Amarin Corp Plc (AMRN)

[MedResCollab]

Hi bogatie,

A great question. If you examine the effects of different doses of statins you’ll notice that between nothing at all and low dose—let’s use atorvastatin 10 mg as example—a marked reduction in LDL-C occurs. About 35% in our example. From there, the net reduction is greatly depreciated with every doubling of dose. The one study we cite shows about an approximate 5% further absolute reduction in LDL-C for every doubling of statin dose. So, 20 mg atorvastatin will cause about a 40% overall reduction from baseline, 40mg will result in about 45%, and 80 mg will result in about 50%. Thus a 15% further absolute reduction in LDL-C results from 8-fold the dose. Do you see the problem with the observed 10%-11% retrace from baseline at years one and two in particular in mineral oil placebo group? What might that signify? A multi-fold reduction in the absorption of statin dose.

Notice that in the TNT study both groups began on 10 mg atorvastatin. Then, one group was given 80 mg and experienced a further 14% absolute reduction in LDL-C. That was from 8-fold the dose. However, the RRR of the 80 mg group vs 10 mg dose group by end of study was 22%.

We highlight the fact that LDL-C began returning during the last years of the study as further evidence—not conclusive, but evidence—that statins were being attenuated, and with dropouts being common late in the study such a phenomenon would be expected. For instance as in ODYSSEY, etc.

Regards,
-MRC