Professor Brian Bergmark.
Olezarsen substantially reduces triglyceride levels without significant adverse effects in patients with moderate to extreme hypertriglyceridemia, international studies suggest.
Findings presented at the American College of Cardiology’s Annual Scientific Session indicate that the investigational drug that blocks production of apolipoprotein C-III (apoC3) is a promising option for patients in the face of an unmet clinical need when it comes to triglyceride management.
“Based on our study’s results, we can say that the drug worked and appeared to be safe. We tested two doses of olezarsen, and both reduced triglyceride levels equally well,” said Professor Brian Bergmark, principal investigator of the BRIDGE-TIMI 73a study.
The phase 2b randomised control trial compared the triglyceride-lowering effects of two doses of olezarsen – a ligand-conjugated antisense oligonucleotide, targeting apolipoprotein C-III (apoC3) messenger RNA – in 154 patients (median age 62 years, 42% women) already receiving the standard-of-care treatment.
Participants were eligible for the trial if they had moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg/dL) and elevated cardiovascular risk or severe hypertriglyceridemia (triglyceride level, ≥500 mg/dL).
They were randomly assigned to receive olezarsen (50 mg or 80 mg) or placebo every four weeks for up to 49 weeks, and followed for one year of treatment.
The study ran across 24 sites in the US and Canada.
Findings published in the New England Journal of Medicine [link here] showed that the 50 mg dose of olezarsen reduced triglyceride levels by 49% and the 80 mg dose reduced triglyceride levels by 53%.
Patients who received the 50 mg dose had an average reduction of 64% in levels of apoC3, while those on the 80 mg dose had an average reduction of 73%.
Levels of apolipoprotein B (apoB) were reduced by about 18% on both doses.
All reductions in lipid levels were maintained for 12 months.
The researchers said clinically significant adverse effects such as abnormalities affecting the kidneys, liver or platelets were uncommon.
Speaking in Atlanta, Professor Bergmark noted that the difference between olezarsen doses was relatively small in terms of the triglyceride-lowering effect.
However, the 80 mg dose resulted in a larger reduction in apoC3 than the 50 mg dose. In addition, the reduction in levels of apoB was of interest since the protein was found on all lipid particles that contribute to cholesterol buildup.
“If you actually want to reduce a patient’s risk for a heart attack or stroke, you would like to see a reduction in apoB, and we did see that in this study, which is very encouraging,” said Professor Bergmark, from Thrombolysis in Myocardial Infarction Study Group at Brigham and Women’s Hospital and Harvard Medical School.
He said phase 3 studies of olezarsen, including in patients with severe hypertriglyceridemia, were underway to help address remaining questions.
Meanwhile, the Balance trial, published in the same journal [link here] and also presented at the meeting, involved 66 patients with genetically identified familial chylomicronaemia syndrome who were randomised to receive olezarsen at 80 mg or 50 mg or placebo every four weeks for 53 weeks.
At baseline, the mean triglyceride level among the patients was 2630 mg/dL, and 71% had a history of acute pancreatitis within the previous 10 years.
Results from the phase 3 double-blind trial, which ran at 29 sites across 11 countries, revealed that triglyceride levels at six months were significantly reduced with the 80-mg dose of olezarsen (−43.5%) but not with the 50-mg dose (−22.4%).
The difference in the mean percent change in the apolipoprotein C-III level from baseline to six months in the 80-mg group versus placebo group was −73.7%.
Between the 50-mg group versus the placebo group , the difference was −65.5%.
By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and one episode had occurred in each olezarsen group.
The researchers said the efficacy and safety results supported further testing of olezarsen to prevent the clinical sequelae of familial chylomicronaemia syndrome.
Writing in an accompanying editorial [link here], Australian cardiometabolic expert and clinician Professor Gerald Watts said an advantage of RNA therapeutics was that injectables were more potent and longer acting than oral agents.
This would likely help address issues with adherence to treatment.
“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, which has recently been granted fast-track designation by the Food and Drug Administration for the treatment of the familial chylomicronaemia syndrome,” Professor Watts said.
He added: “Although gene-silencing approaches are both attractive and promising, robust implementation will require demonstration of long-term effectiveness and safety, a favourable cost–benefit ratio, and unfettered access to therapy.”
The studies were funded by olezarsen manufacturer Ionis Pharmaceuticals.