline

Specific examples from major trials include: - Combined cardiovascular death, stroke, and myocardial infarction (LIFE study) - "Any diabetes-related endpoint" (UKPDS) - Acute myocardial infarction, cardiovascular events, and all-cause mortality (ACE inhibitor trials)

Blood Pressure Measurements

Blood pressure measurements are taken using various methods: - Mercury sphygmomanometer - Automatic devices (e.g., Omron) - 24-hour ambulatory blood pressure measurements (ABPM) - Automated office blood pressure (AOBP)

Blood pressure targets varied across studies: - Target of 140/90 mmHg or a fall ≥ 20/10 mmHg (INSIGHT trial) - Systolic blood pressure categorized as <130, 130-139, 140-149, or ≥150 mmHg (UKPDS) - BP <140/90 mmHg or 130/80 mmHg; systolic BP within 110-130 mmHg or 120-140 mmHg (BP-TTR studies)

Secondary Endpoints

Secondary endpoints often include: - Systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes - Heart rate (HR) - Quality-adjusted life years (QALY) - Life expectancy (LE) - Time to onset of conditions like ESRF - Percentage of patients achieving BP control

Additional measurements include: - Vascular function (flow-mediated dilation, arteriolar flicker light-induced dilation) - Left ventricular mass and stress-corrected midwall shortening - Plasma renin activity - Body composition (body fat, visceral fat)

Safety Assessment

Adverse drug reactions are carefully monitored, including serious adverse events (SAE). Laboratory parameters including potassium, sodium, and creatinine blood levels are regularly assessed to ensure treatment safety.

In comparative studies, ACEIs were found superior to ARBs in reducing cardiovascular events and all-cause mortality, while ARBs were better tolerated by patients.

Drug used in other indications

Zilebesiran Indications Beyond Hypertension

Based on the available information, there is a clarification needed regarding zilebesiran. The therapeutic agent is described as an siRNA targeting hepatic angiotensinogen for hypertension treatment, not a PCSK9 siRNA therapeutic as suggested in one of the related queries.

From the information provided, zilebesiran is currently being developed specifically for hypertension treatment. The available data from 2023 and 2024 sources indicate that zilebesiran is being studied for its efficacy in reducing blood pressure and its safety profile in the context of hypertension management.

There is no evidence in the provided information that zilebesiran is currently being trialed for any indications beyond essential hypertension. The sources do not mention any additional therapeutic areas, clinical trials for other conditions, or intervention models for non-hypertensive indications.

The development focus appears to remain on zilebesiran's primary mechanism of action targeting angiotensinogen (AGT) for the treatment of hypertension exclusively.

Without additional information from clinical trial registries or more recent research publications, it is not possible to identify other indications or intervention models for zilebesiran beyond its application in hypertension management.