The urgency to research new modalities to manage elevated triglyceride levels and reduce associated metabolic risks

The CORE and CORE₂ trials are now enrolling patients with severe hypertriglyceridemia

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The risks of unmanaged elevated triglycerides

Hypertriglyceridemia (HTG) is a common condition, which is defined as having a high level (>150 mg/dL) of TGs, a type of fat, in the bloodstream.¹ In the U.S., it is estimated that more than 3 million adults suffer with severe hypertriglyceridemia (sHTG),² defined as TG levels >500 mg/dL. sHTG is associated with a high risk of acute pancreatitis and systemic atherosclerotic cardiovascular disease (ASCVD).^2,3 HTG can occur as part of the metabolic syndrome and complicate the management of obesity, diabetes and insulin resistance⁴ (as well as increase the risk for diabetes diagnosis and diabetes-related death⁵) and is also a risk factor for the development of fatty liver disease.⁶ People with sHTG (up to 880 mg/dL) have an approximately 2-fold to 9-fold higher risk of myocardial infarction, stroke, aortic stenosis or other major adverse cardiovascular events compared to those with normal TG levels.^6,7,8 However, it remains unclear as to which aspect of human TG biology is responsible for promoting the development of arterial wall lesions.⁹ People with TG levels ≥~500 mg/dL have an 11-fold higher risk for acute pancreatitis compared to the general population and those with genetically influenced sHTG have an even higher risk, ~50-fold.^10,11 Compared to those who suffer from non-TG associated pancreatitis, TG-induced acute pancreatitis can be fatal and increases the risk of persistent organ failure as well as endocrine and exocrine pancreatic insufficiency in these individuals.^4,12,13

Current lifestyle recommendations can be difficult to adhere to and drug therapies may be insufficient to reduce severe HTG levels and its associated risks.^1,14,15 

An investigational RNA-focused approach to potentially reduce severely elevated TG levels

One approach under evaluation is an investigational drug called olezarsen.* Olezarsen is a ligand-conjugated antisense (LICA) medicine designed to inhibit the production of apolipoprotein C-III (apoC-III), a protein that regulates TG metabolism in the blood.¹⁶ Antisense oligonucleotides, or ASOs, are designed to bind precisely with RNA, halting the process of creating a disease-causing protein.^17,18 LICA is a chemical technology that involves the attachment of a molecule called a ligand that binds with receptors on the surfaces of cells in a highly specific manner.^18,19 Olezarsen consists of an antisense oligonucleotide directed against the mRNA for apoC-III and a liver-specific ligand designed to increase the binding and uptake of olezarsen by hepatocytes, where most apoC-III is produced.^16,20

Early-stage clinical studies support the continued development of once-monthly administration of olezarsen to reduce and sustain TG levels with a well-tolerated safety profile.²⁰ Further studies are needed to establish the safety and efficacy of olezarsen for this use.

CORE Trials

Ionis Pharmaceuticals is currently enrolling patients in the CORE and CORE₂ trials to evaluate the efficacy and safety of olezarsen for patients with sHTG. These studies will provide evidence to establish apoC-III inhibition as an important potential therapeutic modality in reducing excessive TG levels in the blood.^21,22

Participants who are 18 years of age or older with TG levels ≥500 mg/dL despite ongoing use of standard-of-care lipid-lowering medications that adhere to standard-of-care per local guidelines may be eligible to enroll in the CORE trials. Upon screening, additional inclusion and exclusion criteria will apply.^21,22

Approximately 940 participants will be randomized 1:1 in the CORE trials to receive investigational drug (olezarsen) or placebo in a 53-week treatment period. The length of participation in the studies will be ~74 weeks, including screening, treatment and post-treatment evaluation. Any symptoms and experiences will be closely monitored and discussed with a study doctor throughout the trial. There is no cost to participate. All study-related visits, tests and study drugs will be covered by the study sponsor.^21,22

Talk to your patients about their potential to participate in the CORE trials

If you know a patient who fits the above criteria and you would like to refer them for possible enrollment in either CORE or CORE₂, please contact ionisSHTGtrials@clinicaltrialmedia.com or call (844) 691-2147.

To learn more about the trials and eligibility criteria, please visit www.TGAware.com/clinical-trial.

About Ionis Pharmaceuticals

For more than 30 years, Ionis has been the leader in RNA-focused therapy, pioneering new markets and changing standards of care with its novel antisense technology.

*Olezarsen is an investigational drug that is not approved by the U.S. Food & Drug Administration or any other Regulatory Authority.

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³ Grundy SM, et al. 2018 Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082-143.
⁴ Laufs U, Parhofer KG, Ginsberg HN, et al. Clinical review on triglycerides. Eur Heart J. 2020;41(1):99-109c.
⁵ Wang, Y. Higher fasting triglyceride predicts higher risks of diabetes mortality in US adults. Lipids Health Dis. 2021:20(1):181.
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¹⁰ Pederson et. al., JAMA Intern Med. 2016;176(12):1834-1842. doi:10.1001/jamainternmed.2016.6875.
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¹³ Nawaz H., Koutroumpakis E., Easler J., et al. Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis. Official Journal of the American College of Gastroenterology. 2015;110(10):1497–1503.
¹⁴ Ann C. Skulas-Ray, et. al.,Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. 2019 American Heart Association, Inc. https://doi.org/10.1161/CIR.0000000000000709
¹⁵ Feingold KR. Triglyceride Lowering Drugs. [Updated 2021 Apr 1]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425699/
¹⁶ Tardif JC, Karwatowska-Prokopczuk E, et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022;43(14):1401-1412.
¹⁷ Moumné L, Marie A, Crouvezier N. Oligonucleotide Therapeutics: From Discovery and Development to Patentability. Pharmaceutics. 2022;14:260.
¹⁸ Crooke S. RNA-directed therapeutics at Ionis. Nature. October 16, 2019. Accessed July 28, 2022. https://www.nature.com/articles/d42473-019-00296-0
¹⁹ Ämmälä C, et al. Targeted delivery of antisense oligonucleotides to pancreatic b-cells. Sci Adv. 2018;4:eaat3386.
²⁰ Alexander VJ, et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J. 2019;40:2785–96
²¹ ClinicalTrials.gov. A Study of Olezarsen Administered Subcutaneously to Participants With Severe Hypertriglyceridemia. ClinicalTrials.gov identifier: NCT05552326. Updated September 26, 2022. Accessed September 30, 2022. https://clinicaltrials.gov/ct2/show/NCT05552326
²² ClinicalTrials.gov. A Study of Olezarsen (ISIS 678354) Administered to Participants With Severe Hypertriglyceridemia. ClinicalTrials.gov identifier: NCT05079919. Updated June 30, 2022. Accessed July 26, 2022. https://clinicaltrials.gov/ct2/show/NCT05079919