Replies to post #198917 on Amarin Corp Plc (AMRN)

[JJPow]

That which is brittle, breaks.
Hmmm....reminds me of another one- THAT WHICH IS BULLSHIT STINKS!

[CalMustang]

That would be an unintended, beneficial consequence of posting here, but not our purpose.

So you just admitted that you would stand to benefit by an increase in short interest and a decrease in stock value. Tell me again how this is possible if you don't have open positions in $AMRN securities or derivatives?

[ggwpq]

If you are wrong, you can always come back with a new handle like you did in previous occasions. If I had listened to your previous bad calls, I would have lost some real money.

[rafunrafun]

MRC -

Our goal is to create a historical record of our statements, and exhibit the expertise in regulatory science, medical sciences, and patent law that we as a company purport to possess

Perfect! Let's examine that historical record of YOUR statements by taking a brief look at some of your doozies:


1) YOU on September 16, 2018 (PPS was around $3, but $19 today):

Btw, you should be focused on the here and now. You may lose 60%-70% of your AMRN bet in one swoop. Then another 40%-50% from there if you stubbornly hold.

2) YOU on September 13, 2018:

You really don’t see the difference? They wholly believed they gave away no inside info in the PR, and wholly believe by terminating job posting they would give away inside info by that act. They deemed it important to issue the last PR, however, but why? They also intentionally avoided stating they were still blinded, whereas before they were eager to do so.

The most logical conclusion to the above imo is a) they are no longer blinded to topline data (PE and SEs especially), b) they felt it legally prudent to inform the public that presenting at AHA had nothing to do with revealing topline data to AHA, and c) because of a), it’s noteworthy they also failed to report the topline data as of yet (if it was positive, wouldn’t they just PR the topline and reveal granularity later at AHA?).

A+B+C= they have topline data and it is negative (the study failed) and they are currently dredging subgroup data to find something positive to report along with the negative (i.e. how did those with TG>250 do by group? Etc). And they told the public no data were shown to AHA so that they don’t get sued later for NOT saying that, once negative results are announced. It’s a prophylactic measure (defensive in nature).

Lots of studies have post hoc data analysis done. All major ones do. But of course it takes time. And if the statistician was told “search all combinations of patient characteristics and find a subgroup that showed benefit” it could take a while.

The other thing is there was an IA done before. The analysis should be even quicker this time.

I’m convinced. Maybe I’m wrong, but I’m convinced.

3) YOU on September 12, 2018:

Hey guys, I believe AMRN just tipped their hat unwittingly in the PR. I believe they have the results and they are negative.

My reasoning is:

-their abstract was accepted by a major conference and thus they felt they needed to comment on it as it is public info than may be construed as material if they did not comment on the AHA not knowing results

-at the same time they were careful not to say they were still blinded.

So it’s logical that they have data, and the study failed, because if data were positive there would be no need to wait to release that info (whereas currently they are dredging).

4) Here is my favorite one from YOU (2016)

Why REDUCE-IT Will Fail


So, in other words, it's about what you don't eat, not what you do. 1/2 a teaspoon of fish oil twice a day ain't gonna do diddly when your intake of saturated mammal fat and trans fat is 20 times that amount. Or 30 times. Or 40 times...

Break it down and look at it simply. There is no way this trial succeeds. Or the odds of it happening are fat too low to consider a long position profitable (even over 1,000 tries). I think most of the advocates here are just "stuck." Nothing compels a player to sit at a table more than the coveted goal of "breaking even." And how much better if they can even somehow manage to turn their losses into profits, and from the same source?! Suddenly they were never wrong!

Sometimes that happens. But in my experience, rarely..

The list keeps growing, and not for the long thesis, but rather the short thesis.

Let's review:



Why REDUCE-IT Will Fail:


1) This study showed 4g/d of pharma grade n-3 supp caused no difference between groups, and in fact corn oil group was trending better, despite nice improvements in lipid profile due to n-3 supp:

ajcn.nutrition.org/content/74/1/50.long

2) DHA has proven beneficial in a variety of ways that are significant to cardiac care, including:

-raises HDL-C (EPA probably does not, and very high doses of EPA without DHA may have an adverse effect on HDL-C)
-impedes oxLDL uptake to a greater degree than EPA
-helps lower TG and VLDL better than EPA alone (EPA 4g vs EPA 2g+DHA 2g)
-positively affects elevated blood pressure and heart rate (EPA does not)
-DHA (but not EPA) is a potent suppressor of SREBP-1, which is intimately tied to processes of atherosclerosis
-DHA increases the size of LDL particles, making them less atherogenic

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=124601316

And so ditching DHA just because LDL-C may raise somewhat is throwing away a host of beneficial effects.

3) More recent meta analyses show no effect of n-3 supplementation on MACE. This is probably in large part to do with statin and aspirin regimens becoming mainstream, as well as awareness of diet (increase fatty fish intake), circumventing any additional benefit from n-3 dosing to curb MACE, especially in patients with advanced CAD, due to similar MOA. It even led to a practice changer:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786657/

Patients will have been in R-IT 2 - 6 years, and most events will occur in under 1 - 2 years. High dose EPA will probably have very little impact on patients so far gone, who are already on high dose statins, low dose aspirin, and for many have made lifestyle changes including switching to Mediterranean style diet with high fatty fish intake. All higher risk patients are advised to do so.

4) There is probably a lack of a dose-response relationship with n-3 supp, as evidenced from the numerous studies that show a curbing of effect on MACE at about 2 - 3 fatty fish meals/wk.

http://content.onlinejacc.org/article.aspx?articleid=1136693

And high doses of supplemental n-3 dosing evidently cause some adverse proinflammatory responses. This may or may not counteract certain of the beneficial effects.

Quote:
During the study period differences in changes between the groups were found; tissue plasminogen activator antigen and soluble thrombomodulin decreased (P for difference between the groups 0.001 and 0.015, respectively), whereas soluble E-selectin and soluble vascular cell adhesion molecule-1 increased (P for difference between the groups <0.01 for both) in group II relative to group I. Our results indicate that n-3 FA supplementation decreases hemostatic markers of atherosclerosis, whereas markers of inflammation may be increased.


http://atvb.ahajournals.org/content/19/7/1681.full

Interestingly, although substituting sat fat intake with linoleic acid (LA) in its natural state (such as from various nuts) improves risk reduction (see point # 9 below), supplementation with concentrated LA, isolated from its food source and relative enzymes, had a negative impact:

Quote:
Although dietary LA lowers blood cholesterol levels, supplementation with concentrated sources of LA may have adverse cardiovascular effects in individuals with preexisting CHD (see Disease Treatment).


(scroll down: http://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids)

This is a fine example of how myopic we can be at times. Truly losing the forest for the trees. We see that LA helps, and so isolate it and toss aside all of the enzymes and other nutrients (both known and unknown) associated with it in its naturally derived form, and expect that dosing with it will help. But that is too naive: "LA from food = good, so lots of LA alone = lots of good." Whenever we manipulate a food source it is no longer the same. And the benefits we noted formerly may not follow (such as noting groups that consume a lot of fish have low CVD, and so dosing patients with lots of fish oil, or isolated EPA, should help--but that's a non-sequitur; it is simply not the same).

Also, serum levels of EPA do not necessarily infer cellular usage, and much of this is likely excreted unused. This may show up in abnormal liver function tests, and in the JELIS study there was higher prevalence of this in EPA group (1.8g/d).

5) JELIS showed a 19% RRR but only a 0.7% ARR, calling into question the relevance of such a finding. Especially because the only significant difference between groups was in unstable angina. And it was open label and subject to investigator bias (and especially when deciding who to hospitalize or not for unstable angina, knowing how it would show up in MACE stats?).

There was no difference between groups in patients with 2 or 4 risk factors. Literally none (numerical or otherwise). Among those with 4 risk factors (which supposedly compares with most in R-IT study), 29/1228 in EPA group had a MACE compared with 30/1205 in control group.

Other subgroup analyses were highly suspect and clearly immature (22 vs 10 events from a group of 957 patients).

6) There may be higher dropouts in placebo vs Vas group, and in particular those with type 2 diabetes, who are at the highest risk of MACE, due to TG count tells. Those with type 2 diabetes have their TG counts actively monitored. This would obviously adversely affect data for Vas group, worsening outcome, and improving outcome for placebo--simply by an imbalance of these arms after randomization.

7) Vegans have the lowest incidence of CVD or MACE and also have the lowest EPA levels of any group. Even corrected for BMI, the incidence of MACE is significantly lower in vegans. Their EPA/AA ratio is particularly "horrible." This shows that CVD and MACE risk may have very little at all to do with EPA and the EPA/AA ratio in particular, and much more to do with other factors. EPA/AA ratio is correlated, but not causative, in other words. Such as those with lung cancer very often smoke, and also often drink alcohol more excessively than norms, but although increased alcohol intake is correlated with lung cancer in this case, it is not causative at all (as other studies have proven). The same probably holds true for EPA/AA ratio. As often those with an improved ratio simply eat less bad fats, which are causative of CVD.

8) The Indian study actually showed no effect on MACE with EPA vs mustard oil (effectively placebo). We know very little ALA converts to EPA, and almost none of that converts to DHA. And "mustard oil" group had the highest past/present smokers by far and was about equal with EPA (1.2g) group. If m.oil is a placebo, and it basically is wrt MACE, then that study actually shows no effect from n-3 supp:

http://www.ncbi.nlm.nih.gov/pubmed/9310278

9) Adding 1/2 teaspoon of fish oil, twice a day, in with 20 or 30 or 40+ teaspoons of various saturated fats, trans fats and other oils, will have a diluting effect and, even though n-3s are "preferential," will affect how these fats are metabolized such that any beneficial impact is greatly diluted. One would need 4:1 ratio, or better yet, closer to 1:1 of n-3 to other fats to achieve significant risk reduction.

http://www.ncbi.nlm.nih.gov/pubmed/12442909

But as shown, not all omega 6 are bad, and in fact replacing saturated fat with linoleic acid reduced risk of MCE appreciably:

Quote:
A pooled analysis of 11 cohort studies, encompassing 344,696 individuals followed for 4 to 10 years, found that replacing 5% of energy from saturated fatty acids (SFAs) with PUFA was associated with a 13% lower risk of coronary events (95% CI: 0.77, 0.97) and a 26% lower risk of coronary deaths (95% CI: 0.61, 0.89) (66). A 2012 meta-analysis of seven RCTs corroborated this beneficial effect, with an estimated 10% reduction in CHD risk (RR: 0.90, 95% CI: 0.83-0.97) for each 5% energy increase in PUFA consumption (67).

In controlled feeding trials, replacing dietary SFA with PUFA consistently lowers serum total and LDL cholesterol concentrations (68, 69). In fact, LA has been shown to be the most potent fatty acid for lowering serum total and LDL cholesterol when substituted for dietary SFA (70). The mechanisms by which linoleic acid lowers blood cholesterol include (1) the upregulation of LDL receptor and redistribution of LDL-C from plasma to tissue, (2) increased bile acid production and cholesterol catabolism, and (3) decreased conversion of VLDL to LDL (71).


That's why Vegans have the lowest CVD and MCE risk of any group, even when corrected for BMI, smoking, etc. They simply avoid "bad fats," replacing them with good fats, and also consume high amounts of fiber, which also reduces various risk:

Quote:
Results: Every additional 10 g of recent dietary fiber intake per day reduced coronary heart disease mortality by 17% (95% CI: 2%, 30%) and all-cause mortality by 9% (0%, 18%). The strength of the association between long-term dietary fiber intake and all-cause mortality decreased from age 50 y (hazard ratio: 0.71; 95% CI: 0.55, 0.93) until age 80 y (0.99; 0.87, 1.12).


http://ajcn.nutrition.org/content/88/4/1119.full

What does any of that have to do with EPA? Nothing. Vegans have the lowest risk of cancer or heart disease and also have the worse EPA serum levels and EPA/AA ratio of any group on the planet.

And so adding a tiny amount of fish oil, which represents 1/20th to 1/40th of the subjects' total dietary fat intake, including high amounts of saturated mammal fat and trans fats, will do nothing to thwart CVD or MCE appreciably. EPA is a *food*. Pure, non-concentrated, unaltered *food*. A mere 4g will be diluted out of the equation in these subjects, many of whom will regularly consume 120g/d or more of unhealthy fats.

What matters far more is what one *doesn't* eat than what one does. Replacing bad fats with good will benefit. Maintaining bad fat intake (especially with high sugar and refined carb intake) and then adding 1/2 teaspoon of fish oil twice a day and expect that to reduce MCE is ridiculous, and ignores a vast wealth of data on MCE risk and CVD.

AMRN: the easiest short in the market today ;)

PPS was what when you wrote that...$2?

What a historical record!

[hayward]

MedResCollab

I call Bullshi** If not for financial gain why don't you give away all your research for free and identify yourself ?

Michael