Zilebesiran for High Blood Pressure

(KARDIA-2 Trial)

No longer recruiting at 170 trial locations

Overseen By Alnylam Clinical Trial Information Line

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Alnylam Pharmaceuticals

Disqualifiers: Secondary hypertension, Diabetes, Cardiovascular event, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well a new treatment called zilebesiran (an experimental drug) controls high blood pressure when added to regular medication. The researchers aim to determine if zilebesiran can safely lower both systolic (top number) and diastolic (bottom number) blood pressure. Participants will receive either zilebesiran or a placebo (a non-active substance) alongside their usual medication, such as amlodipine, olmesartan, or indapamide. Suitable candidates for this trial include those with high blood pressure that remains difficult to manage despite medication. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that patients on antihypertensive medications can participate, suggesting you may not need to stop them.

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

Research has shown that zilebesiran underwent safety testing in earlier studies. In these studies, patients with mild to moderate high blood pressure generally tolerated it well. Most patients did not experience serious side effects. The treatment led to lasting reductions in blood pressure for several months after just one dose, suggesting it could be a safe option for managing blood pressure. However, some people reported mild side effects, though these were uncommon. Since zilebesiran is in a mid-stage clinical trial, evidence of safety exists, but more data is needed to confirm these findings. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Zilebesiran is unique because it targets high blood pressure by inhibiting the production of angiotensinogen, a protein involved in blood pressure regulation. Unlike standard treatments like ACE inhibitors or ARBs, which block the effects of angiotensin II, zilebesiran tackles the root cause earlier in the pathway. Researchers are excited because this approach could lead to more effective blood pressure control with fewer side effects. Additionally, zilebesiran is administered as a subcutaneous injection every six months, offering a convenient alternative to daily oral medications.

What evidence suggests that this trial's treatments could be effective for high blood pressure?

Research has shown that zilebesiran, which participants in this trial may receive, can significantly lower blood pressure. One study found that the average systolic blood pressure (the top number in a blood pressure reading) measured over a day dropped by about 11.9 mmHg after 12 weeks of treatment. Another study reported that a single 300 mg dose of zilebesiran reduced systolic blood pressure measured in a doctor's office by 5 mmHg after three months. These results suggest that zilebesiran might effectively manage high blood pressure when used with existing medications. Participants in this trial will receive zilebesiran as an add-on to either amlodipine, olmesartan, or indapamide, or a placebo matched to zilebesiran as an add-on to these medications. ^{3 5 6 7 8}

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-controlled by standard medications. Eligible participants have a 24-hour average systolic blood pressure between >130 and ≤160 mmHg, and office readings of ≥145 to ≤180 mmHg if on meds or ≥155 to ≤180 mmHg if untreated. They can't join if they've used investigational drugs recently, have very low kidney function, unmanaged diabetes, recent heart issues, or certain other conditions.

Inclusion Criteria

Your average blood pressure over 24 hours is between 130 and 160 mmHg.

My average blood pressure is between 130 and 160 mmHg after 4 weeks on certain blood pressure meds.

My blood pressure is between 145 and 180 mmHg while on medication.

Exclusion Criteria

My kidney function is severely reduced.

Your blood has too much potassium, over 5 mEq/L.

Received an investigational agent within the last 30 days

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in

Participants undergo a run-in period on amlodipine, olmesartan, or indapamide to stabilize their condition before the main treatment phase

2-4 weeks

Treatment

Participants receive either zilebesiran or placebo as add-on therapy during a 6-month double-blind treatment period

6 months

Open-label extension

Participants receive zilebesiran once every 6 months during the open-label extension period, which is closed upon implementation of Amendment 3

Long-term

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's ability to lower blood pressure when added to common antihypertensive drugs like Amlodipine, Indapamide, or Olmesartan. Participants will be randomly assigned either Zilebesiran or a placebo as an add-on therapy while continuing their usual hypertension medication.

How Is the Trial Designed?

Group I: Zilebesiran (Add-on to Olmesartan) Experimental Treatment 2 Interventions

Following a 4-week run-in treatment on olmesartan, 40 mg, orally, QD, (or 20 mg, orally, QD for participants with creatinine clearance ≤60 mL/min at screening enrolled at sites outside of the US consistent with local labeling), eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to olmesartan. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Group II: Zilebesiran (Add-on to Indapamide) Experimental Treatment 2 Interventions

Following a 4-week run-in treatment on indapamide, 2.5 mg, orally, QD, eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to indapamide. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Group III: Zilebesiran (Add-on to Amlodipine) Experimental Treatment 2 Interventions

Following a 4-week run-in treatment on amlodipine, 5 mg, orally, QD, eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to amlodipine. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Group IV: Placebo (Add-on to Amlodipine) Placebo Group 3 Interventions

Following a 4-week run-in treatment on amlodipine, 5 mg, orally, QD, eligible participants were randomized to receive placebo matched to zilebesiran as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to amlodipine. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Group V: Placebo (Add-on to Olmesartan) Placebo Group 3 Interventions

Following a 4-week run-in treatment on olmesartan, 40 mg, orally, QD, (or 20 mg, orally, QD for participants with creatinine clearance ≤60 milliliters per minute \[mL/min\] at screening enrolled at sites outside of the United States \[US\] consistent with local labeling), eligible participants were randomized to receive placebo matched to zilebesiran as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to olmesartan. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Group VI: Placebo (Add-on to Indapamide) Placebo Group 3 Interventions

Following a 4-week run-in treatment on indapamide, 2.5 milligrams (mg), orally, once daily (QD), eligible participants were randomized to receive placebo matched to zilebesiran as a subcutaneous (SC) injection on Day 1 of 6-month double-blind (DB) treatment period as add-on therapy to indapamide. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran once every 6 months (Q6M) during the open-label extension (OLE) period. Upon implementation of Amendment 3, the OLE period was closed.

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 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]

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]

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]

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]

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]

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]

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 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 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]

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]

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]

Citations

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Alnylam to Advance Zilebesiran into Global Phase 3 ...

Results of KARDIA-3 showed a single 300 mg dose of zilebesiran resulted in clinically meaningful, placebo-adjusted reductions of office systolic ...

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roche.com

roche.com/investors/updates/inv-update-2025-08-30

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No incremental SBP reductions were observed with zilebesiran 600 mg at months three or six. Post-hoc analyses suggest that a greater blood ...

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Efficacy and Safety of Zilebesiran for the Management ...

Zilebesiran resulted in a significant reduction of 24-hour ambulatory systolic blood pressure (SBP) at 12 weeks (MD -11.90; 95% CI: -13.42, - ...

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escardio.org

escardio.org/The-ESC/Press-Office/Press-releases/KARDIA-3-trial-examines-blood-pressure-lowering-effects-of-zilebesiran-in-hypertensive-patients-at-high-cardiovascular-risk

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A single dose of zilebesiran 300 mg led to a 5-mmHg reduction in office systolic BP at Month 3 compared with placebo, a difference that did not ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT04936035

A Study to Evaluate Efficacy and Safety of ALN-AGT01 in ...

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 ...

6.

alnylam.com

alnylam.com/sites/default/files/pdfs/ALN-AGT-Fact-Sheet.pdf

Zilebesiran (ALN-AGT)

Zilebesiran is being studied as monotherapy and in combination with standard of care antihypertensive medication to assess its efficacy and safety, including ...

7.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2208391

Zilebesiran, an RNA Interference Therapeutic Agent for ...

In this phase 1 study, we assessed the safety, pharmacokinetic, and pharmacodynamic profiles of zilebesiran in patients with hypertension. We ...

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Safety and Tolerability of Zilebesiran, an RNA Interference ...

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