Plozasiran for High Triglycerides

(SHASTA-3 Trial)

Recruiting at 195 trial locations

Overseen By Joel Neutel, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

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)

Prior Safety Data

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 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.

What data supports the effectiveness of the drug Plozasiran for high triglycerides?

Research shows that targeting apolipoprotein C-III (apoC-III) can effectively lower triglyceride levels, which are linked to cardiovascular disease. Drugs that inhibit apoC-III, like those in development, have shown promise in reducing triglycerides and associated health risks. ^{1 2 3 4 5}

What makes the drug Plozasiran unique for treating high triglycerides?

Plozasiran is unique because it targets apolipoprotein C-III (apoC-III), a protein that regulates triglyceride levels, using an antisense oligonucleotide approach to reduce its production, which is different from traditional treatments like statins or fibrates that do not specifically target apoC-III. ^{2 4 5 6 7}

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, 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.

Trial 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 under a separate protocol

Treatment Details

Interventions

• Plozasiran (Anti-sense Oligonucleotide)

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.

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

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]

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]

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]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

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

2. 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]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Early Investigational and Experimental Therapeutics for the Treatment of Hypertriglyceridemia. [2022]

4. England pubmed.ncbi.nlm.nih.gov

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

5. 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]

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

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

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

Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. [2022]