Zilebesiran for High Blood Pressure

(KARDIA-3 Trial)

Not currently recruiting at 173 trial locations

Overseen By Alnylam Clinical Trial Information Line

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Alnylam Pharmaceuticals

Must be taking: Antihypertensives

Disqualifiers: Secondary hypertension, Orthostatic hypotension, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called zilebesiran for individuals with high blood pressure who are at risk for heart problems. The goal is to evaluate how well zilebesiran works when added to the regular medications for high blood pressure. Participants will receive either zilebesiran or a placebo (a fake treatment that resembles the real one) to compare results. Ideal candidates for this trial are those who have been on 2 to 4 blood pressure medications but still have high blood pressure and an increased risk of heart disease. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for this trial?

No, you must continue taking your current antihypertensive medications as the trial is testing zilebesiran as an add-on therapy.

Will I have to stop taking my current medications?

The trial requires participants to be on stable therapy with 2 to 4 classes of blood pressure medications, so you will not need to stop taking your current medications.

Is there any evidence suggesting that zilebesiran is likely to be safe for humans?

Research has shown that zilebesiran has potential based on earlier studies. These studies found that a single dose can lower blood pressure for up to 24 weeks. Importantly, most patients tolerated the treatment well. While some side effects occurred, they were usually not serious. This suggests zilebesiran could be a safe option for managing high blood pressure, especially when other medications are insufficient. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for high blood pressure?

Most treatments for high blood pressure work by targeting pathways like the renin-angiotensin system, typically using medications such as ACE inhibitors, ARBs, or calcium channel blockers. But zilebesiran is different because it is an RNA interference (RNAi) therapy, which means it works by silencing the gene responsible for producing angiotensinogen, a protein that plays a key role in blood pressure regulation. This unique mechanism can potentially offer more precise control over blood pressure with fewer side effects. Researchers are excited about zilebesiran because it represents a novel approach that could lead to more effective and long-lasting blood pressure management compared to current treatments.

What evidence suggests that zilebesiran might be an effective treatment for high blood pressure?

Research has shown that zilebesiran, which participants in this trial may receive, can significantly lower blood pressure in individuals with hypertension. Studies have found that a single dose of zilebesiran can reduce systolic pressure by more than 10 points and diastolic pressure by over 5 points. These reductions are crucial, as even a 5-point drop in systolic pressure can lower the risk of heart problems. The effects of zilebesiran can last up to 24 weeks, making it a promising option for maintaining healthy blood pressure levels. By aiding adherence to treatment, zilebesiran could help more individuals achieve their blood pressure goals. ^{1 3 4 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Alnylam Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults with high blood pressure not well-managed by 2-4 standard medications and who have a history of heart disease or are at high risk for it. They should have specific blood pressure readings and a moderately reduced kidney function but not severe kidney issues.

Inclusion Criteria

24-hour mean SBP ≥130 mmHg and ≤170 mmHg assessed by ABPM

I am taking 2 to 4 different blood pressure medications without recent changes.

Mean seated office SBP ≥140 mmHg and ≤170 mmHg

Exclusion Criteria

Proteinuria >3 g/day

Serum potassium >4.8 mEq/L

I experience significant drops in blood pressure when standing up.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zilebesiran or placebo as add-on therapy for 6 months

24 weeks

Day 1 visit, regular follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Zilebesiran

Trial Overview

The study tests Zilebesiran, added to usual blood pressure meds, against a placebo. It aims to see if Zilebesiran better controls blood pressure in those at high risk for heart problems.

How Is the Trial Designed?

Group I: Zilebesiran Experimental Treatment 1 Intervention

Participants will receive zilebesiran on Day 1 of the 6-month double-blind (DB) treatment period. Participants must be on stable doses of at least 2, but not more than 4, antihypertensive medications for at least 30 days prior to screening and plan to remain on stable doses of these medications during screening and through the DB treatment period.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive placebo on Day 1 of the 6-month DB treatment period. Participants must be on stable doses of at least 2, but not more than 4, antihypertensive medications for at least 30 days prior to screening and plan to remain on stable doses of these medications during screening and through the DB treatment period.

Who Is Running the Clinical Trial?

Alnylam Pharmaceuticals

Lead Sponsor

Trials

81

Recruited

16,100+

Dr. Yvonne Greenstreet

Alnylam Pharmaceuticals

Chief Executive Officer since 2021

MD from the University of Leeds, MBA from INSEAD

Dr. Pushkal Garg

Alnylam Pharmaceuticals

Chief Medical Officer since 2016

MD from Columbia University

Published Research Related to This Trial

In a 16-week study involving 622 Japanese patients with grade I-II essential hypertension, azilsartan (20-40 mg) significantly reduced diastolic blood pressure by -12.4 mm Hg compared to -9.8 mm Hg with candesartan (8-12 mg), showing a greater efficacy (difference of -2.6 mm Hg, P=0.0003).

Azilsartan also demonstrated a more significant reduction in systolic blood pressure (-21.8 mm Hg) compared to candesartan (-17.5 mm Hg), with similar safety profiles for both medications, indicating azilsartan's potential as a more effective treatment for hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the efficacy and safety of azilsartan with that of candesartan cilexetil in Japanese patients with grade I-II essential hypertension: a randomized, double-blind clinical study. Rakugi, H., Enya, K., Sugiura, K., et al.[2022]

In a study of 212 untreated hypertensive Caucasian individuals, specific AGT gene variants (-532T and -6A) were linked to significantly higher blood pressure levels, indicating their potential role in hypertension.

Haplotype analysis of the AGT gene revealed that different combinations of alleles at positions -532 and -6 were associated with varying blood pressure values, suggesting that understanding these haplotypes could enhance our knowledge of genetic influences on blood pressure regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensinogen promoter haplotypes are associated with blood pressure in untreated hypertensives. Brand-Herrmann, SM., Köpke, K., Reichenberger, F., et al.[2022]

Zilebesiran, a novel RNA therapeutic, effectively reduces systolic blood pressure by up to 20 mm Hg and maintains this effect for 6 months after a single dose, by targeting and silencing angiotensinogen in the liver.

In contrast, IONIS-AGT-LRX showed less effectiveness in lowering blood pressure, highlighting zilebesiran's superior ability to manage hypertension without causing significant side effects like acute kidney injury or hyperkalemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Pharmacological Approaches in the Treatment of Hypertension: A Focus on RNA-Based Therapeutics. Addison, ML., Ranasinghe, P., Webb, DJ.[2023]

Gene therapy has shown promise in reducing blood pressure (BP) by 10-30 mmHg in experimental studies involving 63 studies on small rodents, targeting various systems related to hypertension.

Despite these encouraging results, gene therapy for hypertension has not yet progressed to clinical trials, highlighting the need for improved gene transfection methods and further research in larger mammals before it can compete with existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for hypertension. Paulis, L., Franke, H., Simko, F.[2018]

Irbesartan, an angiotensin II receptor blocker, was found to be well tolerated in a study involving 1,965 patients over 4 to 12 weeks, with no evidence of dose-related adverse effects.

Compared to placebo, irbesartan showed a lower incidence of adverse events and serious adverse events, indicating a safety profile similar to that of a placebo, with no significant changes in laboratory results or rebound hypertension upon withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of irbesartan in the treatment of mild to moderate systemic hypertension. Simon, TA., Gelarden, RT., Freitag, SA., et al.[2019]

In a study of 84 patients, both olmesartan and azilsartan effectively reduced blood pressure over 16 weeks, with no significant differences in efficacy between the two medications.

Both drugs were well tolerated and showed similar safety profiles, with no major adverse events reported, indicating they are safe options for managing hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical efficacy of olmesartan versus azilsartan in patients with hypertension: a multicenter randomized-controlled trial (MUSCAT-4 study). Kakio, Y., Uchida, HA., Umebayashi, R., et al.[2022]

In a study of 50 patients with renoparenchymal hypertension due to chronic pyelonephritis, Candesartan effectively controlled arterial pressure, achieving target levels in 94.3% of patients over 12 months.

The clinical effectiveness of Candesartan was consistent across different genetic variants of the angiotensin II receptor gene, indicating its broad applicability in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacogenetic aspects of candesartan application for the treatment of arterial hypertension in patients with chronic pyelonephritis]. Mormol', IA.[2021]

Azilsartan effectively reduced systolic blood pressure in both elderly patients (≥65 years) and younger patients (<65 years) after 12 weeks of treatment, with no significant differences in blood pressure reduction between the two age groups.

The treatment with azilsartan was found to be safe, as there were no adverse changes in clinical laboratory findings, indicating it could be a valuable option for managing hypertension in both elderly and non-elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antihypertensive efficacy and safety of the angiotensin receptor blocker azilsartan in elderly patients with hypertension. Kamada, T., Hayashi, M., Fujiwara, W., et al.[2019]

Targeting hepatic angiotensinogen (AGT) with small interfering RNA (siRNA) presents a promising new strategy for managing hypertension, potentially overcoming issues like poor patient adherence and the RAS escape phenomenon.

This approach could allow for infrequent dosing (1 to 2 times per year) while effectively blocking the renin-angiotensin system, as shown in preclinical models and the initial human study, suggesting a significant advancement in hypertension treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Angiotensinogen With N-Acetylgalactosamine-Conjugated Small Interfering RNA to Reduce Blood Pressure. Ye, D., Cruz-López, EO., Tu, HC., et al.[2023]

In a study of 60 outpatients post-cardiac surgery, olmesartan was found to be more effective than azilsartan in reducing levels of angiotensin II and aldosterone after one year of treatment.

Patients taking olmesartan required fewer additional antihypertensive medications compared to those on azilsartan, indicating better blood pressure control and potentially greater efficacy in managing hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changeover Trial of Azilsartan and Olmesartan Comparing Effects on the Renin-Angiotensin-Aldosterone System in Patients with Essential Hypertension after Cardiac Surgery (CHAOS Study). Sezai, A., Osaka, S., Yaoita, H., et al.[2019]

In a 24-week study involving 421 elderly patients with isolated systolic hypertension, valsartan demonstrated similar blood pressure-lowering efficacy compared to amlodipine, but with significantly fewer adverse effects.

Valsartan had a lower overall adverse event rate (20.2%) compared to amlodipine (31.9%), particularly showing a much lower incidence of peripheral edema (4.8% for valsartan vs. 26.8% for amlodipine), indicating better tolerability for valsartan in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, active-controlled, parallel-group comparison of valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: the Val-Syst study. Malacco, E., Varì, N., Capuano, V., et al.[2019]

Citations

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It is well known that reductions in systolic blood pressure of five mmHg or more can result in a reduction in cardiovascular risk,” said Neha ...

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siRNA takes a jab at hypertension

Dosed every 6 months, zilebesiran could improve treatment adherence, a key barrier to achieving goal blood pressure for many patients, and thus ...

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The purpose of this study is to evaluate the effect of ALN-AGT01 on systolic and diastolic blood pressure and to characterize the pharmacodynamic (PD) effects ...

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the role of zilebesiran as an siRNA therapeutic agent - PMC

Clinical trials evaluating zilebesiran have shown significant reductions in blood pressure, with effects lasting up to 24 weeks post- ...

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• Phase 1 study data have demonstrated sustained reductions in serum. AGT levels and blood pressure through 24 weeks after a single dose of.

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Roche and Alnylam advance zilebesiran into global phase ...

Zilebesiran has demonstrated the ability to provide continuous control of blood pressure with biannual dosing in patients with mild-to-moderate ...