The CORE and CORE2 trials are now enrolling patients with sHTG
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 from 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 Over the last thirty years, epidemiologic and genetic evidence have supported the concept that elevated plasma levels of TG, TG-rich lipoproteins (TRLs) and TRL remnants are associated with an increased risk of ASCVD.4,5,6,7,8 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.7,8,9 However, it remains unclear as to which aspect of human TG biology is responsible for promoting the development of arterial wall lesions.6 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.5,12,13
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.
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. 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 [email protected] 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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14Ann 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
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16Tardif 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.
17Moumné L, Marie A, Crouvezier N. Oligonucleotide Therapeutics: From Discovery and Development to Patentability. Pharmaceutics. 2022;14:260.
18Crooke S. RNA-directed therapeutics at Ionis. Nature. October 16, 2019. Accessed July 28, 2022. https://www.nature.com/articles/d42473-019-00296-0.
19Ämmälä C, et al. Targeted delivery of antisense oligonucleotides to pancreatic b-cells. Sci Adv. 2018;4:eaat3386.
20Alexander VJ, et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J. 2019;40:2785–96.
21ClinicalTrials.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
22ClinicalTrials.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