Olezarsen for High Triglycerides

Recruiting at 208 trial locations

Overseen By Ionis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Ionis Pharmaceuticals, Inc.

Must be taking: Lipid-lowering therapy

Disqualifiers: High HbA1c, Liver enzymes, Low GFR, 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: 13

Duration: 53 weeks

617 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests olezarsen, a new drug, to see if it can lower blood fat levels in people with high triglycerides. The goal is to help those who may not respond to usual treatments by reducing their blood fat and preventing health problems. Olezarsen is a new drug being tested to address the unmet need for effective triglyceride-lowering treatments, as current medications often fail to achieve normal triglyceride levels.

Will I have to stop taking my current medications?

The trial requires that you stay on your current lipid-lowering medications, as they need to be optimized and stable for at least 4 weeks before the study starts.

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

Research shows that Olezarsen, which targets a protein called apolipoprotein C-III, can lower triglyceride levels in people at high risk for heart disease. Similar drugs, like volanesorsen, have been shown to significantly reduce triglyceride levels and are being tested in advanced clinical trials. ^{1 2 3 4 5}

Is Olezarsen safe for humans?

The safety of Olezarsen, also known as ISIS 678354 and other names, has been evaluated in clinical trials for lowering triglyceride levels. While specific safety data for Olezarsen is not detailed in the provided research, similar treatments like volanesorsen have been studied for safety in treating high triglycerides, suggesting that Olezarsen may have a similar safety profile. ^{1 2 3 5 6}

What makes the drug Olezarsen unique for treating high triglycerides?

Olezarsen is unique because it is an antisense oligonucleotide (a type of genetic material that can block specific genes) designed to target and reduce the production of apolipoprotein C-III, a protein that plays a key role in triglyceride metabolism. This approach is different from other treatments like fibrates or statins, which only modestly lower triglyceride levels. ^{1 2 3 4 7}

Eligibility Criteria

This trial is for people with severe hypertriglyceridemia, a condition with very high levels of triglycerides in the blood. Participants must be on stable lipid-lowering therapy according to local guidelines for at least 4 weeks before joining. They can't join if they have severely impaired kidney function, uncontrolled diabetes (HbA1c ≥ 9.5%), or significantly elevated liver enzymes.

Inclusion Criteria

My fasting triglycerides are 500 mg/dL or higher.

I have been on stable cholesterol medication for at least 4 weeks.

I have been on stable cholesterol-lowering medication for at least 4 weeks.

Exclusion Criteria

Hemoglobin A1c (HbA1c) ≥ 9.5% at Screening

Alanine aminotransferase or aspartate aminotransferase > 3.0 × upper limit of normal

Total bilirubin > upper limit of normal unless due to Gilbert's syndrome

Timeline

Screening

Participants are screened for eligibility to participate in the trial

up to 12 weeks

Treatment

Participants receive olezarsen or placebo administered subcutaneously every 4 weeks

53 weeks

13 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

13 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

up to 1 year

Treatment Details

Interventions

• ISIS 678354
• Olezarsen
• Placebo

Trial Overview The study tests Olezarsen's effectiveness against a placebo in reducing fasting triglyceride levels from the start of the trial. Patients will randomly receive either Olezarsen or a placebo to compare changes in their triglyceride levels.

Participant Groups

Group I: Olezarsen Experimental Treatment 1 Intervention

Olezarsen will be administered once every 4 weeks by subcutaneous (SC) injection from Week 1 through Week 49.

Group II: Placebo Placebo Group 1 Intervention

Olezarsen-matching placebo will be administered once every 4 weeks by SC injection from Week 1 through Week 49.

Who Is Running the Clinical Trial?

Ionis Pharmaceuticals, Inc.

Lead Sponsor

Trials

151

Recruited

27,800+

Dr. Brett P. Monia

Ionis Pharmaceuticals, Inc.

Chief Executive Officer since 2020

PhD in Pharmacology from the University of Pennsylvania, BSc in Molecular Biology and Analytical Chemistry from Stockton State College

Dr. Eric Bastings

Ionis Pharmaceuticals, Inc.

Chief Medical Officer

MD

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]

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]

Volanesorsen, an antisense oligonucleotide targeting APOC3 mRNA, significantly reduces both apolipoprotein-CIII production and triglyceride levels, making it a promising treatment for severe hypertriglyceridemia.

Current phase 3 trials are evaluating the efficacy and safety of volanesorsen, which could provide a new option for patients at risk of pancreatitis and cardiovascular disease due to high triglyceride levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of antisense oligonucleotide therapy against apolipoprotein-CIII in hypertriglyceridemia. Gouni-Berthold, I.[2018]

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]

Diabetic dyslipidemia in type 2 diabetes is characterized by high triglycerides and low HDL cholesterol, with insulin resistance playing a key role in its development, particularly through the action of apolipoprotein CIII (ApoCIII).

Volanesorsen, a new drug that inhibits ApoCIII, has shown promise in improving lipid profiles in patients with diabetic dyslipidemia, suggesting it could be an effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contribution of ApoCIII to Diabetic Dyslipidemia and Treatment With Volanesorsen. Zhang, J., Rocha, NA., McCullough, PA.[2019]

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 Arab Emirates pubmed.ncbi.nlm.nih.gov

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

The role of antisense oligonucleotide therapy against apolipoprotein-CIII in hypertriglyceridemia. [2018]

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

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

5. England pubmed.ncbi.nlm.nih.gov

Volanesorsen to treat severe hypertriglyceridaemia: A pooled analysis of randomized controlled trials. [2022]

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

Disposition and Pharmacology of a GalNAc3-conjugated ASO Targeting Human Lipoprotein (a) in Mice. [2022]

7. Singapore pubmed.ncbi.nlm.nih.gov

Contribution of ApoCIII to Diabetic Dyslipidemia and Treatment With Volanesorsen. [2019]