Olezarsen for High Triglycerides

Recruiting at 205 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 13

Duration: 53 weeks

446 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new medication called olezarsen to see if it can lower blood fat levels in people with high triglycerides. The goal is to find out if olezarsen can effectively reduce triglycerides and help prevent related health issues. Olezarsen has been shown to significantly reduce 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 that participants stay on their current lipid-lowering medications, which should be stable for at least 4 weeks before the study starts. This means you should not stop taking these medications.

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 also been shown to significantly reduce triglyceride levels and improve liver health 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 based on available clinical trial data. ^{2 3 4 5 6}

What makes the drug Olezarsen unique for treating high triglycerides?

Olezarsen is unique because it targets and reduces the production of apolipoprotein C-III (apoC-III), a protein that plays a key role in triglyceride metabolism, using a novel approach called antisense oligonucleotide therapy. This mechanism is different from other treatments like fibrates, statins, and omega-3 fatty acids, which only modestly lower triglyceride levels. ^{2 3 4 5 7}

Eligibility Criteria

This trial is for people with severe hypertriglyceridemia, having fasting triglycerides of 500 mg/dL or higher. Participants should be on a stable lipid-lowering therapy for at least 4 weeks and willing to follow diet and lifestyle advice. Those with certain liver, kidney, or blood sugar conditions are excluded.

Inclusion Criteria

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

Participants must be willing to comply with diet and lifestyle recommendations as able.

Fasting TG ≥ 500 mg/dL (5.65 mmol/L) at Screening and Qualification

Exclusion Criteria

Total bilirubin > 1.5 ULN unless due to Gilbert's syndrome

My kidney function is severely reduced.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

up to 12 weeks

Treatment

Participants receive olezarsen or placebo administered subcutaneously once 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

• Olezarsen
• Placebo

Trial Overview The study tests the effectiveness of Olezarsen in reducing fasting triglyceride levels compared to a placebo. Participants will receive either Olezarsen or a placebo injection and their change in triglyceride levels from the start of the study will be measured.

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 subcutaneous (SC) injection from Week 1 through Week 49.

Olezarsen is already approved in United States, European Union for the following indications:

Approved in United States as Tryngolza for:

• adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS)

Approved in European Union as Olezarsen for:

• treatment of familial chylomicronemia syndrome

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

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]

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]

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]

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

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

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. England pubmed.ncbi.nlm.nih.gov

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

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

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

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

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]