Amarin Corp Plc (AMRN)

[Pyrrhonian]

I think the positive results from the ACS study with 1.8g/d EPA in an all-Japanese cohort may be due to:

-probable confounding, at least to some degree, by the imbalance of prior stroke and Killip class III subjects (twice as many of each) in control vs EPA group (and maybe other imbalances not accounted for from this small sample).

-low dose statin (not SOC for non-Japanese with ACS) being given to all subjects, leaving residual benefit behind, that was possibly procured by 1.8 g/d EPA dosing (anti-inflammatory, additional plaque stability, etc.)

-timing of intervention within 24 hours of PCI, which is crucial to prevent MACE in these subjects. This could potentially be n-3 or any anti-thrombotic agent, if there is residual benefit not being met by high dose statins.

-the optimal dose of EPA (or EPA/DHA) may be 1.8g/d, and not 4g/d (which lowers HDL-C and serum vit E, and increases TBARS--none of which occurs at 2g/d)

-100% Japanese cohort, who are genetically superior at utilizing EPA and DHA, and who are already getting higher levels of DHA in their diet, which may counteract some of the negative effects of EPA-only dosing (such as decreased HDL).

The differences between the EPA study in ACS patients and R-IT are numerous and as follows:

-R-IT subjects are on optimal/high dose statins. Those with ACS are certainly on high dose statins (little or no residual benefit left to be had by EPA dosing)
-R-IT subjects are non-Japanese westerners
-R-IT subjects with ACS will not receive EPA therapy until well after they are clinically stable, missing an ideal window for anti-thrombotics:

In these studies patients were randomly assigned in most cases several days after hospital admission. During such a long period of time, the majority of patients were already clinically stable (clinical stabilization was also an inclusion criterion in some of the trials). In the context of the above-described pathogenesis of vulnerable plaque development and mechanisms of the pleiotropic effects of statins, it is obvious that there are relevant reasons to test administration of these drugs not only for secondary prevention, but also directly for the treatment of ACS when administered to patients who are particularly unstable.

-R-IT subjects do not have diets high in DHA, which may help counterbalance some of the negative effects of 4g/d EPA
-R-IT subjects are receiving 4g/d EPA, not 1.8g/d EPA. This may exceed an optimal dose threshold, and cause more harm than benefit, especially with regard to its negative impact on HDL-C, HDL2, oxLDL uptake by macrophages, TBARS, serum vit E, and fasting glucose levels, none of which occurs at lower doses.

Beyond this, it's clearly an outlier study. Even secondary prevention group in JELIS had just 13% RRR (non-significant) in CV death and was actually equal with control in sudden death.