Replies to post #167043 on Amarin Corp Plc (AMRN)

[jessellivermore]

bogatie....

Interesting observations....

I have gone over JELIS in great detail. I have not gone over R-I in great detail. The reason being I needed to know everything about JELIS to get a read on R-I...But R-I is so spectacular...once you get the general read the rest seems unimportant...but everything is important to some extent...

Anemia is a wastebasket diagnosis..which means low RBCs..The lower RBCs can be caused by low production (input) or high destruction (output)...And there are a whole number of diseases including cancers and deficiencies...Decreased vitamins excluding iron which is a problem in pre menopausal women (not many in this study) are not common causes...But even post menopausal women tend to have lower hematocrits than men..

I have very mixed feelings about the MO issue..It's such a pain in the ass..There is no way it could explain the RRRs seen in R-I..But we really don't know if it could have subtle effects...There is only one way to find out and that is to run trials..and no one wants to do that...

I will try to research this..but it will take some time....I don't think its related to vitamins...

":>) JL

[chas1232123]

bogatie - Amarin's primary problem right now is not really science but ignorance and FUD.

The mineral oil issue was never more than minor, and is really negligible. I am in the process of submitting an article to Seekingalpha (my first). It has a section that thoroughly addresses mineral oil since that is what critics have been harping on. I cut and paste it here:


The Mineral Oil Controversy

RI had a slight (7 mg/dl) increase in LDL-C in the placebo arm, which some suggested may have resulted from the mineral oil (MO) placebo hindering absorption of the statin, which, if true, might mean the RI results were slightly exaggerated. I agree with professor Bhatt and others that MO impact is clearly between zero and very minor. But, given the inordinate attention some gave it, apparently strongly suppressing the stock price and perhaps discouraging some people from starting life-saving treatment, we’ll examine the issue thoroughly. Those who already understand that very strong evidence from numerous sources overwhelmingly supports minimal MO impact and blockbuster Vascepa performance can skip to the next section.

Statins are absorbed in the small intestine, which is typically an inch in diameter and over 20 feet long. Even assuming they’re taken simultaneously with the statin (which is not known), it’s hard to believe two 1 gram capsules of MO would coat enough of the intestine thoroughly enough to significantly block statin absorption. (A gram is 1/28 of an ounce.) Extraordinary claims require extraordinary evidence, so the burden of proof is clearly on the MO critics.

RI’s modest LDL-C increase is consistent with normal natural variation, and smaller than increases routinely reported in many other studies and clinical trials, including the ODYSSEY trial[14]. (See Amarin’s extensive FAQ page on this topic, and its 54 scientific references[15]). RI recruited subjects with LDL-C under a threshold, some of whom probably had higher average LDL-C but got in during a temporary dip. Their LDL-C levels naturally returned to their average, which is called regression to the mean. It’s well-known, should be expected, and probably caused at least some of RI’s LDL-C increase.

JELIS was highly successful without MO. MO placebos were considered at length and approved by the FDA years ago for RI and numerous other trials. An independent Data Monitoring Committee (DMC) checked the un-blinded RI data for signs of MO impact quarterly throughout the 7 years of the trial. They reported no effect attributable to MO.

Professor Bhatt called MO a flawed line of inquiry, and pointed out that even if it were valid, the RRR impact would be no more than 2% to 4%. He also cited an RI subgroup analysis reported in NEJM showing similar risk for placebo subjects independent of whether their LDL-C rose or fell, which is very strong evidence the MO impact is near zero[2,13,15]. The subjects with increased LDL-C actually had slightly fewer events. That alone should settle the matter.

Vascepa’s benefit can be viewed as the difference between the two curves in Figure 1 (from the NEJM paper[2]), corresponding to events with placebo and with drug. For the first year or so, the two curves nearly coincide, reflecting a startup period before drug benefits fully kick in. MO could only slightly affect the upper curve, which rises only slightly above its initial slope (indicated by an added straight line), consistent with the expected effects of aging and random variation. The lower curve, with no mineral oil, bends down strongly after a year or two, as Vascepa overcomes the effect of aging and then some. Almost all the benefit is from the lower curve bending down (drug benefit) not from the upper curve bending up (affected by aging, random variation, and possibly placebo). If there were a serious MO problem, there should be more rise in the placebo curve and less decline in the drug curve.

Having trouble including figure so I'm including a link to it:

Figure 1 link



Figure 1 - RI primary end point event curves, with an added line at the initial placebo slope. (from NEJM November 2018 [2], except the added line)

Since Aristotle, educated people have understood that two things occurring together (such as rising LDL and ingestion of MO) is not proof that one of them caused the other. Anyone casually opining that a couple grams of MO caused significant harm should be asked for their evidence and asked to put their name on a clear claim. Scrutiny often reveals such remarks are hedged and/or made by someone with an axe to grind. From a November Jeffries analyst report[14], two key opinion leader (KOL) cardiologists “agreed that colleagues and respected KOLs who may appear bearish may have various agendas or biases that may impact their views.”

[sts66]

Is there baseline data for RBCs? Meaning did those on EPA show higher levels at the end, or did the MO group have lower levels at the end? Huge diff between the two outcomes, and one of them rules out MO as the problem.

[north40000]

bogatie, both theses in 1) and 2) deserve further investigation; perhaps the PIs in various R-I trial sites might help, if contacted. Thanks for the observations.