Plozasiran for High Triglycerides

(SHASTA-3 Trial)

Not currently recruiting at 422 trial locations

Overseen By Dylan Steen, 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, Acute pancreatitis, 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 if it safely reduces very high triglyceride levels (a type of fat in the blood). Participants will receive either the plozasiran injection or a placebo (a harmless substance resembling the treatment) every three months for a year. The trial seeks adults diagnosed with severe hypertriglyceridemia, meaning they have consistently high triglyceride levels despite following a low-fat diet and taking standard medications. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial requires participants to be on standard lipid-lowering medications unless they are intolerant. The protocol does not specify if you need to stop other medications, but certain medications targeting lipids and triglycerides are restricted.

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

Research has shown that plozasiran is well-tolerated in people. Earlier studies found single doses of plozasiran safe for healthy participants. In a study involving individuals with high triglyceride levels, plozasiran proved as safe as a placebo, with the main concern being some changes in blood sugar levels at higher doses. Longer treatment in other trials also demonstrated that it continues to lower triglyceride levels without major safety issues. Overall, the evidence suggests that plozasiran is safe for use in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for high triglycerides focus on lifestyle changes, statins, or fibrates. But Plozasiran is unique because it targets a specific protein called apolipoprotein C-III (APOC3) using RNA interference. This novel mechanism directly reduces triglyceride levels by inhibiting the production of APOC3, which plays a key role in lipid metabolism. Unlike existing options that may take longer to show effects, Plozasiran's targeted approach has the potential to deliver faster and more significant results in managing triglyceride levels. Researchers are excited about its potential to offer a more efficient and precise treatment for those struggling with high triglycerides.

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

Research has shown that plozasiran, which participants in this trial may receive, effectively lowers triglyceride levels in people with very high triglycerides. Recent studies reported that plozasiran reduced these levels by an average of 60% to 74%, bringing triglyceride levels below the critical 500 mg/dL mark, crucial for preventing sudden health problems. The treatment reduces APOC3, a protein that raises triglyceride levels. Importantly, the studies identified no major safety concerns with plozasiran. ^{1 5 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, low LDL cholesterol at screening, stable blood sugar control (HbA1C ≤8.5%), and be willing to follow a low-fat diet while on standard lipid-lowering meds unless intolerant.

Inclusion Criteria

Willing to follow diet counseling and maintain a stable low-fat diet

Mean fasting TG level ≥500 mg/dL (≥5.65 mmol/L) collected at 2 separate and consecutive visits at least 7 days apart and no more than 17 days apart during the screening period

Screening HbA1C ≤8.5%

Exclusion Criteria

Body mass index >45kg/m^2

I haven't used specific liver-targeting gene therapies in the last year, except inclisiran.

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

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 under a separate protocol

What Are the Treatments Tested in This Trial?

Interventions

• Plozasiran

Trial Overview

The trial is testing Plozasiran injections against a placebo in adults with severe hypertriglyceridemia. Participants will receive four doses every three months and will be monitored for safety and effectiveness. After one year, they may continue in an extension study.

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

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]

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]

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]

Hypertriglyceridemia is a significant risk factor for cardiovascular disease and acute pancreatitis, highlighting the need for effective treatments beyond existing options like fibrates and ω-3 fatty acids.

Novel therapies, including apolipoprotein C-III inhibitors and fibroblast growth factor 21 analogues, are currently in early clinical development to better manage very high triglyceride levels and reduce cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Investigational and Experimental Therapeutics for the Treatment of Hypertriglyceridemia. Parthymos, I., Kostapanos, MS., Liamis, G., et al.[2022]

ISIS 304801 significantly reduced plasma APOC3 levels in a dose-dependent manner, achieving reductions of up to 79.6% in patients not on fibrates and 70.9% in those receiving fibrate therapy, indicating its efficacy in lowering triglyceride levels.

The treatment was well-tolerated with no safety concerns reported during the 13-week study involving 85 patients, suggesting that ISIS 304801 is a safe option for managing elevated triglyceride levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. Gaudet, D., Alexander, VJ., Baker, BF., et al.[2022]

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]

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]

Citations

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

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

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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.

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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 ...

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Press Release Details

Title: Plozasiran and Triglyceride Levels in Hypertriglyceridemia: Long-Term Efficacy and Safety Data from Subjects in an Open-Label ...

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

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Safety, pharmacokinetics and pharmacodynamics of ...

Single SC administration of plozasiran at 25 or 50 mg was well tolerated in healthy Chinese subjects; in addition, plozasiran demonstrated the ...