Olezarsen for High Triglycerides

Recruiting at224 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Ionis Pharmaceuticals, Inc.

Must be taking: Lipid-lowering therapy

Disqualifiers: New or worsening conditions, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing a medication called olezarsen to see if it is safe and can be tolerated by people with very high levels of blood fat (triglycerides). The study involves up to 700 participants who will take the medication for several months. The goal is to help reduce the fat in their blood and prevent serious health issues. Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease.

Will I have to stop taking my current medications?

The trial requires participants to stay on a stable regimen of lipid-lowering therapy, so you should not stop taking these medications if they are part of your current treatment.

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

Research shows that Olezarsen, which targets a protein called apolipoprotein C-III (apoC-III) involved in triglyceride metabolism, can lower triglyceride levels in patients at high risk for cardiovascular disease. Similar drugs like volanesorsen have also been shown to significantly reduce triglyceride levels and improve liver fat content in patients with severe hypertriglyceridemia. ^{1 2 3 4 5}

Is Olezarsen safe for humans?

Olezarsen, also known by other names like AKCEA-APOCIII-LRx, has been studied for its ability to lower triglyceride levels, which are fats in the blood. While the research primarily focuses on its effectiveness, it is generally considered safe in humans, as it targets specific proteins in the liver to reduce triglycerides without major safety concerns reported in the studies. ^{1 2 3 4 6}

How is the drug Olezarsen unique in 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, statins, and omega-3 fatty acids, which only modestly lower triglyceride levels. ^{1 2 3 4 7}

Research Team

Eligibility Criteria

This trial is for people with severe hypertriglyceridemia who are already on a stable regimen of lipid-lowering therapy. Participants should have completed previous olezarsen studies (ISIS 678354-CS5 or CS6) without serious issues. Those with new or worsening conditions that could affect study participation, or who need disallowed medications, can't join.

Inclusion Criteria

I am on a stable cholesterol treatment plan as per local health guidelines.

I completed a specific treatment course without major side effects.

Exclusion Criteria

Have any new condition or worsening of existing condition which in the opinion of the Investigator would make the participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study, including need for treatment with disallowed medications, or need to change the required stable regimen as per either ISIS 678354-CS5 or ISIS 678354-CS6 study entry criteria.

Trial Timeline

Qualification

Participants undergo a 31-day qualification period before starting treatment

4 weeks

Treatment

Participants receive olezarsen, subcutaneous injection, once every 4 weeks from Week 1 through Week 49

53 weeks

Post-treatment

Participants are monitored for safety and effectiveness after treatment

13 weeks

Treatment Details

Interventions

• Olezarsen (Antisense Oligonucleotide)

Trial Overview The trial is testing the safety and tolerability of a drug called Olezarsen when given by injection to patients with very high triglyceride levels in their blood. The goal is to see how well participants handle the medication over time.

Participant Groups

Group I: Olezarsen Experimental Treatment 1 Intervention

Participants who completed either ISIS 678354-CS5 (NCT05079919) or ISIS 678354-CS6 (NCT05552326) study would be enrolled to receive olezarsen, subcutaneous (SC) injection, once every 4 weeks 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 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]

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 oligonucleotide targeting APOC3 mRNA, significantly reduced hepatic fat fraction (HFF) in patients with severe hypertriglyceridemia, showing a reduction of -3.02% in the COMPASS trial and -8.34% in the BROADEN trial, indicating its efficacy in lowering liver fat.

The treatment demonstrated a strong inverse correlation between baseline HFF and changes in HFF in the volanesorsen groups, suggesting that patients with higher initial liver fat may benefit more from the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

APOC3 inhibition with volanesorsen reduces hepatic steatosis in patients with severe hypertriglyceridemia. Prohaska, TA., Alexander, VJ., Karwatowska-Prokopczuk, E., et al.[2023]

AKCEA-APOCIII-LRx significantly reduces levels of apolipoprotein C-III and triglycerides in healthy volunteers, with reductions of up to 92% and 77% respectively after a single dose, indicating its potential efficacy in treating hypertriglyceridaemia.

The treatment was well tolerated with minimal side effects, showing no serious safety concerns, which suggests it could be a safe option for improving lipid profiles in patients at risk for coronary heart disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Alexander, VJ., Xia, S., Hurh, E., et al.[2020]

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 States pubmed.ncbi.nlm.nih.gov

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

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

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

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

APOC3 inhibition with volanesorsen reduces hepatic steatosis in patients with severe hypertriglyceridemia. [2023]

6. England pubmed.ncbi.nlm.nih.gov

N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. [2020]

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

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