AMR101’s Effect on Lipoprotein Concentration and Size

Orlando—A follow-up analysis of a phase 3 trial found that patients with very high triglyceride levels who took 4 g/day of AMR101 had a significant reduction in the lipoprotein concentrations of the large very-low-density lipoprotein (VLDL), total low-density lipoprotein (LDL), small LDL, and total high-density lipoprotein (HDL) particles. The authors also concluded that AMR101 significantly reduced the VLDL particle size but did not change the LDL particle size. Harold E. Bays, MD, the study’s lead author and the medical director and president of Louisville Metabolic and Atherosclerosis Research Center Inc, Louisville, Kentucky, presented the results in an oral abstract session at the AHA meeting. AMR101 is an omega-3 agent being investigated to treat patients with high or very high triglycerides. The MARINE (Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study with an Open-Label Extension) study included 229 patients from the United States, South Africa, India, Ukraine, Finland, Germany, Italy, and the Netherlands. Results of the trial presented previously found that AMR101 significantly reduced triglyceride levels, but the drug did not increase the amount of cholesterol in LDL. “We found that to be very interesting,” Dr. Bays said. In this analysis, Dr. Bays said the authors wanted to determine the effects of AMR101 on lipoprotein particle concentration and size. Patients were included if they were >18 years of age and had a triglyceride level between 500 and 2000 mg/dL with or without background statin therapy. The 25% of patients who had statin therapy were required to continue taking the same dosage throughout the study. The trial began with a 4- to 6-week lead-in period and a 2- to 3-week qualifying period before patients entered a 12-week double-blind period, in which they were assigned to take 4 g/day of AMR101 (n=77), 2 g/day of AMR101 (n=76), or placebo (n=76) for 12 weeks. After the 12 weeks, there was a 40-week open-label extension in which patients took 4 g/day of AMR101. At baseline, the patient characteristics were similar in the 3 groups. The mean baseline triglyceride level was 680 mg/dL and the mean LDL cholesterol level was 86 mg/dL. In addition, 39% of patients had triglyceride levels >750 mg/dL. The particle concentration and size were measured by nuclear magnetic resonance spectroscopy. The authors defined a large VLDL particle as >60 nm, a medium VLDL particle as 42 to 60 nm, and a small VLDL particle as between 29 and 42 nm. They defined a large HDL particle as 9.4 to 14.0 nm, a medium HDL particle as 8.2 to 9.4 nm, and a small HDL particle as 7.3 to 8.2 nm. A large LDL particle was defined as 20.5 to 23.0 nm, and a small LDL particle as 18.0 to 20.5 nm. Patients who took 4 g/day had a significant median change in placebo-adjusted concentrations of large VLDL (−27.9%; P=.0211), medium VLDL (+28.0%; P=.0238), total LDL (−16.3%; P=.0006), small LDL (−25.6%; P<.0001), and total HDL (−7.4%; P=.0063). The 4-g/day dosage of AMR101 also decreased the placebo-adjusted VLDL particle size by 8.6% (P=.0017). There was a 0.5% increase in the LDL particle size and a 1.1% increase in the HDL particle size, but those differences were negligible and not statistically significant. Dr. Bays said that the baseline lipoprotein particle size could help assess the risk of coronary heart disease, although changes in particle size after patients receive treatment have not been proven to lead to better cardiovascular disease outcomes. “Particle size may be important for assessing risk, but I know of no data that suggest that the post-treatment particle size is correlated with improved outcomes,” Dr. Bays said. “I think that’s a really critical point that we have to realize.”