ALN-AGT01 RVR for Healthy Volunteers

Overseen By Alnylam Clinical Trial Information Line

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Alnylam Pharmaceuticals

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

Compensation: Varies

Number of Visits: 2

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ALN-AGT01 RVR (also known as Zilebesiran or AGT siRNA) to determine its safety and how the body processes it. Healthy volunteers will receive either a single dose of the treatment or a placebo (a harmless pill with no effect). The trial seeks healthy adults with a body mass index (BMI) between 18 and 28. Participants must not have liver issues or certain viral infections like hepatitis or HIV. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since this study is for healthy volunteers, it's possible that you may not be on any regular medications.

Is there any evidence suggesting that ALN-AGT01 RVR is likely to be safe for humans?

Research shows that ALN-AGT01 RVR is undergoing testing to determine its safety for people. As an early-stage trial, the primary goal is to assess the treatment's safety and tolerability.

Limited information exists on ALN-AGT01 RVR, which is typical for treatments at this stage. This phase ensures the treatment does not cause serious side effects in healthy volunteers. Participants will receive a single dose to observe their body's response.

Since this is the first human trial, researchers will closely monitor any side effects to ensure participant safety. The safety data from this trial will inform decisions on further testing of ALN-AGT01 RVR.

Why do researchers think this study treatment might be promising?

Researchers are excited about ALN-AGT01 RVR because it offers a fresh approach to managing conditions related to the angiotensin pathway. Unlike current treatments, which often include ACE inhibitors or angiotensin receptor blockers (ARBs), ALN-AGT01 RVR works by a novel mechanism, potentially offering more precise targeting with fewer side effects. This new treatment could provide an alternative for patients who do not respond well to existing therapies. Additionally, the single-dose administration is convenient, which could improve patient compliance compared to daily medications.

What evidence suggests that ALN-AGT01 RVR could be effective?

Research has shown that ALN-AGT01 RVR, also known as zilebesiran, holds promise in lowering blood pressure. This treatment uses RNA-based technology to target and reduce angiotensinogen, a protein that helps control blood pressure. Consequently, it can effectively lower blood pressure with fewer doses. Early results indicate it reduces both systolic and diastolic numbers in blood pressure readings. These findings suggest that ALN-AGT01 RVR could effectively manage high blood pressure. Participants in this trial will receive either a single dose of ALN-AGT01 RVR or a placebo to evaluate its effects. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

This trial is for healthy adult volunteers who want to participate in a study evaluating the safety of a new medication. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and not be taking conflicting medications.

Inclusion Criteria

Has a body mass index ≥18 kg/m^2 and ≤28 kg/m^2

I am a healthy adult.

Exclusion Criteria

Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN)

My kidney function test shows less than normal results.

I have HIV, hepatitis B, or hepatitis C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single ascending dose of ALN-AGT01 RVR or placebo

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 day

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• ALN-AGT01 RVR

Trial Overview The trial is testing ALN-AGT01 RVR, which is likely a new drug. Participants will receive either this drug or a placebo (a substance with no therapeutic effect) to assess the drug's safety, how well it's tolerated by the body, and its pharmacokinetics (how it's processed by the body).

How Is the Trial Designed?

Group I: ALN-AGT01 RVR Experimental Treatment 1 Intervention

Participants will be administered a single dose of ALN-AGT01 RVR.

Group II: Placebo Placebo Group 1 Intervention

Participants will be administered a single dose of placebo.

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

The study demonstrated that adeno-associated virus (AAV)-based vectors can effectively transduce the NeoR gene into various human leukemia cell lines, with the highest efficiency observed in K-562 cells at a multiplicity of infection (MOI) of 7, achieving a 27% transduction rate.

Integration of the NeoR gene into the host genome was confirmed, but it occurred outside the expected chromosome 19q13.3 location, indicating that while AAV can deliver genes to leukemia cells, the integration sites may vary significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant adeno-associated virus-mediated gene transfer into human leukemia cell lines. Itou, T., Miyamura, K., Abe, A., et al.[2019]

A novel approach using a single recombinant adeno-associated virus (rAAV) vector successfully delivered both zinc-finger nucleases (ZFNs) and a DNA repair substrate, enhancing gene targeting efficiency in human cell lines and mouse models.

The study demonstrated that combining FDA-approved drugs with rAAV treatment can increase gene correction rates by up to sixfold, suggesting a promising strategy for optimizing gene therapy for monogenic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zinc-finger nuclease-mediated gene correction using single AAV vector transduction and enhancement by Food and Drug Administration-approved drugs. Ellis, BL., Hirsch, ML., Porter, SN., et al.[2021]

The newly developed AAVR-HeLa cell line, which overexpresses the AAVR receptor, significantly enhances the transduction efficiency of various rAAV serotypes, particularly AAV8 and AAV9, making it a valuable tool for detecting neutralizing antibodies (NAbs) in gene therapy trials.

Using AAVR-HeLa cells, the sensitivity for detecting NAbs increased by at least 10 to 20 times for AAV8 and AAV9, respectively, indicating that this cell line can improve the accuracy of assessments for patient eligibility in gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced sensitivity of neutralizing antibody detection for different AAV serotypes using HeLa cells with overexpressed AAVR. Zheng, Z., Ye, J., Leng, M., et al.[2023]

Recombinant adeno-associated virus (rAAV) serotypes 5 and 6 effectively transduce human adipose-derived stem cells (ASCs) without reducing cell viability, making them safer options for gene therapy.

Transduction with rAAV6 Y731F mutant further enhances efficiency while maintaining the adipogenic potential of ASCs, suggesting these vectors are promising for genetic manipulation in cellular therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transduction of human adipose-derived mesenchymal stem cells by recombinant adeno-associated virus vectors. Locke, M., Ussher, JE., Mistry, R., et al.[2018]

The study developed a novel system using AAVS1 ZFN-mediated knock-in techniques to effectively detect genome-editing activities, achieving a correction efficiency of 0.11% in targeted cell lines.

This new method is simpler and more efficient than existing techniques, such as the FLP-in method, due to its dual positive and negative selection mechanisms for assessing ZFN biological activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishment of a cell line carrying single copy of an exogenous mutant reporter gene for assaying the biological activity of ZFNs. Zhang, W., Zheng, X., Wang, Y., et al.[2012]

Citations

1. sigma.larvol.com sigma.larvol.com/product.php?e1=842715&tab=newstrac

zilebesiran (ALN-AGT) News RNA-based therapies, like zilebesiran, provide a novel approach to suppress angiotensinogen, offering durable antihypertensive effects with less frequent dosing ...

2. 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 ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11831239/

Safety and Efficacy of Novel RNA Interference Therapeutic ... Zilebesiran is a subcutaneously administered novel RNA interference therapeutic agent that reduces blood pressure by targeting angiotensinogen (AGT) synthesis.

4. investors.alnylam.com investors.alnylam.com/press-release?id=25816

Alnylam Initiates KARDIA-1 Phase 2 Study of Zilebesiran (ALN ... The KARDIA-1 Phase 2 trial is a randomized, double-blind (DB), placebo-controlled, dose-ranging study to evaluate the efficacy and safety of zilebesiran as ...

5. hra.nhs.uk hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/a-study-to-evaluate-aln-agt01-in-patients-with-hypertension-v10/

A Study to Evaluate ALN-AGT01 in Patients with ... The aim is to evaluate the safety and tolerability of subcutaneously administered ALN-AGT01 in these patient volunteers as well as to assess the way ALN-AGT01 ...