Plozasiran for High Triglycerides

(SHASTA-4 Trial)

Recruiting at 147 trial locations

Overseen By Robert Rosenson, 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

300 Participants Needed

Trial Summary

What is the purpose of this trial?

This Phase 3 study will evaluate the safety and efficacy of plozasiran injection (ARO-APOC3) in adult participants with severe hypertriglyceridemia (SHTG). After providing informed consent eligible participants will be randomized to receive 4 doses (once every 3 months) of plozasiran or placebo, and be evaluated for efficacy and safety. After Month 12, eligible participants will be offered an opportunity to continue in an optional open-label extension under a separate protocol.

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.

What data supports the effectiveness of the drug Plozasiran Injection, ARO-APOC3, for high triglycerides?

Research shows that targeting apolipoprotein C-III (apoC-III) can effectively lower triglyceride levels, which are linked to heart disease risk. Similar drugs that inhibit apoC-III, like volanesorsen, have shown significant reductions in triglyceride levels, suggesting that Plozasiran may also be effective. ^{1 2 3 4 5}

Is Plozasiran safe for humans?

There is no specific safety data available for Plozasiran, but similar treatments targeting apolipoprotein C-III, like volanesorsen, have been evaluated for safety in clinical trials for high triglycerides and cardiovascular risk. ^{1 2 3 6 7}

What makes the drug Plozasiran unique for treating high triglycerides?

Plozasiran (ARO-APOC3) is unique because it targets apolipoprotein C-III (apoC-III), a protein that raises triglyceride levels, using a novel approach called antisense oligonucleotide therapy. This method specifically reduces the production of apoC-III, which can help lower triglyceride levels and potentially reduce the risk of cardiovascular disease. ^{1 2 3 5 8}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease? [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Metabolic characterisation of disturbances in the APOC3/triglyceride-rich lipoprotein pathway through sample-based recall by genotype. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

New therapeutic approaches for the treatment of hypertriglyceridemia. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. [2021]

6. United Arab Emirates pubmed.ncbi.nlm.nih.gov

APOC-III Antisense Oligonucleotides: A New Option for the Treatment of Hypertriglyceridemia. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

A population pharmacokinetic and pharmacokinetic-pharmacodynamic analysis of vupanorsen from phase I and phase II studies. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Targeting ApoC-III to Reduce Coronary Disease Risk. [2018]