Amarin Corp Plc (AMRN)

[MedResCollab]

Tastytheelf,

In EVOLVE, which had a similar lead-in stabilization period as ANCHOR, there was noted a 10% increase in median LDL-C in the olive oil placebo group. However, other atherogenic markers were reduced or did not significantly change in this group. Also, the least squares mean value recorded in the study (which reflects changes across the entire arm) showed an insignificant 3% increase in LDL-C in the placebo group. It seems then that the elevations in LDL-C primarily occurred in those placebo group subjects with baseline values near the median, and little change in the rest.

There could also have been some impact on LDL-C from the modest TG and VLDL-C lowering effect of olive oil (-10% and -11% median change, respectively) by mechanisms similar to those by which DHA can cause an increase in LDL-C along with a decrease in TG and VLDL-C—especially in those with very high triglycerides at baseline. An increase in LDL-C from a triglyceride-lowering therapy is much more likely to occur when the baseline TG levels of subjects are very high. In ANCHOR, the median baseline TG level was ~260 mg/dL, and in EVOLVE it was >700 mg/dL, and so an increase in LDL-C from a TG-lowering therapy would be more likely to occur in EVOLVE than in ANCHOR. The discrepancy in changes in median and mean TG values (-10% vs -4.3%, respectively) from baseline in the olive oil placebo group in EVOLVE also lends credence to the possibility that such a phenomenon affected those with values near the median more than the rest of the group. Thus, the comparison between EVOLVE and the ANCHOR/REDUCE-IT trials breaks down on multiple levels.

Importantly, most of the atherogenic/inflammatory markers in EVOLVE’s placebo group either decreased (such as TG and VLDL-C) or stayed the same. LDL-C was the exception. By contrast, the highly significant increase of all eleven atherogenic/inflammatory markers tested in ANCHOR, and confirmed in a separate study with patients of equivalent background therapy and characteristics (REDUCE-IT), is much more reminiscent of a treatment effect than a regression to the mean.