Zilebesiran Offers An RNA Interference Therapeutic Agent for Hypertension

Commentary
Article

The potential for RNAi to offer targeted and sustained control of blood pressure may represent a transformative approach in the broader landscape of cardiovascular therapeutics.

In the ever-evolving landscape of medical science, researchers and pharmaceutical companies are constantly striving to develop innovative therapies that can address unmet medical needs. One such promising development in the field of RNA interference (RNAi) therapeutics is the drug zilebesiran for treatment of hypertension.1

RNA interference (RNAi) has emerged as a promising avenue in the treatment of hypertension, offering a novel approach to modulate gene expression and address the underlying causes of elevated blood pressure. Hypertension, characterized by persistently high blood pressure, is a significant risk factor for cardiovascular diseases, making innovative therapeutic strategies crucial for effective management.1

RNAi involves the use of small RNA molecules to selectively silence or downregulate the expression of specific genes. In the context of hypertension, one of the key targets for RNAi is angiotensinogen (AGT), a precursor to angiotensin peptides, including the potent vasoconstrictor angiotensin II. By interfering with the expression of AGT, RNAi aims to disrupt the cascade of events that lead to increased blood pressure.1

Zilebesiran is an experimental RNAi therapeutic administered subcutaneously. It is currently under development with a focus on targeting liver-expressed AGT for the treatment of hypertension. AGT, as the origin of all angiotensin peptides, including the powerful vasoconstrictor angiotensin (Ang) II, is considered a genetically validated target for hypertension, playing an important role in its pathology.1

Measuring blood pressure

Image credit: grinny | stock.adobe.com

KARDIA-1 is a phase 2 study with a randomized, double-blind (DB), placebo-controlled, dose-ranging design. The primary objective of this study is to assess the efficacy and safety of zilebesiran in adults with mild-to-moderate hypertension.2 It enrolled adults aged 18 to 75 years, either with untreated hypertension or under stable therapy with one or more antihypertensive medications. Antihypertensive medications may include angiotensin converting enzyme inhibitors (ACEi), angiotensin II-receptor blockers (ARB), renin inhibitors, calcium channel blockers, thiazide diuretics, and/or thiazide-like diuretics. Before randomization, patients need to discontinue prior antihypertensive medications for a washout period lasting at least 4 weeks. Patients should have a mean 24-hour systolic blood pressure (SBP) between ≥135 mmHg and ≤160 mmHg by ambulatory blood pressure monitoring (ABPM), at least 4 weeks after the washout of background antihypertensive medication.2

Key exclusion criteria include secondary hypertension, orthostatic hypotension, elevated liver enzymes, high potassium levels, low estimated glomerular filtration rate (eGFR), recent investigational agent use, type 1 or poorly controlled type 2 diabetes mellitus, cardiovascular events within 6 months, and history of intolerance to subcutaneous injections.2

Participants were randomly assigned to 1 of 5 treatment arms, involving different doses and frequencies of subcutaneous zilebesiran or placebo during a 12-month double-blind period and double-blind extension period. Patients initially receiving placebo were later randomized to 1 of the 4 initial dose regimens of zilebesiran starting at month 6. The study enrolled 375 patients and was conducted at approximately 50 clinical study centers globally.2 The main focus of assessment is the alteration in SBP from the initial measurement, as evaluated by ABPM, following 3 months of treatment. Additionally, secondary and exploratory end points will scrutinize further indicators of blood pressure reduction throughout various time points (including at 6 and 12 months), as well as broader clinical outcomes and safety measures.2

The phase 2 findings of the KARDIA-1 study revealed that a sole administration of the investigational drug zilebesiran was both safe and efficacious in lowering systolic blood pressure in individuals with mild-to-moderate hypertension for a duration of up to 6 months.2 Sustained reductions in serum angiotensinogen levels and 24-hour ambulatory blood pressure, dependent on the dosage, were evident for a period of up to 24 weeks following a single subcutaneous administration of Zilebesiran at 200 mg or higher. Only mild injection-site reactions were noted as side effects. The KARDIA-1 trial helped establish dose ranges and sets the stage for further evaluation of zilebesiran in the subsequent KARDIA-2 trial.3

KARDIA-2 is a phase 2 study employing a randomized, double-blind (DB), placebo-controlled design to assess the effectiveness and safety of zilebesiran when utilized alongside traditional antihypertensive medications. The primary objective of this study is to evaluate how well zilebesiran performs as an additional therapy in adults whose blood pressure remains inadequately controlled despite receiving standard antihypertensive medications.4 The primary aim is to assess the effectiveness and safety of zilebesiran when used concurrently with standard antihypertensive medications in adults whose blood pressure is not adequately controlled.4

It will include adults aged 18 to 75 years, either with untreated hypertension or receiving stable therapy with up to 2 antihypertensive medications. These may include an ACEi, ARB, renin inhibitor, calcium channel blocker, thiazide diuretic, and/or thiazide-like diuretic.4 Participants should have a 24-hour mean SBP >130 mmHg and ≤160 mmHg by ABPM after at least 4 weeks of a run-in period on protocol-specified background antihypertensive medication.4

The key exclusion criteria include secondary hypertension or orthostatic hypotension, elevated liver enzyme levels, total bilirubin exceeding 1.5 times the upper limit of normal and an international normalization ratio (INR) exceeding 2.0, potassium levels below the lower limit of the normal range, or exceeding 5 mEq/L sodium levels below the lower limit of the normal range eGFR ≤30 mL/min/1.73m2. Additional exclusion criteria include use of an investigational agent within the last 30 days, diagnosis of type 1 diabetes mellitus, poorly controlled type 2 diabetes mellitus, or newly diagnosed type 2 diabetes mellitus. Patients with a history of any cardiovascular event within the 6 months preceding randomization were excluded, as well as patients with previous intolerance to subcutaneous injections.4

Participants in the study will be randomly assigned to undergo a run-in period with 1 of 3 specified background antihypertensive medications (olmesartan, amlodipine, or indapamide) in an open-label manner for a minimum of 4 weeks. At the conclusion of the run-in period, individuals with uncontrolled blood pressure (>130 mm Hg and ≤160 mm Hg) will be randomized in a 1:1 ratio to receive either zilebesiran or a placebo for a 6-month period during the double-blind (DB) phase.Following the completion of the 6-month DB phase, patients may be eligible to participate in a separate zilebesiran open-label extension study.4

The planned enrollment for this study involves approximately 800 patients to be randomized into the run-in period, and eligible individuals will then be randomized into the DB period. The study is anticipated to take place at around 80 clinical study centers worldwide.3

The main objective is to assess the alteration from the initial measurement in the 24-hour mean SBP, as evaluated by ABPM, following 3 months of treatment. Additionally, crucial secondary and exploratory end points will analyze supplementary indicators of blood pressure reduction over time (including up to 6 months), as well as broader clinical outcomes and safety considerations.4

Although zilebesiran represents a groundbreaking advancement in RNAi hypertension therapeutics, there are challenges and considerations that researchers and regulatory agencies must address. These include ensuring the drug's safety profile, optimizing dosage regimens, and understanding potential side effects. Regulatory approval processes are rigorous, and the success of zilebesiran will depend on comprehensive data demonstrating its safety and efficacy. Additionally, the cost and accessibility of such innovative therapies pose challenges to widespread adoption.

As research advances, the potential for RNAi to offer targeted and sustained control of blood pressure may represent a transformative approach in the broader landscape of cardiovascular therapeutics. Zilebesiran stands at the forefront of RNAi therapeutics, offering a glimpse into the future of medicine where diseases can be treated at the genetic level. The journey from discovery to widespread clinical use is a complex one, but the strides made with zilebesiran underscore the relentless pursuit of medical breakthroughs that could transform the lives of patients around the world. As we await further developments, the impact of zilebesiran on the field of RNAi therapeutics is a testament to the power of innovation and the hope it brings to those in need of effective and targeted treatments.

References

1. Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N Engl J Med. 2023;389(3):228-238. doi:10.1056/NEJMoa2208391

2. Alnylam Pharmaceuticals. A Study to Evaluate Efficacy and Safety of ALN-AGT01 in Patients With Mild-To-Moderate Hypertension (KARDIA-1). https://clinicaltrials.gov/ct2/show/NCT04936035.

3. Single dose of zilebesiran safely and effectively lowered blood pressure for six months. American Heart Association. https://newsroom.heart.org/news/single-dose-of-zilebesiran-safely-and-effectively-lowered-blood-pressure-for-six-months

4. Alnylam Pharmaceuticals. Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (KARDIA-2). https://clinicaltrials.gov/ct2/show/NCT05103332.

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