Olezarsen for High Triglycerides

Recruiting at 295 trial locations

Overseen By Ionis Pharmaceuticals, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Ionis Pharmaceuticals, Inc.

Must be taking: Lipid-lowering therapy

Disqualifiers: New or worsening conditions, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: Unknown

Duration: 53 weeks

800 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called olezarsen, an injection, to assess its safety and manageability for individuals with very high triglycerides—fats in the blood that can impact heart health. Participants will receive an injection every four weeks for nearly three years. This study suits those who have completed a previous related study with good results and are on a consistent lipid-lowering medication plan. As a Phase 3 trial, it represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment for heart health.

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.

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

Research shows that olezarsen is generally safe for people. Earlier studies found it significantly lowers triglyceride levels, which are fat particles in the blood. Participants in these studies did not report major safety concerns. The FDA has approved olezarsen to treat familial chylomicronemia syndrome (FCS), a rare condition, indicating its safety for that use. While all treatments can have side effects, evidence so far suggests that olezarsen is safe for most people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for high triglycerides, which often include lifestyle changes and medications like fibrates, statins, and omega-3 fatty acids, Olezarsen offers a novel approach by specifically targeting the genetic pathways involved in triglyceride production. Researchers are excited about Olezarsen because it is designed as an antisense oligonucleotide, which means it can block the RNA that produces proteins responsible for high triglyceride levels. This precise mechanism has the potential to more effectively and safely lower triglycerides with fewer side effects. Plus, Olezarsen is administered via a convenient subcutaneous injection every four weeks, which could improve patient adherence compared to daily medications.

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

Research has shown that olezarsen, the investigational treatment in this trial, can effectively lower triglyceride levels in the blood. In one study, patients taking olezarsen saw their fasting triglycerides drop by up to 72% compared to those who took a placebo (a pill with no active drug). Another study found that certain doses of olezarsen reduced triglyceride levels by up to 53%. Additionally, olezarsen decreased the risk of acute pancreatitis, a sudden inflammation of the pancreas, by 85%. Overall, these studies suggest that olezarsen can significantly lower triglycerides and may help prevent related health issues. ^{2 4 6 7 8}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Olezarsen

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.

How Is the Trial Designed?

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 153.

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2402309

Olezarsen for Hypertriglyceridemia in Patients at High ... Olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified.

2. 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.

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

218614Orig1s000 INTEGRATED REVIEW - accessdata.fda.gov Safety Results, Trial ISIS 678354 ... of olezarsen effectiveness to substantiate the results of CS3 and provided supportive safety data.

6. ir.ionis.com ir.ionis.com/news-releases/news-release-details/tryngolzatm-olezarsen-approved-us-first-ever-treatment-adults

TRYNGOLZA™ (olezarsen) approved in U.S. as first-ever ... TRYNGOLZA shown to significantly reduce triglycerides and substantially reduce acute pancreatitis events in adults with FCS ; a rare, ...

7. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/34/NCT04568434/Prot_SAP_000.pdf

A Randomized, Double-Blind, Placebo-Controlled, Phase ... This study helped researchers find out if a drug called olezarsen could lower fat particles in blood (triglyceride levels) in participants who ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8986458/

Apolipoprotein C-III reduction in subjects with moderate ... Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at ...