Breakthrough Clinical Results
Roche and Alnylam announced the initiation of a Phase III cardiovascular outcomes trial (CVOT) for zilebesiran, an RNAi therapeutic, to reduce major adverse cardiovascular events in patients with uncontrolled hypertension. This decision follows positive results from the Phase II KARDIA program, particularly KARDIA-3, which showed clinically meaningful blood pressure reductions with zilebesiran, especially in patients on diuretics. The ZENITH trial will enroll approximately 11,000 patients and compare zilebesiran to a placebo. Zilebesiran targets angiotensinogen, a key component in blood pressure regulation, offering a potential best-in-class treatment with twice-yearly dosing.
Key Highlights
- Phase III cardiovascular outcomes trial (ZENITH) for zilebesiran initiated.
- Zilebesiran demonstrated clinically meaningful blood pressure reductions in Phase II KARDIA-3 study.
- Twice-yearly subcutaneous dosing offers potential for improved patient adherence.
- Trial informed by comprehensive data from the KARDIA Phase II program.
Incidence and Prevalence
Global Hypertension: Latest Estimates of Incidence and Prevalence
Hypertension stands as the major factor responsible for the most deaths worldwide, accounting for 12.8% per year or more than seven million deaths according to a 2021 study. It ranks third on the list of factors responsible for the burden of disease during life, as measured by disability-adjusted life-years.
Global Prevalence
A 2022 meta-analysis found that the pooled prevalence of hypertension among the general population in high-altitude areas was 33.0% (95% CI: 29.0-38.0%). The total number of patients with hypertension is likely to grow as the population ages.
Regional Variations
Asia
- Half of the cases of CVD are estimated in Asia, the world's most populous continent
- More than half (54%) of the world's population live in Asia
- The proportion of the elderly population aged 65 years or more in Asia is expected to increase from 7.4% in 2015 to 10.9% in 2030
- In China, hypertension prevalence increased from 18.9% in 2002 to 29.6% in 2019
- By 2019, hypertension prevalence was higher in Chinese men (34.2%) than in women (25.4%)
- Western regions of China exhibited the highest prevalence (32.9%)
United States and Europe
- In the United States, hypertension affects nearly a third of adult males
- In a European study across 12 countries, only 28.1% had controlled blood pressure
Africa
- In Nigeria, the prevalence of hypertension among older adults (60+ years) was 36.1%
Incidence Rates
A 2011 study on ethnic differences showed that the crude incidence rate of hypertension, per 1000 person-years, was: - 56.8 for whites - 84.9 for blacks - 65.7 for Hispanics - 52.2 for Chinese
After adjustment for age, sex, and study site, the incidence rate ratio (IRR) for hypertension was increased for blacks age 45 to 54 (IRR: 2.05), 55 to 64 (IRR: 1.63), and 65 to 74 years (IRR: 1.67) compared with whites.
In a Korean cohort study of 94,798 adults (age ≥ 40 years), 30.7% developed hypertension during a median follow-up of 7.4 ± 2.5 years.
Risk Factors
Several factors have been associated with hypertension: - Severe noise exposure was associated with an increased risk of hypertension incidence with a hazard ratio of 1.28 (95% CI 1.11-1.47) - In China, age, BMI, smoking, alcohol consumption, and physical inactivity were identified as significant relevant factors - Lower socioeconomic status was associated with higher hypertension prevalence, especially in participants with no education compared to those with higher education levels (OR 2.29, 95% CI 2.05-2.56)
Comorbidities
Hypertension is an important precursor and most common risk factor of heart failure (HF). Among patients with chronic kidney disease (CKD), 44.14% had H-type hypertension (combined hypertension and hyperhomocysteinemia).
Additional Indications for Zilebesiran Beyond Hypertension
Zilebesiran is currently being investigated for several clinical applications beyond standard essential hypertension. Based on the available information, these include:
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Resistant hypertension: Zilebesiran is being studied specifically for patients with resistant hypertension, a condition where blood pressure remains uncontrolled despite the use of multiple conventional antihypertensive medications.
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Adjunct therapy for patients with high cardiovascular risk: Clinical trials are evaluating Zilebesiran as a supplementary treatment option for patients who have an elevated risk of cardiovascular events.
The therapeutic applications under investigation encompass both: - Monotherapy in patients with essential hypertension - Adjunct therapy for specific patient populations with additional risk factors
The mechanism of action that makes Zilebesiran potentially valuable for these expanded indications involves: - Targeting hepatic angiotensinogen synthesis - Achieving prolonged suppression of the renin-angiotensin-aldosterone system (RAAS)
This unique approach to RAAS inhibition may provide clinical benefits in these additional hypertension-related conditions where conventional treatments have limitations.
Current clinical trials are actively evaluating the efficacy of Zilebesiran in these expanded indications beyond standard essential hypertension treatment.
It's worth noting that no specific disease indications beyond hypertension-related conditions are mentioned in the available information. The current clinical development program appears to be focused on various forms of hypertension and cardiovascular risk management rather than entirely different disease categories.
The specific intervention models for these trials, including detailed dosing regimens and administration protocols, are not specified in the available information.