Olezarsen reduces triglyceride levels in patients with hypertriglyceridemia at high CV risk

medwireNews: Olezarsen administered monthly for 6 months reduces triglyceride levels by around 57–60% in patients with moderate-to-severe hypertriglyceridemia who are at increased cardiovascular (CV) risk, shows the Bridge–TIMI 73a trial. The researchers highlight in The New England Journal of Medicine that currently available therapies “typically lower triglyceride levels by values ranging from less than 10% to approximately 30 to 40%.” For the phase 2b study, which took place at 24 US and Canadian sites, Brian Bergmark (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and colleagues enrolled 154 patients presenting with either moderate hypertriglyceridemia, defined as a triglyceride level of 150–499 mg/dL, plus an increased risk for atherosclerotic CV disease, or severe hypertriglyceridemia, defined as a triglyceride level of at least 500 mg/dL. The investigators randomly assigned the participants to receive monthly subcutaneous doses of 50 mg or 80 mg olezarsen, an antisense oligonucleotide that targets messenger RNA for apolipoprotein C-III (APOC3), or matched placebo for 12 months. The patients had a median age of 62 years, 58% were men, and 92% were White. The mean triglyceride level at baseline was 303.1 mg/dL and 90% of patients had moderate hypertriglyceridemia, with 97% receiving lipid-lowering therapy. “At 6 months, triglyceride levels were significantly reduced by both doses of olezarsen compared with placebo,” report the researchers. The 57 patients in the 80 mg olezarsen group had a mean decrease in triglyceride levels of 60.9%, from a mean 315.1 mg/dL at baseline to 102.4 mg/dL. This reduction was 53.1 percentage points greater than the mean 7.8% decrease for the 39 patients in the placebo group (302.1 mg/dL to 257.6 mg/dL). The 58 patients in the 50 mg olezarsen group had a mean decrease in triglyceride levels of 57.1%, from a mean 292.1 mg/dL at baseline to 115.4 mg/dL, corresponding to a significant absolute difference compared with placebo of 49.3 percentage points. The reductions in triglyceride levels associated with olezarsen treatment were “accompanied by significant reductions in apolipoprotein B and non-[high-density lipoprotein] cholesterol levels,” the investigators note. The reduction from baseline in these measures was a corresponding 18.5 percentage points and 23.1 percentage points greater with olezarsen 80 mg than with placebo, and 18.2 percentage points and 25.4 percentage points greater with olezarsen 50 mg. Olezarsen was also associated with significantly greater reductions from baseline in APOC3 levels, with differences at 6 months relative to placebo of 73.2 percentage points with olezarsen 80 mg and 64.2 percentage points with olezarsen 50 mg. However, olezarsen had no significant effect on low-density lipoprotein (LDL) cholesterol levels at either dose. Adverse event rates were similar across the three groups, at 67% in the olezarsen 80 mg group, 72% in the olezarsen 50 mg group, and 74% in the placebo group, and there were no serious adverse events related to olezarsen. None of the patients had a total bilirubin elevation of two or more times the upper limit of normal, and no pancreatitis events were reported in any group. A reduction in the platelet count to less than 100,000 per μL was noted in three patients in the olezarsen 80 mg group and in one patient in the placebo group, but the count did not drop to below 75,000 platelets per μL in either of the olezarsen treatment groups. Olezarsen was, however, “associated with a greater incidence of any elevation in aminotransferase levels,” observe Bergmark and team, but they point out that “clinically meaningful increases in liver aminotransferases were infrequent.” In a linked editorial, Gerald Watts (Royal Perth Hospital, Western Australia) notes that the reduction in triglyceride-rich lipoproteins with olezarsen “could translate into a reduction of major cardiovascular events by 20%,” but he cautions that a clinical trial to investigate this is warranted as Bergmark et al found no change in LDL levels. Watts believes that “current therapies for severely elevated levels of triglycerides are ineffective, with a continuing risk of life-threatening acute pancreatitis, a gap that will probably be closed by olezarsen.” The trial was also presented at the American College of Cardiology Scientific Sessions 2024 in Atlanta, Georgia, USA. medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group N Engl J Med 2024; doi:10.1056/NEJMoa2402309 N Engl J Med 2024; doi: 10.1056/NEJMe2402653 ACC 2024; Atlanta, Georgia, USA: 6–8 April

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