Plozasiran for High Triglycerides

(SHASTA-4 Trial)

Not currently recruiting at 307 trial locations

Overseen By Jeffrey Wayne, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Arrowhead Pharmaceuticals

Must be taking: Lipid-lowering medications

Must not be taking: Hepatocyte-targeted siRNA

Disqualifiers: Familial chylomicronemia, BMI >45, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 4

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new injection treatment called plozasiran to determine its safety and effectiveness for people with very high triglycerides (a type of fat in the blood). Participants will receive either the plozasiran injection or a placebo every three months, while researchers track changes in triglyceride levels and any side effects. Individuals with severe high triglycerides, confirmed by fasting blood tests showing levels of 500 mg/dL or higher, may be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to the potential availability of a new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must be on standard lipid-lowering medications unless you can't tolerate them. Some specific medications targeting lipids or triglycerides are not allowed within certain time frames before starting the trial.

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

Research has shown that plozasiran is generally well-tolerated. In one study, LDL cholesterol (a type of fat in the blood) increased, but the overall safety remained acceptable. Another study found that even with long-term use, participants maintained lower triglyceride levels, and the treatment stayed safe. These findings suggest that plozasiran has a strong safety record in previous trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for high triglycerides, which often include lifestyle changes, statins, or fibrates, Plozasiran works by targeting a specific protein, APOC3, that plays a significant role in triglyceride regulation. This makes Plozasiran unique because it directly interferes with the production of APOC3, potentially offering a more precise way to lower triglycerides. Administered as a subcutaneous injection, it also provides a convenient alternative for patients who may have difficulty with oral medications. Researchers are excited because this targeted approach could lead to more effective and quicker reductions in triglyceride levels compared to existing therapies.

What evidence suggests that plozasiran might be an effective treatment for severe hypertriglyceridemia?

Research shows that plozasiran injections, which participants in this trial may receive, effectively lower triglyceride levels in people with severe hypertriglyceridemia (SHTG). Studies have found that plozasiran reduces triglyceride levels by 60% to 74% on average compared to a placebo. This reduction can help bring triglyceride levels below the risky threshold of 500 mg/dL. The treatment targets a protein called ApoC-III, involved in fat processing. By reducing ApoC-III, plozasiran lowers triglyceride levels and improves fat balance in the body. These studies have reported no major safety issues. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

Adults with severe hypertriglyceridemia (very high triglycerides) can join this study. They must have a history of fasting triglyceride levels over 500 mg/dL and meet specific criteria for LDL cholesterol and HbA1C during screening. Participants should be on standard lipid-lowering medications unless they're intolerant.

Inclusion Criteria

I have severe high blood fat levels with a past test showing over 500 mg/dL.

Screening HbA1C ≤8.5%

Fasting low density lipoprotein-cholesterol (LDL-C) ≤130 mg/dL (≤3.37 mmol/L) at screening

Exclusion Criteria

I have a confirmed genetic diagnosis of familial chylomicronemia syndrome.

Body mass index >45kg/m^2

I haven't used specific liver-targeted gene therapies recently, except inclisiran.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 4 doses of plozasiran or placebo, administered once every 3 months

12 months

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Plozasiran Injection

Trial Overview

The trial is testing Plozasiran injections against a placebo in adults with severe hypertriglyceridemia. Participants will receive four doses every three months, followed by an optional extension phase to further assess the drug's safety and effectiveness.

How Is the Trial Designed?

Group I: Plozasiran Injection Experimental Treatment 1 Intervention

4 doses of plozasiran (ARO-APOC3) by subcutaneous (sc) injection

Group II: Placebo Placebo Group 1 Intervention

calculated volume to match active treatment by sc injection

Who Is Running the Clinical Trial?

Arrowhead Pharmaceuticals

Lead Sponsor

Trials

45

Recruited

6,200+

Published Research Related to This Trial

A study involving 115 plasma samples from adolescents and adults identified 161 metabolites associated with a rare APOC3 variant, indicating that targeting apoC-III can significantly influence lipid metabolism.

The findings suggest that therapies like volanesorsen, which target apoC-III, may not only reduce harmful triacylglyceride levels but also promote a healthier lipid profile, potentially improving metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic characterisation of disturbances in the APOC3/triglyceride-rich lipoprotein pathway through sample-based recall by genotype. Corbin, LJ., Hughes, DA., Chetwynd, AJ., et al.[2022]

Volanesorsen, an antisense drug targeting apoC3 mRNA, significantly reduced levels of apoC-III on various lipoproteins (apoB, Lp(a), and apoA-I) by over 80% compared to placebo in patients with hypertriglyceridemia, indicating its potential efficacy in lowering cardiovascular risk.

The study utilized novel high-throughput ELISAs to measure lipoprotein-associated apoC-III, providing a new method for assessing cardiovascular risk factors and demonstrating that volanesorsen may effectively reduce triglycerides and associated cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. Yang, X., Lee, SR., Choi, YS., et al.[2021]

Vupanorsen is an antisense oligonucleotide that effectively targets ANGPTL3 mRNA, leading to significant reductions in ANGPTL3 levels, triglycerides, and non-HDL cholesterol in patients with dyslipidemia, as shown in a study involving 286 participants.

The pharmacokinetic model indicates that a monthly dose of 320 mg of vupanorsen can achieve a 75% reduction in ANGPTL3, but this dose may not be sufficient to meet target reductions for triglycerides and non-HDL cholesterol in dyslipidemic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A population pharmacokinetic and pharmacokinetic-pharmacodynamic analysis of vupanorsen from phase I and phase II studies. Ahn, JE., Terra, SG., Liu, J.[2023]

ApoC-III has been linked to lower triglyceride levels and a reduced risk of cardiovascular disease, making it a promising target for new treatments for dyslipidemia and CVD.

Clinical trials using antisense oligonucleotides to inhibit apoC-III have shown encouraging results, suggesting that targeting this protein could effectively manage lipid levels and cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease? Taskinen, MR., Borén, J.[2018]

Icosapent ethyl, a purified omega-3 fatty acid, has been approved in Germany to reduce cardiovascular events in patients with hypertriglyceridemia and established cardiovascular disease or diabetes, showing its efficacy in this high-risk group.

New drugs targeting proteins like ApoC-III and ANGPTL3 are in development, with promising genetic data supporting their potential effectiveness, but larger long-term studies are needed to confirm their roles in treating hypertriglyceridemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapeutic approaches for the treatment of hypertriglyceridemia. Gouni-Berthold, I., Schwarz, J.[2022]

In a clinical trial involving 114 patients with high triglyceride levels, olezarsen significantly reduced triglyceride levels by up to 60% compared to a 6% increase in the placebo group, demonstrating its efficacy in lowering triglycerides in patients at high risk for cardiovascular disease.

Olezarsen also led to significant reductions in other harmful lipoproteins and showed a good safety profile, with no major adverse effects on liver or kidney function, and only mild injection site reactions reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Tardif, JC., Karwatowska-Prokopczuk, E., Amour, ES., et al.[2022]

Volanesorsen, an antisense oligonucleotide targeting APOC3 mRNA, has shown strong efficacy in significantly reducing both apoC-III production and triglyceride levels, which are crucial for managing severe hypertriglyceridemia.

Current phase 3 trials are evaluating the safety and effectiveness of volanesorsen, highlighting its potential as a new treatment option for patients at high risk of pancreatitis and cardiovascular disease due to elevated triglyceride levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

APOC-III Antisense Oligonucleotides: A New Option for the Treatment of Hypertriglyceridemia. Schmitz, J., Gouni-Berthold, I.[2019]

Apolipoprotein C-III (apoC-III) is linked to higher triglyceride levels and increased risk of coronary artery disease (CAD), making it a target for new therapies.

Current and developing treatments, including statins and an antisense oligonucleotide targeting APOC3, aim to lower apoC-III levels, which may reduce triglycerides and subsequently lower cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting ApoC-III to Reduce Coronary Disease Risk. Khetarpal, SA., Qamar, A., Millar, JS., et al.[2018]

Citations

1.

arrowheadpharma.com

arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-presents-new-data-at-aha24-from-palisade-phase-3-study-and-open-label-extension-from-muir-and-shasta-2-studies-of-plozasiran/

Arrowhead Pharmaceuticals Presents New Data at AHA24 ...

The goal of treatment with plozasiran is to reduce the level of APOC3, thereby reducing triglycerides and restoring lipids to more normal levels ...

2.

jacc.org

jacc.org/doi/10.1016/j.jacc.2025.03.496

Effect of Targeting ApoC-III With Plozasiran on Lipoprotein ...

In recent clinical trials, plozasiran reduced triglyceride levels, relative to placebo, by an average of 60% with 25- and 50-mg plozasiran dosed ...

3.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2404143

Plozasiran, an RNA Interference Agent Targeting APOC3, ...

In this trial involving participants with mixed hyperlipidemia, we found that plozasiran significantly lowered triglyceride levels as compared ...

4.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38583092/

Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia

In this randomized clinical trial of patients with sHTG, plozasiran decreased triglyceride levels, which fell below the 500 mg/dL threshold of acute ...

5.

acc.org

acc.org/About-ACC/Press-Releases/2024/04/07/11/45/plozasiran-reduces-triglyceride-levels-by-74-at-24-weeks

Plozasiran Reduces Triglyceride Levels by 74% at 24 Weeks

The investigational drug plozasiran reduced triglyceride levels by an average of 74% after 24 weeks of use without causing any significant safety concerns.

6.

ahajournals.org

ahajournals.org/doi/10.1161/circ.150.suppl_1.4139852

Abstract 4139852: Plozasiran and Triglyceride Levels in ...

Extended open-label treatment with plozasiran in subjects with moderate to severely elevated TGs continue to show reductions of TG levels and safety.

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06822790

Long-Term Safety and Efficacy of Plozasiran in Adults With ...

This is an open-label study to be conducted in adults with hypertriglyceridemia (HTG) and severe hypertriglyceridemia (SHTG).

8.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11000138/

Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia

As shown in the phase 1 study data,19 plozasiran provides significant and durable APOC3 reductions for 12 weeks after a single subcutaneous dose. As a result, ...