Another HDL Therapy Crashes and Burns

–Failure of pre-beta HDL mimetic puts another nail in the HDL coffin

Once again, an HDL-inspired therapy has failed when put to the test in a clinical trial. Although there are still ongoing trials with other HDL-related therapies, most experts now feel that it is time for the field to turn its attention elsewhere and give up on HDL as a worthwhile model for new therapies and trials.

“This meeting has again reinforced the importance of the LDL hypothesis,” said Stephen Nicholls (University of Adelaide, Australia), the lead investigator of the phase II CARAT study, referring to the FOURIER trial presented the day before here at the American College of Cardiology meeting.

By contrast, he noted, “we do not have an HDL hypothesis, we do not have a consistent story.” Although epidemiology studies have consistently linked HDL to cardiovascular disease, agents that raise HDL or attempt to mimic its activity have been unable to achieve any sort of success in clinical trials.

CARAT studied CER-001, a pre-beta HDL mimetic, in 301 patients with acute coronary syndrome and a high plaque burden who were randomized to receive 10 infusions of the study drug or placebo. There was no significant difference in the primary endpoint, which was the percent atheroma volume as measured by intravascular ultrasound (IVUS). There were also no significant differences between the groups in other IVUS measurements or in other parameters of interest, including LDL, HDL, triglycerides, and high-sensitivity C-reactive protein.

In recent years, genetic studies, including Mendelian randomization studies, have led to a shift in emphasis away from a causal role for HDL and toward a causal role for triglycerides, although HDL remains a useful marker of risk. Nicholls said that he was very interested in seeing more trials targeting triglycerides, including those using fish oils and other new agents specifically designed to target triglyceride associated lipoproteins.