These are lipoprotein particles that comprise about 90% triglycerides. Patients with the condition often develop severe acute pancreatitis and suffer from a range of chronic health issues, including severe and recurrent abdominal pain and fatigue.
Those with the disease rarely respond to standard therapies to lower triglyceride levels and the only way to manage it involves a complex and extremely restrictive diet. Ionis has been investigating an antisense oligonucleotide-targeting messenger RNA product that might help.
Olezarsen is designed to reduce the amount of apolipoprotein C-3 (APOC3) the body produces. This protein is made in the liver and regulates the metabolism of triglycerides in the blood.
A Phase III trial has been done with 66 patients with FCS.1 Subjects were given 50 or 80 mg of the drug or a placebo in subcutaneous doses every 4 weeks for 49 weeks.
After 6 months, triglyceride levels had reduced significantly in those given the higher dose (43.5%) but not with the lower dose (22.4%). APOC3 levels were down in both groups. After 53 weeks, there had been 11 cases of acute pancreatitis in the placebo group and just one in each group given olezarsen.
It is also being investigated as a potential treatment for severe hypertriglyceridaemia. In a randomised, double-blind, placebo-controlled dose-ranging trial, 114 patients with moderate hypertriglyceridaemia and elevated cardiac risk were given 10 or 50 mg of the drug every 4 weeks, 15 mg every 2 weeks, 10 mg every week or a placebo as subcutaneous doses for 6–12 months.2
The 10 mg monthly dose gave a mean percentage triglyceride reduction of 23% after 6 months, 56% with 15 mg every 2 weeks, 60% with 10 mg every week and 50 mg every month, and an increase of 6% across the placebo groups.
Significant decreases in APOC3, VLDL cholesterol, non-HDL cholesterol and apolipoprotein B were also seen.
In a randomised controlled Phase IIb trial, 154 adults with either severe or moderate hypertriglyceridaemia plus elevated cardiac risk were given either 50 or 80 mg of the drug or a placebo in monthly subcutaneous doses for 6 months.3
The lower dose gave a 49.3 point reduction in triglyceride levels, whereas the reduction with the higher dose was 53.1 points. Each dose also gave significantly better reductions than the placebo in levels of APOC3, apolipoprotein B and non-HDL cholesterol, with no significant change in LDL cholesterol.
Adverse event profiles were similar across all groups.
References
- E.S.G. Stroes, et al., N. Engl. J. Med. 390, 1781 (2024).
- J-C. Tardif, et al., Eur. Heart J. 43, 1401 (2022).
- B.A. Bergmark, et al., N. Engl. J. Med. 390, 1770 (2024).
