Amarin Corp Plc (AMRN)

[Pyrrhonian]

Ridiculous assertion. You are very wrong again.

1. They agreed to the MO placebo in the SPA - remember its THEIR CVOT study more so than Amarin's.

That’s true, but we know from ANCHOR SPA rescindment just how “binding” that is. When new data come to light it can and does change FDA’s opinion about things. Plus, when you say “FDA agreed to the MO placebo” you really mean (whether you know or not) that the reviewer(s) given charge over examining their SAP and in granting the SPA had no issue. The approval of drugs is far more arduous and involves many more FDA personnel and higher ups. Just because one less arduous process said “MO okay” doesn’t mean the much more arduous process will also say “MO did not inhibit statins to any meaningful degree.” In fact there are multiple examples of FDA taking issue with a trial design after allowing a study to commence. They have even put holds on trials due to problems with design even tho they allowed them to commence after one or more FDA reviewer had examined the design, lol. When saying “FDA” we’re not referring to one king or anything. Lots of moving parts/levels of review.

Btw, it was only in late 2013 after FDA really dissected and agonized over ANCHOR data that they made this statement:

The changes in lipid and lipoprotein parameters from baseline to Week 12 in the mineral oil placebo group are rather atypical for a trial that included a stabilization period for diet and lipid-lowering therapy, raising the possibility that mineral oil may not be as inert as assumed. If true, the treatment effects observed with Vascepa may be overestimated.

But at the time 6,000 subjects were already randomized into the study. So they decided to just charge the DMC with monitoring lipids. But DMC wasn’t likely to raise any flags unless they saw something incredibly obvious like > 40 mg/dL jumps in LDL-C. And too, just because the DMC didn’t recommend the study be halted for safety doesn’t mean FDA won’t take issue with data. Think of all the studies that the DSMB rec continue but that during review FDA said no bueno due to excess SAEs in treatment group.

2. The RRR margin is so significant, its practically moot.

It seems that MO may block 50%-70% of the absorption of statins. In which case the REDUCE-IT study becomes effectively a “moderate to high-dose statin therapy + 4g/d Vascepa vs low-dose statin therapy” study. Even if Vascepa is totally ineffective, a study like that would be expected to show a 10%-20% RRR for the group given higher intensity statins. You don’t necessarily need to see a 1 mmol/L LDL-C difference either. In a number of those studies the diff was closer to 0.6 mmol/L. And as I showed, patients with lower baseline LDL-C see less of a drop than those with higher baseline LDL-C, but hsCRP usually remains as dramatically impacted in CVD patients.

Actually the 11 point jump in LDL-C at peak in mineral oil group in R-IT was probably much higher in high-intensity statin subjects with higher baseline values. But even the 11 point spike could mean a 50% retrace for patients that saw their baseline LDL-C of 100 go down to 80 with moderate intensity statin and then back up to 90 due to statin inhibition. When you look at ALL of the values it tells a bigger story (and FDA will have the complete breakdown):

ANCHOR mineral oil group changes vs baseline:

TG: +5.9%
LDL-C: +8.8%
LDL-P: +11%
oxLDL: +11.6%
Non-HDL-C: +9.8%
VLDL-C: +15.0%
Apo B: +7.1%
hsCRP: +17.1%
LpPLA2: +6.7%
Tot. Chol.: +9.1%

REDUCE-IT mineral oil group changes vs baseline at next blood panel:

TG: +2.7% (note that subjects in R-IT had lower avg TG levels at baseline than those in ANCHOR)
LDL-C: +8.7% (very similar!)
LDL-P: ?
oxLDL: ?
Non-HDL-C: ?
VLDL-C: ?
Apo B: +7.8% (very similar!)
hsCRP: +32.3%
LpPLA2: ?
Tot. Chol.: ?

Also relevant is that when statins are given in high dose there is an initial drop in hsCRP in just a couple months, which grows and then stabilizes after 6 months. See that 17% jump in ANCHOR after 12 weeks? Then the 32% jump in R-IT after one year? Makes sense if in effect the mineral oil group subjects had their statin dose cut by 50%-70% due to malabsorption. You’d likely see a similar change and then stabilization over time.

Also note the various established recommendations now for hsCRP to be <2.0 mg/L. There is a great increase in risk of MACE in those with hsCRP near 3 vs under 2, regardless of LDL-C differences. FDA is well aware, and are perhaps going to be even more concerned about that. And look how consistent the value stays! Just like in JUPITER...

3. The FDA will hopefully see that you and others criticising placebo are merely doing it because you and your employer's business is threatened. Hopefully the FDA will ask some tough questions as they should, but will not allow conflicted people with biased agendas on the panel.

FDA will definitely ask tough questions, but they will be directed towards Amarin, the sponsor. And I personally think they will require a DDI study.

Maybe I’m wrong, but I think I’ve got a point here.

GL