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Cashed out
I've had Amarin shares since July 2013. At one point I had 50,000 shares. Last Friday I had 23K shares but in last two sessions I sold them all between 14.60 and 15.05.
Good luck to those of you that hang around, but I no longer trust management. The company has clearly been communicating a fair amount of data to the FDA (look at JT's comments in his opening on 31 July) and they floated the offering of the additional 460 million worth of shares knowing they had FOIA'd five different sets of communications with FDA. That was material information that an investor should have known about.
At this point, Amarin is not an investment, but more like putting all your chips on one color at the casino. The FDA could set up a breifing book for the ADCOM that will cause Amarin to have to run additional tests or a study of mineral oil - delaying label expansion until late 2020 or even 2021. By such time AstraZeneca has its results.
Good luck, it sure was al lot sweeter just a month ago, but sometimes you just have to cut bait....
If this was already posted, then forgive the duplication (but this is really wonderful amplifying evidence for REDUCE-IT submission):
Omega-3 PUFAs and Reduced Risk for Heart Failure
Jul 30, 2019
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Authors: Block RC, Liu L, Herrington DM, et al. Citation:Predicting Risk for Incident Heart Failure With Omega-3 Fatty Acids: From MESA. JACC Heart Fail 2019;7:651-661. Summary By:Ragavendra R. Baliga, MBBS, FACC
Study Questions:
Is the plasma eicosapentaenoic acid (EPA) abundance (%EPA) associated with reduced hazard for primary heart failure (HF) events? Specifically, the authors tested the following hypotheses: 1) Is plasma %EPA inversely associated with all HF incidences, 2) is high plasma %EPA inversely associated with incidence of HF with preserved ejection fraction (HFpEF), and 3) is the inverse association of high plasma %EPA with HF incidence unique among omega-3 polyunsaturated fatty acids (PUFAs)?
Methods:
In the MESA (Multi-Ethnic Study of Atherosclerosis) cohort, the study authors tested if plasma phospholipid EPA predicts primary HF incidence, including HF with reduced EF (HFrEF) (EF <45%) and HFpEF (EF ≥45%) using Cox proportional hazards modeling. They tested for associations of EPA with HF risk using a four-step approach: 1) testing a univariate association; 2) adjusting for age, gender, race, and study center; 3) adjusting for other lead fatty acids; and 4) adjusting for other known risk factors.
Results:
A total of 6,562 participants (of the 6,814 total MESA participants) 45-84 years of age had EPA measured at baseline (1,794 black, 794 Chinese, 1,442 Hispanic, and 2,532 white; 52% women). Over a median follow-up period of 13.0 years, 292 HF events occurred: 128 HFrEF, 110 HFpEF, and 54 with unknown EF status. Median %EPA was 0.70% for all MESA participants. %EPA in HF-free participants was 0.76% (0.75-0.77%), but was lower in participants with HF at 0.69% (0.64-0.74%) (p = 0.005). Log %EPA was associated with lower HF incidence (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.60-0.91 per log-unit difference in %EPA; p = 0.004). Adjusting for age, gender, race, body mass index, smoking, diabetes mellitus, blood pressure, lipids and lipid-lowering drugs, albuminuria, and the lead fatty acid for each cluster did not change this relationship. The final adjusted HR for docosahexaenoic acid (DHA) abundance (%DHA) was 0.51 (95% CI, 0.38-0.70; p < 0.0001); for proportion omega-3 DPA, it was 0.59 (95% CI, 0.37-0.95; p = 0.03); and for %EPA plus %DHA, it was 0.54 (95% CI, 0.39-0.73). Sensitivity analyses showed no dependence on HF type.
Conclusions:
The study authors concluded that higher plasma EPA was significantly associated with reduced risk for HF, with both reduced and preserved EF.
Perspective:
The important findings of this study raise questions such as, 1) “Is the reduced risk of HF mainly in ischemic cardiomyopathy patients?” 2) “What is the mechanism for the reduced risk of HF?” because it is well known that low-density lipoprotein cholesterol levels increase in patients treated with the triglyceride-lowering omega-3 fatty acids, and as authors point out, 3) “Is there a threshold level for the protective effect of EPA?” Prospective, randomized studies are needed to confirm the important findings of this study.
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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Acute Heart Failure
Keywords: Cardiomyopathies, Cholesterol, LDL, Docosahexaenoic Acids, Dyslipidemias, Eicosapentaenoic Acid, Fatty Acids, Fatty Acids, Omega-3, Fatty Acids, Unsaturated, Geriatrics, Heart Failure, Metabolic Syndrome X, Primary Prevention, Risk Factors, Stroke Volume, Triglycerides
ICER Page 40
To allay fears posted here in last 30 minutes, here is the ICER summary on mineral oil (Page 40):
Although we are uncertain whether the use of mineral oil may have caused some harm to the placebo group, we do not believe that this theory can account for the entire benefit observed in the REDUCE-IT trial. We believe that the results of REDUCE-IT likely apply across a range of baseline triglyceride levels, but are uncertain whether the results generalize to patients not treated with statins. For adults with established CVD or at high risk of cardiovascular events who are being treated with statins, we have high certainty that icosapent ethyl provides a small-to-substantial net health benefit (“B+”).
Again Thanks, but not end of story.
This is Amarin's response to the original proposal - please note it is dated 5 April, 2019. The model with the actual numbers was written and published later (June 6, 2019) than this letter from Amarin. Amarin's response letter is about the general methodology, but it is not informed by the actual modeling data ICER decided to use.
Rather than belabor this point, I am just going to bring the issue up to Amarin's IR department. They should be the ones to get with ICER if the modeling data is incorrect.
Best regards
LINK to ICER
https://icer-review.org/material/cvd-modeling-analysis-plan/
Click on the link on this page and you'll get the Modeling Plan for their analysis of Vascepa.
The data I've cited are:
NEJM (where the discontinuation rate for Vascepa arm was 9.9%)
Amercian Cardiology article where the adherence rate for Vasepa at first CV event is stated as 18.7%
Love to hear from anyone who really knows the terminology of the trials as "adherence" and "discontinuation". I am very concerned that ICER is going to run the numbers on a drop-out assumption rate of 18.7% not 9/9% and therefore their data is going to assume far more cost to benefit (i.e. assuming to high a rate of people who start Vasepa in their model will discontinue use before the benefit of first event prevention.)
Really want to hear some educated thoughts on this as I intend to engage with ICER soon as their draft date is 24 July, but I also don't want to engage on the issue if I am totally wrong....
Thanks
JL - would love to read your thoughts on post 202768, given your medical expertise. Basic question - has the ICER model erroneously taken "adherence" data and made it their model for "discontinuation?" (I am concerned because any economic analysis that has a drop-out rate at twice reality, is going to skew data against the cost-effectiveness of Vascepa.) If they have incorrectly modeled the discontinuation rate, I plan to contact ICER as I don't want a negative reprot out there. (I ave 23,000 shares from 2013 so I am very "invested" both time and money, in the truth of Vascepa being presented)
Thanks
rafunrafun ICER - doubts.
Thanks for the reply. But I still have my doubts,
From the Journal of American Cardiology:
“We explored study drug adherence in patients with recurrent events. At the time of a first primary endpoint event (fatal or nonfatal), 81.3% (573/705) of icosapent ethyl and 81.8% (737/901) of placebo patients with a first primary endpoint event were receiving randomized study drug. At the time of subsequent primary endpoint events (fatal or nonfatal), 79.7% (188/236) and 79.5% (299/376) of patients with a second event, 68.1% (49/72) and 74.1% (106/143) of patients with a third event, and 68.0% (17/25) and 71.6% (48/67) of patients with a fourth event were receiving randomized study drug in the icosapent ethyl and placebo groups, respectively. Therefore, the majority of the first, second, third, and fourth events occurred while patients were on randomized study treatment. Numerical differences in study drug adherence among patients with recurrent events were not statistically significant between treatment groups.”
ICER seems to mistakenly conflate adherence and disconituation: “For icosapent ethyl, after an average follow-up of approximately two years, 18.7% of patients in the icosapent ethyl arm had discontinued treatment at the time of a first event." From the ICER Model paper.
From NEJM REDUCE-IT article (2018) "Early discontinuation from study (9.9% icosapent ethyl; 11.2% placebo) includes patients that discontinued after having a primary event (25 [0.6%] icosapent ethyl; 52 [1.3%] placebo) and prior to having an event (380 [9.3%] icosapent ethyl; 408 [10.0%] placebo)."
So I still have my original question. Study Drug adherence is not the same a discontinuation. ICER model is based on 18.7% of Vasecepa users totally discontinuing use. I think that number is inflated as during REDUCE-IT, the discontinuation rate was 9.9%.
Not taking one’s drug precisely as prescribed (adherence) is not the same as totally discontinuing its usage.
Thoughts? Again, I think the ICER model is going to give too negative an answer with this “discontinuation” rate of 18.7% built in: I think it should be 9.9%.
ICER model have it wrong???
A serious question for anyone who has read the ICER modeling paper.
THE ICER modeling paper states the following:
“For icosapent ethyl, after an average follow-up of approximately two years, 18.7% of patients in the icosapent ethyl arm had discontinued treatment at the time of a first event.
While ICER footnotes this 18.7% discontinuation to NEJM article, when reading through the NEJM article and the appendix, I found only the following:
"Early discontinuation from study (9.9% icosapent ethyl; 11.2% placebo) includes patients that discontinued after having a primary event (25 [0.6%] icosapent ethyl; 52 [1.3%] placebo) and prior to having an event (380 [9.3%] icosapent ethyl; 408 [10.0%] placebo)."
So my question is does ICER have it right at a 18.7% discontinuation rate or is it 9.9%? If it is 9.9% (which I think is correct, then the ICER model will be virtually worthless if not corrected as it has the discontinuation rate twice as high as reality.
Thoughts?
I understand that they have not heard anything about delay or an ADCOM. That does not mean that additional data since 28 March has been requested by or provided to the FDA. If Amarin failed to disclose that the FDA has requested additional data, especially in light of the public offering, I would say that information could destroy the company. Not disclosing that the FDA had asked for additional info in the prospectus would make the entire placement of the 22 million shares a sham, especially if an expanded label were denied.
For this reason, I hope that they have had no info requests (i.e. more data) from the FDA. Don't conflate that with delay or ADCOM info - they are not the same.
I remain optimistic that such data has not been requested. If it was, then Amarin's wording in the prospectus was written by the worst lawyers ever and I think their legal team is pretty darn sharp.
This all comes down to one question: does FDA make CaPre run a CV trial? Does biometric data replace an outcomes trial? Amarin is making it very clear that this is EPA as the mechanism and not trig lowering. Better hope future FDA thought is the same - i.e. if they change their position they could open the door to other EPA / DHA mixtures. EPANOVA's trial will be the key. If that has similar results to Vascepa, then FDA might say that trig reducing is part. If their results are worse, then FDA would likely attribute success to EPA and failure to the DHA muddying the active ingredient. If EPANOVA is not at 25% RRR, it would be totally hypocritical of the FDA to start giving any Omega 3 a CV label based on anything other than an outcomes trial.
I have to throw down the flag on some of these thoughts. The FDA does not care one bit about Amarin's business plan, can they ramp-up, etc. Their concern is one dimensional : from a regulatory standpoint do we grant an expanded label and what is that label. That is based 100% on the scientific data to efficacy, safety, and reliability / repeatability of the REDUCE-IT trial. The FDA does not care one whit about how Amarin executes their business plan.
Frankly, this is not riding on subtle things like body language! What Amarin knows (and we don't) are the two key questions - did they submit additional data since 28 March 2019 submission or did FDA ask for more information since 28 March? If it has been silent, then I'd say 99% no ADCOM and broad approval. If there has been additional data transferred, then FDA would have grounds to alter their deicison and or timeline. Let's hope that FDA has not asked for more data. I think that is the case for one reason: if the FDA asked for follow-up since 28 March, Amarin should have disclosed that in the prospectus dated 16 July. Failure to disclose that very materially relevant information would set them up for some damn big shareholder lawsuits, basically from anyone who purchased shares at a date after the FDA's request for more data. That would mean all the big money behind this offering would be lining up to sue the pants off Amarin.
I don not like IR's answer that they don't discuss communication with the FDA. In this case, they better not be hiding anything. I think they aren't because from what I've seen their legal team has done a very good job over the last 3-4 years.
MNBioMike - do you really think a sales rep gets 250K a year? I think you are off by a factor of four to five fold. I would say even simpler math
400 sales reps x 60K/year = $24 million for the whole year.
I think much more of this 383 million (that's what they'll have left after the underwriters get their 4 plus percent fee) is going to be spent on advertising, buying inventory, and perhaps even a supplier, than on the added sales force.
I have a couple of relatives for big pharmas who are sales reps and they don't make anywhere near what you are suggesting. Especially entry level, which is what many of these will be.
I think there are two good reasons to be salty (and if you check my history, you'll see I am a long for the last 6 years, although I rarely post.)
My biggest gripe is the discount to market. The prospectus date last trade was 21.74. 18 per share is a huge discount to that. Had it been 19.5 to 20 I would have been less aggrieved. The discount for the underwriters risk was far too great. 10% might have been a little more palatable.
Next is the timing. Perhaps GS and JP Morgan said "do it now" before FDA announcement as we aren't interested when the market price is higher and reflects less risk - which means their clients potentially don't profit as much. But, had Amarin waited to see, perhaps 30 share price post FDA approval, they could have commanded a better price and floated less shares.
My thinking is that Amarin wanted GS and JP Morgan now. If there were to be a buyout or need for more financing, these two firms are now in Amarin's corner.
It just sucks to be on the sideline while bankers / brokers get to make far more and take far less risk.
Last thought is that Amarin must have sold GS and JP Morgan a pretty good story about communication with FDA. If this doesn't not get label expansion, those two firms will have really shafted some big clients.
Question for MRC
I read your Citizens Petitions. I have a question regarding pages 7-8 of your first Petition. You state that given the percentages of Placebo Arm patients (mineral oil) on low, medium, and high dose statins, the pre-statin controlled LDL-C (Hopkins) would have been 146 mg/dl. (This is the number I came up with as well.)
Here is the question: since starting Hopkins LDL-C for placebo arm was 86.7 at baseline, if mineral oil blocked most of the effect of the statin, why did the median not go back to 146? (The highest it ever got was 96.1)
The worst year for placebo LDL-C Hopkins was year 2 at 96.1. 96.1 is not 146. The bio marker LDL-C indicates that actually the statin dosages were still very effective since below 100 LDL-C is "optimal."
Not a question, but more of a note, you choose 96.1 mg/Dl at year two as the "correct" placebo LDL-C number and disregard that by years 4-5 placebo LDL-C was at 91.6 and 92.1 respectively. You state that this occurred by year 4-5 because patients were dropping out and stopped taking their mineral oil. The fact is, you have absolutely no evidence to make such an assertion. You cherry-picked the worst year (96.1) and then have an unsubstantiated reason for why placebo LDL-C is lower in years 4-5.
At other points you make similar unsubstantiated assertions - such as what time of day people would have taken their medications. In reality, you have no proof as to whether patients in REDUCE-IT took their medications with meals, at bedtime, etc. If they followed instructions, most would have taken the placebo at meals and their statin at bedtime. We have no evidence (your footnote notwithstanding) that most did not follow the prescribed regimen. You assume that to imply that most of the patients were taking their mineral oil and statin simultaneously.
There are lots of other big errors in your work, but the seminal one is the question I ask - why did LDL-C not go back to 146 from its start of 86.1? Please give a logical answer.
JL - thanks for the compliment (especially coming from someone with your scientific background). I passed it to investor relations and perhaps not surprisingly, they were aware of the post and it contents. Despite what some might say -we "retail" investors can influence things. Amarin clearly pays attention to the ideas passed around here. Hopefully, they have already been sorting the data on water and fat soluble statins. Also hope they have been getting as much data as possible on mineral oil that was discovered after WWII. Every little dotted i and crossed t could help with the FDA. After the 2013 ADCOM, I would not doubt in the least that there will be someone on a panel (like Hiatt) trying to cast doubt on every last aspect of REDUCE-IT. If you recall W. Hiatt even started discussing how he didn't think the REDUCE-IT primary end-point wasn't correct. He started laying the work for sabotaging REDUCE-IT back in 2013. I guess the good doctor was unaware that angina is usually included in all these CV trials. I remain very cautious - how the FDA let someone who had received payments from AstraZeneca, who had bought Omthera two months prior, sit on that panel shows the lack of due diligence one can come to expect from bureaucrats.
Two new thoughts on Mineral Oil:
Although some attempts have been made at debunking mineral oil, I think all of those attempts have overlooked some important data – the actual studies done on mineral oil’s effect on the absorption of fat soluble vitamins. The studies are quite old – actually in the period just after WWII. What one study found was that mineral oil in higher quantities, consumed with the mineral oil mixed directly into the food, interfered with the absorption of Vitamin A. However at a dose of 2.5 grams per meal (twice a day) – the mineral oil had no effect on Vitamin A levels. Very nice of that study to have gone down to 2.5 grams as the dosage that was used in REDUCE-IT placebo arm was 2 grams twice daily at mealtime. Most statins are taken at bedtime, but a few timed-release statins are taken at the evening meal. As was pointed out by Mr. Lyon in his article for Seeking Alpha is that the small intestine, where nutrients and statins are both absorbed, is about 20 feet long. A small dosage of mineral oil (under 2.5 grams) cannot coat a sufficient surface of the small intestine to significantly interfere with fat-soluble vitamin uptake. This also was the finding, with the mineral mixed directly into the food and therefore getting to the small intestine simultaneously with the food. However, if we assume at least some of the REDUCE-IT participants took their medication as prescribed, the evening dose of mineral oil would precede the statin dose by 2-3 hours – the mineral oil would have passed to the large intestine, by that time. Even if some participants were “lazy” and took the statin with the evening dosage of placebo mineral oil, the dosage of 2 grams would have had a negligible effect on statin absorption. Another factor to consider is the timing of statin and mineral oil to pass from stomach to small intestine. The mineral oil was in capsules and various statins were used in REDUCE-IT. The dissolve rate of all these different pills could not have been exactly the same. So not only do we have a very small dosage of mineral oil, theoretically most of the participants should have consumed it hours before the statin dosage and even if they were taken together, time separation of uptake would have been greater than in studies where the mineral oil was mixed directly into food.
The second thought on mineral oil is one that hopefully Amarin is looking into with the trial data. While most statins are fat soluble (and therefore would likely be affected by mineral oil in large doses – 15-30 grams, sufficient to cover more of the small intestine,) two statins are water soluble and likely would have no interaction with mineral oil. Those statins are pravastatin and rosuvastatin. Of the 4000-plus participants in the placebo arm, some good percentage was likely on pravastatin. By comparing the average changes in LDL C between fat soluble and water soluble statin takers, Amarin ought to be able to further isolate any effects of mineral oil. My guess is that given the low dose of mineral oil, the group differences will be very minimal or non-existent. Such an analysis would be useful for the FDA submission. Amarin obviously has thought along similar lines as they already had looked at the RRR in placebo arm of those whose LDL C had gone down and those who had gone up. Remember that the RRR was actually better for those whose LDL C had gone up – indicating that the minor LDL C changes had no effect on the positive benefit seen by Vascepa arm. Last thought on all the fear being spread about this issue – LDL C in placebo arm went up 7 points – it was so low already that this was a 10% change. It wasn’t as if LDL C changed from 200 to 220, the average went from 77 to 84. The Vascepa side also rose from 74 to 76. What the fear mongerers fail to mention is that these LDL C levels are still in the ideal range. I have seen no convincing study that shows a significant change in CV events when LDC ranges from 76 to 84. One recent study actually had patients with LDL C in low 80s fare better than those with LDL C lowered to low 70s.
Posted to yahoo as well --- thoughts?
Think you have the wrong Feuerstein guys:
Adam D Feuerstein lives in Winchester Mass and I am 99% sure he is the same AF who writes biotech for STAT. This link shows that he lived in Atlanta (Emory for his BA in PolSci) and that his his high school was Rosslyn (not JFK). These facts are exactly what AF biotech writers Linkedin page state as well.
https://www.mylife.com/adam-feuerstein/e222102439950
I think tweeting this may have started an unneeded firestorm as I do not think "our" AF is Adam Seth Feuerstein. Perhaps an apology is in order?
Hi, could you give the sources for your information about Feuerstein's home town and highschool? On linkedin - Adam lists his high school as Rosslyn High in Rosslyn Heights, NY. Seth's linkedin page does not list high school (as he has much more higher education compared to Adam's BA from Emory.) You state they both went to JFK High, but I am unsure that is the case. I'd like to keep digging but think your internet sources are needed - as from what I have found there is no connection. Thanks
Why Amarin will receive buyout offers before March 31
Despite recent articles undercutting the idea that Amarin will receive a buyout offer, it is the most logical outcome and therefore it has a very high probability of fruition. That does not mean, however, that Amarin management will accept an offer by 31 March. I would conjecture that Amarin has already been approach by a Big Pharma or two.
Some have argued that the it would make most sense for BP to bid after Amarin has made an sNDA application or even after it receives label expansion from the FDA. Amarin would be then totally de-risked (one exception – that Astra Zeneca’s trial comes in as equal to Vascepa.) There are several flaws was this thesis. First is that not only would Amarin be de-risked, but it would also be far more valuable, driving up the price Amarin would expect. Additionally, a positive ruling by the FDA, especially with the broadest label expansion, would motivate Amarin management to believe even more that GIA would be the most lucrative (longer term) for shareholders. So, the calculus for a BP competitor is to bid now with some risk or bid later at less risk, but much higher price.
The next reason for BP to bid now is to shepherd the sNDA application and negotiation with the FDA. In the hands of a seasoned team, the odds of receiving a fast-track status or eventual approval, with the widest possible label expansion, is more likely than with Amarin’s team. This is no slight to Amarin’s team; primarily they lack what is realistically an unsavory part of the business – insider connections within the FDA and the medical community – such as the hacks who often sit on ADCOMs. All one has to do is recall William Hiatt’s sabotaging the ADCOM in October 2013. Hiatt went out of his lane numerous times and never declared that he had been paid fees by AstraZeneca on his financial disclosure to the FDA. A BP would have more pull with the FDA to ensure a panel was stacked in its favor, whereas Amarin, will have to accept the panel it gets. Another thing for Amarin management to consider is the bad blood with the FDA – especially the humiliation of losing the freedom of speech case to Amarin. It would be only typical bureaucratic behavior for the FDA to stack a panel in such a way that Amarin does not prevail, or at a minimum is given a minimal label expansion – i.e. only for trigs above 150 and on statin treatment. This factor is probably the most critical for Amarin management accepting an offer in the next two months. The FDA could pull several tricks from its sleeve – 1. State that since the mechanism of action is unknown, a second smaller trial to confirm, or wait for AsraZeneca’s DHA/EPA mixture trial results. 2. State the mineral oil has clouded the RRR and that Amarin will have to run studies showing the effect of mineral oil on lipids and CV outcomes. (I have 30 years executive branch government service within the military and at a high policy level and have encountered numerous bureaucrats who do whatever they want without repercussion.) Amarin management must realize that a vindictive reaction by the FDA is possible, and frankly well above the level of remote.
Another reason for BP to bid now is intertwined with those in the paragraph above. By taking control of the sNDA process, a BP could ensure the full value of Vascepa's intellectual property is realized between now and 2030. Allowing Amarin to face the FDA on its own assumes the risk that some or all of Vascepa’s earnings potential is lost. Delay, denial, follow-up trials, or a mediocre label expansion are all possible outcomes. Taking control of Amarin now optimizes the chances of the most favorable outcome from the FDA. While analysts are predicting $ 1-2 billion sales per year for Vascepa, many with a better understanding of the market, see those figures as off by a factor of ten. BP realizes this as well – USA, Canada, EU, China – trigs above 150 and on statins could generate $30 billion per annum. Prescriptions for diabetics, high trigs but not on statins, etc. are only gravy. The limiting factor could possibly be supply, which could easily be outstripped by demand.
So, I believe BP has been or will be negotiating with Amarin between now and 31 March. The bigger unknown is if Amarin will accept. Price will likely be lower than what management wants, but fear of dealing with FDA may tip the balance toward accepting.
Scientific discussion – JL, et al.
While we have this lull in news from Amarin, I would like to engage the minds on this board to discuss some scientific issues that I have been mulling over / researching.
First, let me say that I am not trying to revive the ghost of Pyrrhonian , but I do think that one should always have an open mind and constantly evaluate a position in a stock.
In my humble opinion, Amarin trades in the 16s now, as opposed to mid 20s, for one reason: mineral oil. Whether we like it or not, it has created enough doubt to really hamper the company’s perceived market value. Markets hate uncertainty is an axiom. In Amarin’s case, MO has been the MO to create the uncertainty. (Sorry but I love puns.)
So, here are a few things I’d like to discuss to hear opinions on the issue.
The first is anemia. There were 45 more cases of anemia in the placebo arm than Vascepa arm (NEJM appendix p 40.) This had a P value of .03. At first blush, this concerned me as I thought that the 4 grams of mineral oil per day may have hindered vitamin uptake in the small intestine. Worse, is that anemia is a large factor in CV events (lots of literature on this). After more thought, I wondered if Vascepa might actually have another beneficial effect – aiding the body in production of red blood cells? 4 grams of mineral oil is a very small amount to have much of an effect, especially since it doesn’t get absorbed. Could such a small amount (2 grams with two meals a day) coat 20 plus feet of small intestine sufficiently to inhibit vitamin absorption to the point that the placebo arm was having greater rates of anemia? To get to the point, my conjecture is that EPA must somehow be assisting the body in red blood cell production and it wasn’t that the placebo arm had higher than normal anemia, but rather the Vascepa arm was having lower than normal anemia. Love to hear some educated thoughts on the hypothesis.
Second, can we learn anything from the Number Needed to Treat of 21? This number is less than half on any NNT that I know of from a statin trial. (I don’t like NNT as measure as it does not include time. I personally think all NNTs should be standardized to a “per annum basis.” While that doesn’t mean that a medicine may be effective in the first year of use, it would at least take the randomness out of NNT. NNTs are usually calculated over the average patient time in a clinical trial, so the time factor can vary greatly. ) Next, of course is that patient populations vary greatly from trial to trial – the entry criteria can be quite different. Having said all that, is there anyway to compare length and patient populations in statin trials to REDUCE-IT? I ask that question because even a ballpark comparison could eliminate the mineral oil “uncertainty” factor. Some have suggested (foolishly IMO) that mineral oil accounted for all the RRR in Reduce-it - i.e. give the patients a different placebo and Vascepa would have done exactly the same as those on statins only. What does an NNT more than twice as good as any statin trial say about the "mineral oil accounted for all differences" argument? Again would love to hear the opinions of those who like to read trial reports and do lots of math. (I have been doing a lot of both in the last few weeks, but I don’t want to “lead the witnesses” with my opinions / conclusions.)
Again, I am not doing this to throw doubt on Vascepa. I own almost 1 million dollars worth of shares. I just want to continue to think about and evaluate my investment and I think these are two good topics to develop.
Best wishes,
All Amarin share holders
Here is the link to the editor of NUTRA
https://www.nutraingredients-usa.com/Info/Contact-the-Editor
Please, along with me, contact them and tell them that they need to retract the guest article they published. Also contact Amarin IR; if they get enough complaints, perhaps they will take action as well. Here is the article:
https://www.nutraingredients-usa.com/Article/2018/12/12/EPA-and-DHA-Omega-3s-Reflections-on-2018
It contains falsehoods regarding the efficacy of other Omega 3s; specifically it contains false information about the ASCEND and VITAL trials. Unless someone can point to evidence to the contrary, I believe this to be purposefully misleading, with the intent of pushing the sales of supplements.
Thanks
Best wishes
What is this BS?
This article says that Ascend and Vital were both successful. Here are quotes from both trials:
"Meanwhile, the separate ASCEND study, also simultaneously published in NEJM, addressing use of fish oil supplements in 15,480 diabetic patients found no significant differences in outcomes between those taking supplements and those taking a placebo. According to researchers, a first serious vascular event occurred in 689 participants (8.9 percent) allocated to fish oil supplements and 712 participants (9.2 percent) allocated placebo over an average follow-up period of 7.4 years."
"CONCLUSIONS VITAL:
Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259.)"
Am I missing something or is this article from "nutraingredients" simply lies to promote the continued selling of Omega3 supplements? Something seems fishy - pun intended.
Jeffries and Cantor
I am long on Amarin since 2013 and have close to a million dollars now invested in the company, so please don't read this as a "bash." The fact that Jeffries and Cantor are the agents behind this are the kinds of unethical but legal actions that occur on Wall Street everyday. The excuse is that the banking arm or brokerage arm is firewalled from the research arm - which we all know is a complete lie. I am happy that Amarin is raising the cash as it opens options, but I don't like the way one company can be on both sides - making money from the sale of the stock in a public offering and making recommendations on the same stock.
I can't figure out the legalese of the placing - while we know that the price was $18, I am unsure if that is binding on the two companies. If the share price doesn't get back to 18 quickly and it was a binding sale we will know as both firms' analysts will issue repeat "buys" and even find new reasons to increase their price targets. Such are the ways big money is made on the street and the little guy has no say in it. They will figure a way to unload the shares without taking a loss. Then they'll take advantage of the option for an additional 30 millions' worth.
Last, the selling yesterday was way overdone as this was not really a 3% dilution. The only dilution that is occuring at this moment is the difference between what the shares were sold for and what Amarin actually nets after the bankers take their cut. Sure there will be 3% more shares out there to trade, but there also will be 200 million dollars in the company's coffers. I say dilution is later on, in the sense that a propspective buyer of Amarin down the road now has to calculate their offering price inclusing the additional shares. (Chump change in the event of a buy-out, especially since much of the currency used will simply be the shares of the buying company.) IMO the sell off was most likely from those hoping for a quick flip on a buy-out. The offering doesn't mean there isn't a buy out coming, it just means that one is less likely on the table right now. Those looking for the quick gain (or those paying margin interest left the field to longer hands.
Long and strong (actually added 5,000 more shares yesterday bewteen 16.2 and 16.36) but still not liking the way Wall Street does business.
Best
I am sure the FDA is going to use a study of 46 people from Iran in which none of the baseline data is cited in a usable manner and they don't even clarify what medicines the 46 people were taking. At face value, the paper indicates they took nothing other than Omega3 or placebo. You cannot assume they were statin treated, especially since there are no meaningful baseline data presented.
I also read several of the other papers you cited last week - they were retrospective studies done in Korea on exceptionally small amounts of patients. From those papers there is no way to tell the magnitude of effect of MACE increase / reduction from a change of LDL-C in the 75-84 mg/dL range (which is where the REDUCE-IT population were.) Oh, and the vast majority of the cases cited in these papers were elective revascularizations. One of the papers had 20 events total - seriously a retrospective study where thousands of people were culled down to a population that produced a grand total of 16/4 events is not useable for showing the effects of statin doses in a very finite range of LDL-C control.
I think perhaps the biggest red herring being purported by some all-knowing individuals is how and what time of day the 8200 REDUCE-IT enrollees took their pills. If by instruction, the Vascepa or mineral oil should have been taken in two doses with meals and the overwhelming amount of statins, should have been taken before bed (some exceptions such as time-released statins). So, if patients in the placebo arm were following instructions, the 2 grams of mineral oil from the evening dose should have slid a long way down the small intestine before the statin ever got to the stomach. To assume that one knows for certain that most people in the trial just took all the pills at once is just BS. Such an assumption cannot be made. Worst case, a minority percentage of the placebo arm was taking their statin with 2 grams of mineral oil (the evening dose).
So what is the theory now? The article you posted was a trial in which neither arm was treated with statins. Previously, for hundreds of posts, you have been telling us that MO inhibits the absorption of statins, changing high dosages into lower dosages.
This article you posted (inadvertently on your part) blasted your own theory.
I guess the new theory is that mineral oil, all on its own caused the changes in LDL-C and hsCRP? while the article asserts that it was the omega 3s that brought about a lowering in these on the non-placebo arm.
You should read your FUD articles more carefully before shooting yourself in the foot.
Yes, it has been discussed in detail. Bottom line is that Amarin's data says that event percentages in placebo arm were pretty much unchanged whether LDL-C went up or down ( surprisingly, up was actually a little lower in event %.)
Pyrrohnian – your answer to me about studies backing up your dramatic LDL-C hypothesis is “You’re not going to find many of those, and as far as AMRN goes it doesn’t really matter."
You realize that in the ONE study you cite (TNT TRIAL) LDL-C differed by 29% in the two arms (77 mg/dL and 101 mg/dL) and to get those differences the test arm was given 80 mg of atorvastatin and the placebo arm was given 10 mg of atorvastatin (difficult math I know, but that is an 8-fold difference in the strength of the statin between the two arms of the trial).
Let’s review the REDUCE-IT data to put this in context:
“At baseline, the median LDL-C was 75.0 mg/dL. The median change in LDL-C was 3.1% (+2.0 mg/dL) for VASCEPA and 10.2% (+7.0 mg/dL) for the mineral oil placebo arm; placebo-corrected median change from baseline of -6.6% (-5.0 mg/dL; p < 0.001).”
So the difference between the two arms in REDUCE-IT is an LDL-C difference of exactly 5mg/dL. 77 and 82, Vacepa / Placebo. Note, however that MACE events was actually lower among those in the placebo group whose LDL-C went up! This pretty convincingly argues that once in the 75-85 range LDL-C is maximized for reduction vs. events. (The Odyssey trial found the exact same result. The drug was actually more effective in the less than 80 mg subgroup than in the sub-group 80-100mg. (What they really found overall is that it didn’t really matter in these two sub-groups, statistical significance was only being achieved once around 100mg/dL.) The only logical deduction from these two data points (REDUCE-IT and Odyssey) is actually that LDL-C is pretty much optimized around 80 mg/dL.
But let’s get back to your non-sense about the magnitude of effect mineral oil might have had. Your backing evidence for this is a trial that used an 8 fold difference in the statin strength to obtain its results. Does anybody in their right mind think that mineral oil reduced the statin’s potency in REDUCE-IT Placebo arm by 800%? Reminder the difference in the two arms of REDUCE-IT is a total of 5 mg/dL in what is already the “maximized efficacy zone for outcomes” versus the 22 mg difference in TNT, which took the placebo average to 101 mg/DL. Mineral oil may have had a very marginal effect on statin absorption (or Vascepa may have actually been providing the benefit to the active arm and mineral did nothing to placebo arm) but it clearly did not have the effect of an 8 fold difference in statin uptake.
As Amarin has clearly stated, mineral at the absolute maximum, affected this trial by 4% (but the actual results in the placebo arm say it had no effect). You argued initially that it was mineral oil that caused the trial to be a success. Remove mineral oil as placebo and REDUCE-IT fails. Now you argue that FDA will require more testing.
What will that prove? Let’s say that indeed mineral oil on its own changes a median LDL-C from 77 to 82. Once that is done, is there any evidence out there that definitely shows that LDL-C at 77 is 25% “safer” than LDL-C at 82? Of course not, especially since these LDL-C levels are pretty much optimized; there are greatly diminishing returns at these low levels.
Until you can provide some real evidence about the effect of LDL-C changes at these low levels, I for one am going to have to say that you are simply trying to obfuscate, confuse, and create fear. I have an open mind, but I also want facts.
Pyrrhorian - please give me the names of the other trials that show these major changes in RRR in changes of LDL-C under 100.
The TNT trial is a 29% difference in LDL-C and as importantly, out of the sweet spot of 70-80s (77) to above 101 (placebo median).
I'd like to review that data (seriously). I am open-minded about this. Right now, the evidence says to me that mineral oil had no or a very, very minor affect on outcomes.
Thanks for providing the sources, as I am always willing to re-consider an investment decision. I am just no anywhere near that point.
Congrats on your short; I think you should cover it sooner than later.
I'd like to respond to the FUD you posted by citing the TNT Trial. In that trial, LDL-C in the 80mg statin group was at median 77mg/dL at year 4.9 years. The 10 mg statin group was at 101mg/dL. That is a 29% difference (not a 9% difference as was seen in REDUCE-IT 77 vs 84 mg/dL LDL-C.) As important, was that the 80mg statin side was in the sweet spot of LDL-C 70s-80smg/dL, as opposed to the 10 mg statin group which was above 100mg/dL.
So you take a trial with a 29% difference in LDL-C bewteen its arms and use it as evidence for why a trial that sees a 9% difference in LDL-C (although that difference made no outcome difference across the placebo group, regardless of whether LDL-C went up or down) and then conflate the result to state REDUCE-IT would have failed if not for the mineral oil.
Nice job at some sophisticated lying.
I personally think that mineral oil made no difference in the outcomes, but even in a worst-case scenario, perhaps a 2-4% difference in outcomes - not 25%. (As Amarin has stated)
Debunk the FUD
Some thoughts on mineral oil and LDL-C to totally debunk the FUD:
When one looks at the graphs of the Odyssey data one is struck by the fact that Alirocumab (Pyrrhonian’s favorite drug!) was virtually ineffective in the two sub-groups LDL-C less than 80 and 80 to 100. The incidence rates were A 8.3 Placebo 9.5 for less than 80 and then (read carefully) A 9.2 and Placebo 9.5 for 80-100 mg /dL. That’s right – contrary to what the LDL-C lowering hypothesis would tell you, the drug was less effective at preventing events in the 80-100 range than in the sub 80.
A very similar phenomenon is to be noted on slide 51 of the REDUCE-IT final brief. There is no difference in event percentages in the placebo arm, regardless of whether the LDL-C was raised slightly on not, i.e. in the 70-80s mg/dL range.
What this tells me is common sense – the law of dimishing returns. Big gains are made in reducing LDL-C in the well over 100 range, but once below that, continuing reductions are minimal or non-existent for event outcome percentages. I submit that even if mineral oil raised median placebo mg/dL to the mid-80s – IT MADE NO DIFFERENCE IN OUTCOMES. REDUCE-IT placebo data shows this and the Odyssey trial shows it as well – LDL-C under 100 mg/dL does not follow a linear pattern of consistent reductions in LDL-C with similar reductions in MACE events. (Actually both trials would indicate one is better off being in the 80-100 range than below 80.)
As others have shown, Odyssey saw median placebo LDL-C rise from 87 to 103.1 by the 48 month mark. Yep, that’s way higher than the “mineral oil” effect in REDUCE-IT. So where are the FUDsters crying to throw out the Odyssey trial? Oh, yeah, that’s right – they are telling you that Alirocumab is the one to use – it is going to get all the over 100 mg/dL business! (Let’s not forget that it was statistically insignificant in lowering CV death, but it will get all of Vascepa’s business!)
I am left with several conclusions from looking at the data:
A. If your LDL-C is below 100, try something other than a drug that lowers your LDL-C – you are very, very likely already optimal. (Too low – like 50 mg/dL might even start interfering with natural processes in the body.)
B. Mineral oil as a placebo made no difference for outcome percentages. There really is no difference in having LDL-C from 70-90 – “it is all good.”
C. People writing articles trying to undercut Vascepa are hypocrites when looking at 1. LDL-C placebo rate increases in other trials and 2. the horrible, terrible things that happen when your LDL-C is 85 instead of 79. Sorry folks, the stats say there really is no difference at this level. Oh and a 10% increase at this level is not comparable to say 150 and 165. The constant use of 10% is FUD in and of itself. This range is pretty much perfect so 10% is meaningless!
Enough said. (Other than – Pyrrhonian – I dare you to reply to this with facts. You conveniently have ignored my other posts, when showing you the statistics surrounding mineral oil, etc.)
Concerning Mineral Oil
Please take a look at slide 51 of the final results packet to be found on Amarin's website under investor relations. The two red lines on the slides for the primary and key secondary endpoints show that the frequency of events basically tracked whether or not a person in the placebo group had LDL-C increase or decrease. If one enlarges the slides, one will even see that from year 4 on, those with increased LDL-C in the placebo group had slightly lower frequency of events! You read that right - slightly higher LDL-C equaled slightly lower MACE events years 4-5. Amarin probably didn't draw too much attention to this as they wisely don't want to stir up the debate about whether statins lowering LDL-C is really what is causing the positive CV outcomes. Regardless of where one stands on the efficacy of statins, these charts show that LDL-C of 75 or 84 or frankly whatever as everyone was still well treated regardless of any "numerical" effect mineral oil might have had (Amarin noted that LDL-C difference might be yet another positive effect of Vascepa as opposed to a negative of mineral oil) - the MACE outcomes in the placebo group were not affected by it. If anything, those with the slightly higher LDL-C in placebo group did better longer term.
Those spreading FUD - Pyrrhonian, etc. take a long look at those slides.
How many shares are you short at 21?
"Landmark"
Read the AHA sign folks and then look at the dictionary definition: "an event, discovery, or change marking an important stage or turning point in something."
That's from Websters.
Clearly, Amarin management believes they have a drug that will change CV treatment. I would suspect at least one lawyer on staff vetted their promo materials for the AHA.
Please, oh please, oh please short this going into the weekend. My schadenfreude at people covering at huge losses next week will be immeasurable.
Pyrrhonian,
Please do us all a favor and post today at 16:00 (4PM) exactly how many shares you have short going into the weekend. This way, there will be a "record" of where you stood on your predictions. Since you love to post how well you do on your investment strategies, please make a record of this move, so that we all here on the IHUB board can marvel at your brilliance next week.
PS - "Landmark results"
Tasty, what do you think the chances are that the total number of events will be 219% of 1612 (219% = 1286 / 586 from JELIS including strokes) as opposed to the 180% you modeled after FOURNIER + extra 2.5 years.? JELIS time is very similar REDUCE-IT.
Dan,
I rarely post but you have truly upset my baseball sensibilities. How could you say you live in "Wrigleyville" and then call the park a stadium? There are only two proper words for Wrigley (just as there are for Fenway) - park or field, as in ballpark or ballfield. The Yankees and Dodgers play in stadiums, the Cubs do not.
Please take no offense, but please use terms of reference that connote the proper reverence.
Best regards
TTE,
I looked through you numbers and could not figure out where you got 4266 as the number of secondary events? (I used the original chart in the NEJM) and came up with 4028 (or 4160 if counting their rather confusing cardio revasc numbers by the urgent and elective categories). Regardless of the way, I didn't get a number as high as 4266. These modeling percentages for comparison to REDUCE-IT would be 138.6% or 143.1% respectively. Could you tell me where 4266 came from?
Also, I think 180% is pretty generous, but understand your reasoning given the much longer length of average time in the REDUCE-IT trial. I however would love to see the numbers with just a straight comparison of 1.386% (or 146.7% based upon 4266). I think a conservative approach is better for modeling and expectation. (Otherwise one might be disappointed on Saturday or even set expectations among other investors too high.) Thanks for any reply.
3 biggest clues
I rarely post, although I've been here since 2013 and communicated significantly with the FDA and Congress after the ADCOM. My biggest gripe in all that fiasco was the presence of Dr William Hiatt on the ADCOM and his behavior. He had been paid by AstraZeneca in the years before ADCOM and AZ had just bought Omthera two months before the ADCOM (EPANOVA). Hiatt declared none of this on his statement to the FDA. He was very vocal about safety (no issues) and the design of REDUCE-IT. Which was totally irrelevant to that ADCOM. My biggest fear is that FDA will, in typical government fashion (I know, I have 30 years of federal government service), ignorantly allow such conflicted individuals to be involved in future decisions on Vascepa.
Anyway, my current thoughts are that there are three big clues, that when put together indicate very highly (90% or better) that AHA will be a blow-out:
1. On their website they have recently added a page showing the increase in CV deaths in US, despite statin usage going higher. (BB first noted this) No reason to post this unless they now know that Vascepa reduces CV death in a statistically significant manner. 2. listen again to CEO's comments on CNBC from 24 Sep (youtube) and he states that there is now a trial that shows reductions in deaths, MI, etc. He didn't say angina. He would not have said this, if they did not know that RRR on the key secondary endpoints were good and stat sig. 3. It has been exactly a month since Top-line read out and no secondary. Amarin could "cashed-in" with a secondary worrying that the stock price would be lower after AHA, and they have not done so. That is a very strong indication that they are confident that Market Cap will be higher after AHA. Their patience and these subtle hints are the signs that we are going much higher.
Best regards
No discount rate as would only be necessary if Amarin were to take on more borrowings. I was initially going to factor in inflation and discount rates, but kept the model simpler by just assuming that COGS, revenues, admin and sales, etc all inflate at the same rate. This was only to show the order of magnitude of the NPV. A more precise spreadsheet could be done, but the magnitudes would change very little.
Net Present Value range:
Amarin – Net Present Value
Assumptions:
Current Cost of Goods (COGS) will remain stable; they will rise in price directly with the inflation rate. (This assumption is a worst case scenario; with economies of scale COGS could actually drop. (COGs are currently 25% of revenue – generating 75% gross margins – all of which is being eaten by Admin, Sales, Research, and Development.)
Inflation from 2019 – 2030 will be offset – any increases in COGS / Admin and sales will be covered by corresponding increases in revenue through increased prices for Vascepa.
Amarin will remain the sole licensed vendor of Vascepa in the U.S. until August 2029 (TEVA agreement) and Amarin will maintain patent protection in similar to U.S– sized markets, globally until 2030.
U.S. corporate tax rates will remain unchanged.
AstraZeneca’s Epanova will not have RRR as high as Vascepa and the gastro-intestinal side-effects – mainly diarrhea – will make Vascepa the standard of care for statin-add on care.
Vascepa will have 7-8 years (from 2022-2029) of peak sales after three year ramp up.
25% of 38 million statin-treated people have TG greater than 150. (Market of 9.5 million people in U.S. if Vascepa approved only as a statin add on by FDA.)
Best case scenario: Vascepa is approved for additional 50-70 million people in U.S. with high TG, as a method of CV treatment, regardless of stain add-on. (This scenario would likely occur only if exceptional hard MACE RRR announced at AHA.)
Best case scenario: Vascepa has a global market similar in size to the U.S. market.
Share count will be 370 million.
The range of scenarios:
Doomsday scenario: Amarin has 6 million patients (1/3 of possible statin add on market, U.S. and another 3 million abroad) and generates only 10% net profit (i.e. selling and admin continues to take almost all of gross revenue.) In this scenario Amarin generates $1.44 billion in profit per annum for total net profit through 2029 of $11.52 billion. Net Present Value with float of 370 million shares - $31 dollars per share.
Poor case scenario: Amarin has same market share but reduces admin and sales to the point that net profit is 25% of sales – Net Present Value - $78 dollars per share.
Good scenario: Amarin gets 9 million patients U.S. and 9 million abroad – i.e. the entire statin treated population with high TG. At 10% net profit NPV is $93 per share.
Same scenario of 18 million patients but net profit of 25% - NPV is $233 per share.
Great scenario – same patient population but admin and sales reduced to a net 40% profit – NPV is $373 per share.
Amazing scenario – 50 million patients (half of total possible high TG patients – assuming Vascepa is granted status as a stand-alone treatment for non- statin treated people.) At a 25% net profit – NPV is $649 dollars per share.
Blow-out scenario – 50 million patients and 40% net profit – NPV is $1037 per share. Nearly $400 billion in profits (in current dollars).
So, whether you are just like us holding shares or a Pharma exec looking at acquiring Amarin - the value ranges from $31 per share at worst to over $1000 per share. In a "dream" scenario of 100 million patients, Vascepa could even generate $800 billion or $2000 a share.
I think that great results announced at AHA and we are in the good scenario or better - at least 5 times higher than current share price. Very worst, and we are up only 40-50% from here and I think that really is not that likely. If CANTOR and CITI have done any real analysis of the revenue stream this could generate, I don't understand how they have such conservative price targets of 60 and 50. I think 90-100 per share is a "conservative" PT!
Best regards,