Monthly olezarsen reduced triglyceride levels by 50%
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Key takeaways:
- Investigational therapy inhibits production of apolipoprotein C-III, which plays a key role in triglyceride levels.
- Results showed substantial triglyceride reductions with no major safety concerns.
ATLANTA — Monthly administration of subcutaneous olezarsen substantially reduced triglyceride levels compared with placebo among patients with predominantly moderate hypertriglyceridemia and elevated CV risk, according to new phase 2 data.
“The triglyceride effect was greater than is possible with currently available treatments,” Brian A. Bergmark, MD, with the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital and Harvard Medical School, said during a late-breaking clinical trial presentation at the American College of Cardiology Scientific Session.
The investigational therapy also had effects on lipid measures beyond triglycerides, with meaningful reductions in apolipoprotein B and non-HDL cholesterol, according to Bergmark.
Moreover, no major safety concerns were identified, Bergmark said.
Olezarsen (Ionis Pharmaceuticals) is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III, which is a genetically validated target for triglyceride lowering, according to Bergmark.
“Reducing triglyceride-rich lipoproteins remains an unmet clinical need. Elevated triglyceride-rich lipoproteins are associated with increased cardiovascular risk,” Bergmark said.
The phase 2 Bridge-TIMI 73a trial enrolled 154 adults with moderate hypertriglyceridemia (150-499 mg/dL; 90% of population) and elevated CV risk or with severe hypertriglyceridemia ( 500 mg/dL). Patients were randomly assigned in a 1:1 ratio to olezarsen 50 mg or 80 mg or placebo; within each cohort, patients were randomly assigned to olezarsen every 4 weeks or matching placebo for up to 49 weeks and followed for 1 year. Nearly all patients were on lipid-lowering therapy at the time of randomization and one-third were receiving two or more lipid-lowering therapies.
The median age of participants was 62 years, 42% were women, 92% were white and 68% also had diabetes.
Results were simultaneously published in The New England Journal of Medicine.
The median triglyceride level at baseline was 242 mg/dL. The primary endpoint was percent change in triglyceride levels at 6 months.
“Both doses of olezarsen led to rapid and sustained reductions in triglyceride levels,” Bergmark said.
At 6 months, olezarsen 50 mg reduced triglyceride levels by 49.3% and olezarsen 80 mg reduced levels by 53.1% compared with placebo (P < .001 for both comparisons).
The finding was consistent across key subgroups including age, sex, triglyceride level and diabetes status, Bergmark said.
Among 128 patients with moderate hypertriglyceridemia at baseline, 86% of the 50 mg group and 93% of the 80 mg group achieved triglycerides below 150 mg/dL at 6 months compared with 12% of the placebo group (P < .001 for comparison of olezarsen doses vs placebo). The effect on triglycerides occurred as early as 1 month after treatment initiation and persisted through 1 year, Bergmark said.
“With respect to differences between the two olezarsen doses, although the effects on triglyceride levels were similar at 6 months, the results support a larger reduction with the 80 mg dose at 12 months. Further trials will inform to what extend the higher dose provides additional safety for triglyceride lowering and other lipid measures, especially in patients with severe hypertriglyceridemia,” the researchers wrote in NEJM.
Both doses of olezarsen significantly reduced levels of ApoC-III, the target of this therapy, as well as VLDL, remnant cholesterol, ApoB and non-HDL cholesterol. Treatment also increased HDL cholesterol and apolipoprotein A1. Reductions in lipid levels were maintained for 1 year, according to the researchers. The researchers reported no significant change in LDL cholesterol.
The proportion of patients with adverse events was similar across treatment groups. Serious adverse events were reported in 8% of patients, but none were deemed related to treatment. There was no significant change in HbA1c with either dose of olezarsen compared with placebo. Olezarsen was associated with a higher incidence of any elevation in aminotransferase levels, but clinically meaningful increases in liver aminotransferases were not frequent and were not different among the treatment groups. No major elevations in bilirubin or incidences of severe thrombocytopenia were reported, according to the findings.
“It is important to interpret these results in the context of a changing landscape for metabolic disease management. Antisense oligonucleotide, small interfering RNA and monoclonal antibody agents targeting the same or related pathways, such as angiopoietin-like protein 3, have been or are in development. It will be critical to understand how agent- and class-level efficacy and safety compare with that of olezarsen while also considering additional features, such as frequency of administration,” the researchers wrote in NEJM.
Bergmark noted several limitations of the study, including its small size, limited follow-up and inclusion of few patients with severe hypertriglyceridemia.
“It’s an exciting time to think about therapeutics for a group of patients that don’t have great options for them and still have very high residual atherosclerotic CVD risk on therapy,” Daniel Soffer, MD, clinical associate professor of medicine in the division of general internal medicine and translational medicine at the Perelman School of Medicine of the University of Pennsylvania, said during a discussion following the trial.
Phase 3 studies are underway, including in patients with severe hypertriglyceridemia.
Reference:
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Bergmark B, et al. Late-breaking clinical trials II. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.
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