Olezarsen for High Triglycerides

No longer recruiting at 232 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called olezarsen (also known as ISIS 678354) to determine if it can lower high triglycerides (a type of fat in the blood) more effectively than a placebo (a fake treatment). Participants will receive a shot once every four weeks for about a year. Individuals who may be suitable for this trial have very high triglyceride levels and are already on a stable medication plan to manage their cholesterol. As a Phase 3 trial, this treatment is in the final step before FDA approval, providing participants an opportunity to contribute to a potentially groundbreaking therapy.

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.

Is there any evidence suggesting that olezarsen is likely to be safe for humans?

Research has shown that olezarsen is generally well-tolerated. In one study, patients taking olezarsen experienced significant drops in triglyceride levels, with few serious side effects. Specifically, the 50 mg dose reduced triglycerides by 49%, and the 80 mg dose reduced them by 53% compared to a placebo. The safety results were positive.

Another study demonstrated that olezarsen could lower triglyceride levels by up to 72%, indicating its potential effectiveness. These studies have focused on safety and tolerability, showing that olezarsen is generally safe for people, with side effects being rare and mostly mild. This suggests that olezarsen is well-tolerated and could be a promising treatment for those with high triglycerides. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike current treatments for high triglycerides, which often include lifestyle changes, statins, and fibrates, Olezarsen offers a novel approach by targeting specific genetic factors involved in lipid metabolism. Olezarsen works by reducing the production of apolipoprotein C-III, a protein that plays a key role in regulating triglyceride levels. This unique mechanism of action could potentially offer a more effective and targeted way to lower triglycerides compared to existing therapies. Researchers are excited about Olezarsen because it represents a new frontier in precision medicine, aiming to address the underlying genetic causes of high triglycerides rather than just the symptoms.

What evidence suggests that olezarsen might be an effective treatment for high triglycerides?

Research has shown that olezarsen, which participants in this trial may receive, effectively lowers triglyceride levels—fats in the blood linked to heart disease. One study demonstrated that a 50 mg dose of olezarsen reduced triglycerides by 49%, while an 80 mg dose achieved a 53% reduction compared to a placebo. Another study found that olezarsen could lower fasting triglycerides by up to 72% and showed an 85% reduction in sudden pancreatitis attacks. These findings suggest that olezarsen could significantly aid in reducing triglyceride levels. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05355402

NCT05355402 | A Study of Olezarsen (Formerly Known as ... The purpose of the study is to evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels compared to placebo at Months 6 and 12.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03385239

NCT03385239 | Study of ISIS 678354 (AKCEA-APOCIII- ... ... ISIS 678354 for reduction of serum triglyceride (TG) levels in participants with hypertriglyceridemia and established CVD or at a high risk for CVD.

3. acc.org acc.org/Latest-in-Cardiology/Articles/2024/10/21/17/35/Efficacy-and-Safety-of-Olezarsen-in-Managing-Hypertriglyceridemia

Efficacy and Safety of Olezarsen in Managing ... Olezarsen significantly reduced TG levels, with the 50 mg dose achieving a 49% reduction and the 80 mg dose achieving a 53% reduction compared with placebo.

4. ir.ionis.com ir.ionis.com/news-releases/news-release-details/olezarsen-significantly-reduces-triglycerides-and-acute

Olezarsen significantly reduces triglycerides and acute ... Up to 72% (p<0.0001) placebo-adjusted mean reduction in fasting triglycerides –. – 85% (p=0.0002) reduction in acute pancreatitis events, ...

5. clinicaltrials.eu clinicaltrials.eu/inn/isis-678354-sodium-salt/

Isis 678354 Sodium Salt – Application in Therapy and ... These trials aim to evaluate the safety, efficacy, and tolerability of the drug when administered subcutaneously to patients with high triglyceride levels, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05610280

NCT05610280 | A Study of Olezarsen (ISIS 678354) in ... The purpose of the study is to evaluate the effect of olezarsen on percent change in fasting triglyceride (TG) levels compared to placebo in participants with ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2025/218614Orig1s000IntegratedR.pdf

218614Orig1s000 INTEGRATED REVIEW - accessdata.fda.gov Safety Results, Trial ISIS 678354-CS3 ... trial results in a related condition in patients with moderate to severe hypertriglyceridemia.