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I'd also be curious to know who are the bottom 3, the judges we don't want.
Ranjo - I took a look at the Vascepa optimal dose issue a while back. Amarin tried two doses years ago (2g and 4g) and picked 4g. I believe one rationale they gave was that they estimated it would give Americans similar plasma EPA level to that of the Japanese subjects in JELIS, which showed good results. JELIS used 1.8g on a population that eats a lot of fish and has naturally higher EPA levels than Americans. Because 4g gave more benefit (primarily trig reduction) than 2g that was another argument for the 4g dose.
If I recall correctly, a subgroup analysis of JELIS plotted risk reduction vs plasma EPA level for various subgroups. Each curve demonstrated diminishing improvement with increased EPA level above a certain plasma EPA level. There would be limited benefit and added expense above that level, so it could be considered the optimum target level of plasma EPA. That optimum level increased with age and was higher for men than women. It would presumably correspond to a higher daily dose of V for larger people, with a larger volume of blood. It seems reasonable to speculate that diet and other lifestyle choices might also influence optimal dose.
My takeaway was that for an older man who ingests some AA now and then and is keen on avoiding CV events, 5 or even 6 grams of V or similar per day would not be crazy. I take the 4g/day of V available to me via prescription and often supplement with another gram or two of dietary supplement EPA. Barry "The Zone" Sears, a pioneering expert on benefits of EPA, has said years ago up to 10g/day wouldn't be crazy. (He does sell omega-3 supplements, but I think he meant it.)
Take it for what it's worth, I'm not a medical doctor.
Thanks Meowza.
Question from a non-doctor - Curious where calcified plaque comes from. Is it from soft plaque that hardened over time, or is it just a different type that was never soft? Is one more common than the other?
Seems likely.
jfmcrr - Seems very clear V very probably substantially improved your situation. There are far worse things than stents, and seems very possible to me V might have saved your life or prevented a serious stoke. Of course, no way to know for sure what would have happened if you hadn't taken V or similar.
Take care and best wishes
My expectations re FDA are limited. The only time I can think of they acted promptly related to Amarin was lightning fast (for them) approval of the generic, which any reasonable decent person might have thought would be as good an opportunity as any to foot drag a bit.
If you insist on absolute 100% proof, like FDA does, case could be made there are multiple modes of action and MO didn't impact the EVAPORATE mode (plaque reduction), but could possibly have an effect on some other mode (beneficial statin effect not related to plaque volume). Given the near perfect safety, low cost, and life-saving benefit otherwise unavailable, V was very clearly in the best interest of patients beyond the label before EVAP results. This new evidence strengthens the case, but what would matter more pragmatically would be a strengthening of FDA desire to live up to their mission statement and seek to optimize the public good instead of the FDA's perceived self interest. Not holding my breath on that.
Agree completely Zip. Frankly, the case for relaxing the trig limit on the label was already strong, but now much stronger. I'm not holding my breath for FDA to act though. But, insurance companies and other health care providers will understand and provide beyond the FDA label IMO because it will save them money.
Yes, there is no question in my mind that AF and MH cost lives, arguably a great many. We're all human, but in the case of AF, his fairly recent Twitter attack on professor Bhatt (for co-authoring that paper explaining the statistical error underpinning the Du ruling) and his refusal to consider indisputably clear facts and correct the record seem inexcusable to me.
A case can be made that the dual articles from AF and MH, which were picked up and spread far and wide, motivated the FDA to unexpectedly schedule the adcom, which was announced far later than normal, delaying approval to after the annual insurance policy adjustments, including Medicare. For many that delayed coverage one more year. That most certainly bears a substantial price in death and suffering (including devastating non-fatal strokes). FDA included substantial MO analysis that most informed scientists wouldn't have considered necessary, likely as a result of the furor from the MH/AF misreporting IMO. I won't run the numbers, but I'd expect them to make Charles Manson seem like a slouch (probably in the thousands, not joking).
I think FDA has much to be both embarrassed about and ashamed of, especially in their ugly history with Amarin. Very prompt to approve the generics without any amicus brief to support Amarin, however, and slow as molasses OKing DTC.
I wouldn't count on the FDA for much. This certainly bolsters the case for a broader label, but that case was already very strong, so strong that a reasonable person with the best interests of the public in mind would have had very little choice but to broaden (to include those at risk independent of trig or LDL level or statin use). Especially with the low risk and very probable secondary benefits from the reduced systemic inflammation. But FDA's top priority is the absolute reduction of risk of embarrassment to them. Insurers and other health care providers have money at stake and will promote use beyond the current label IMO.
Looks like a statistical aberration re trigs. It would be interesting to do a little subgroup analysis, even with the tiny sample size, and divide the subjects into two groups randomly and see if the no-trig-reduction result holds up more or less (could do it for multiple partitions). Not clear that will happen, probably wouldn't be publishable with N that small, but I'd be curious.
V lowers trigs, but didn't happen to in this very small sample trial (only 80 vs over 8,000 for RI). This trial didn't need a very large number of subjects because it directly measured plaque and didn't need a ton of subjects to overcome the uncertainties resulting from the conversion of plaque volume to cardiac event rate. That events result from plaque is settled science, the very stat sig plaque reduction suffices to answer a lot of questions and add value despite the small trial size.
The EVAP results are fabulous in my view, with the lack of trig reduction a good thing, an unexpected bonus (a cherry on top so to speak). It helps establish the multiple modes of action, with very strong benefit persisting even for those without high trigs. That's a big deal for making the case for broader label (or for health care providers to provide V off-label even for those with normal trigs). Subjects had high trigs, but the benefit did not come from lowering them. This is on top of the result in the other paper related to statins, that benefit persisted regardless of the type of statin (some are stronger than others), again bolstering the case for broader use to those not taking statins.
The very clear reduction of plaque, not just stopping its accumulation, is great. A case could be made that if it didn't reduce existing plaque but just stopped its accumulation, that would motivate people to start taking it years earlier, before reaching the age of high risk, but the incentive to start taking it now for people currently at risk or about to enter the age range of higher risk (which happens to include me) is higher today, and the incentive extends to insurers as well as patients given the reasonable pricing.
Home run results IMO. It's never certain how well the market will appreciate them immediately, but the marketing job for V will be a lot easier and that should be worth money in the long run, with or without an appeal win.
The absolutely definitive nail in the coffin for mineral oil doubts is also satisfying, although it was quite clear already and no one credible in possession of the basic facts was expressing doubts about that anyway. I doubt AF and MH do a big article correcting their misreporting about it, but the evidence is now about 100% clear the effect was not only slight but virtually zero.
Refreshing to see it called Vascepa instead of icosapent ethyl.
Refreshing to see it called Vascepa instead of icosapent ethyl.
Nice to see confirmation that V benefit is independent of statin type, consistently strong for more or less intense statin doses. That confirms that V benefit would extend to those at risk but not taking statins.
Hey Jakey - Thanks for the kind words. A group of potential patients such as those with severe triglyceridemia (over 500) is characterized by the probability density of their TG levels, which is a function with nonzero values over a range from 500 to some much higher number. If, for simplicity, someone wants to represent it with a single number, that should generally be at the center of the probability mass in some sense, such as the mean (average) or median. To use the minimum (500) to represent the whole group is generally bad science IMO.
Zip - I like your numbers better than mine. Hope you’re right.
MNBioMike - After years of unpredictable AMRN price moves I'm reluctant to predict, but the conventional wisdom would be with two catalysts near end of year there could be a run up starting perhaps around October. It would be possible to play that and get out pre-catalyst. I think chance of winning on appeal seems like a bit over 60%, so a case can be made for holding through. If appeal is lost, the stock can be expected to dip sharply from where ever it is then (perhaps from $8 back to $6 or who knows). Even with lost appeal, ex-US is worth substantially more than current price in the long run, although it would likely take a year or two to ramp up sales and bio investors don't like waiting with dead money.
I'm not a huge fan of hedging. Feels like betting both sides. Maybe someone who is good at it can explain it. I pick a time frame and stick with it. I think AMRN will be worth more than today in 18 months based on European sales alone, almost certain. 62% it pops up with an appeal win, and a smaller pop on EU approval (less of a surprise).
Only thing that's sure is the right move will seem clear after it's too late to do anything about it.
GLTA
Survey response & remarks:
Reverse: 62% affirm: 30% Remand: 3% Settle: 5%
Caveat about my guess: I don’t have legal expertise so take it for what it’s worth. I believe the evidence clearly shows Amarin to be in the right scientifically and legally, but that doesn’t mean they’ll prevail. Facts, fairness and law seem to provide less reliable protection these days, and they were never completely reliable. Remand seems inappropriate, but I’m reluctant to say anything’s impossible these days. Could seem like a good idea to an appellate judge that’s a fellow traveler with Du. There are sound arguments against settlement, but there also seem to be big potential incentives for it on both sides (no price war etc.). JT has displayed strong risk avoidance in the past (e.g., unexpected money raise), making settlement seem more likely.
The technical note by Curfman, Bhat and others should strongly support the appeal if the judges are unbiased. If it’s not allowed into evidence for some reason, I expect the legal team to probably find a way to make the judges aware of it anyway.
Regarding the “500” issue (generics incorrectly claim 500 adequately represents all severely high TGs, and isn’t much different than 400, which is in the same class as TGs in the 200s, so severely high TGs are similar to moderately high TGs) : Key to this is a common problem of oversimplifying a complex phenomenon. Partitioning something into two categories with a simple threshold is very common (TGs above or below 500 for example), but there are generally problematic issues (grey areas) near the border. Night and day have very different visibility, but there’s little difference between a few minutes before sunset and a few minutes after. It would be absurd to suggest that means there’s no significant visibility difference between night and day. (Mathematically that results from imprecisely modeling a fuzzy set as if it were a crisp set.)
It is scientifically unsound to model the subgroup of the population with TG above 500, who have a wide range of TG levels that can go over 1,000, as if they all had TG levels of 500, and then note that they are similar to those whose TGs are 400, who in turn are arbitrarily lumped in with a group whose average TG level is perhaps 200. That twisted logic can lead to the false implication that a group of people with averge TGs around 200 is comparable to a group with average TGs of 800. (It’s like falsely arguing that fifteen minutes before sunset isn’t that much different than fifteen minutes after, so there’s no significant difference between noon and midnight.) Such reasoning is inconsistent with common sense and logic.
This is one of many reasons Amarin deserves to win its appeal, but that’s no guarantee they will.
I think the market, in typical fashion, over-compensated for the adverse court ruling, and Amarin remains under priced due to chance of winning the appeal, and rest of world and at least small US earnings even if they lose are, in the long run, worth much more than current price even if we lose. If we lose, the dip would be a long-term buy opportunity IMO. I don't expect a BO because, if Amarin's price they would accept went down (as I assume it must have), big pharma's would have too, by at least as much. Amarin is still not desperate IMO and big pharma is hooked on the deep discounts that accompany desperation. They get plenty of opportunity to prey on that.
Having data that doesn’t show a significant increase in LDL for the EPA arm while it does for the DHA arm is not the same as showing DHA increases LDL more than EPA does, as the recent note co-authored by Bhatt pointed out. For example, if there had only been 2 subjects in Mori’s EPA arm, they extremely likely would not have shown a significant LDL increase, and it would be absurd to suggest such a trial supported any conclusion about a differential effect on lipids between EPA and DHA.
raf - I have very limited time right now, but held my nose and took a quick look at that MRC material. He predicted Amarin would lose on both obviousness and inducement. Obviously he was wrong about inducement, as he was about mineral oil, RI success etc.
Re obviousness, he cited a 2010 Amarin investor presentation that said prior papers supported DHA raising LDL and EPA being LDL-neutral, including Mori and several others. He (they?) also harped on Epadel in Japan and that the patent was flawed because the examiner didn't seem aware of some of the papers. A good case can be made that small trials on dissimilar subjects are at best hypothesis-generating, as Bhatt et al point out in their recent note.
It's been my experience that for most important inventions, with hindsight one can go back and find people who came at least close to finding it. In fact, there are all kinds of investigations, many of which reach opposite conclusions, and at any time you can find claims on both sides of most important issues, some of which will end up being true in hindsight, when the truth was far from obvious at the time.
For example, Semmelweis clearly proved the value of medical hygiene in the 1860s, twice, and published it. It was rejected despite being widely seen and discussed. After it was re-discovered a decade or so later, people found at least a couple examples of it having been known about decades before Semmelweis. But that was completely overwhelmed by the many "experts" who were so very sure hygiene didn't matter. It was far from obvious long, long after the first people suspected or even knew it.
For those interested in Ken Fisher’s take on the corona virus and market, his firm is monitoring it closely. He considers this a sharp market correction and not an imminent bear. Classic market over-reaction, not playable in terms of getting out, great time to add to positions if you have cash. Corona not yet demonstrating anywhere near impact enough to justify the panic. Ken’s a mostly perma bull, for good reasons, and he’s fully bullish today.
No need to explain here the many reasons AMRN is insanely good long-term buy here. I believe EPA helps pretty much anyone at high risk, far beyond the label, which is pretty broad. I think this will pretty quickly become clear to health care providers and expect ramp up beyond what most expect.
A plea for medical advice: I’m in very rural Iowa for a death in the family. Got a bad cold and cough with congestion. Starting to get an earache in my left ear. I’ve had that a couple times, years ago, and the pain became unbearable then. I think the primary care before was strong pain pills and wait it out.
With pain killers harder to get these days (I assume) and a long drive to reach minimal medical care, I Binged home remedies. Seeing stuff like vinegar on cotton ball. Is that homeopathy BS? Any harm trying it? Any home remedy? Pain not bad enough to go to doc yet, but I worry about later.
Any advice?
concapk - I attended adcom but am not attending the trial in Reno.
sts - There is strong evidence in JELIS that CVD benefit of EPA is dose dependent. JELIS active arm had comparable plasma EPA level as RI, but half or more of it was from the higher fish diet. So, adding 1.8 G per day on top of the equivalent of about 2 or more grams from dietary fish gave a higher RRR per gram of EPA administered than was observed for RI (19% RRR/1.8g of EPA vs 25% RRR/4g of EPA). In effect, we more or less have data on event rate at 3 different dose levels (both arms of JELIS and the active arm of RI), if we include the JELIS dietary EPA. The doses of JELIS and RI active arms are roughly comparable. We don't know that more EPA wouldn't help. (It probably would, especially for older males with risk factors.)
"Will be live blogging from the can all day."
I'm glad my smart phone isn't equipped with smell-o-vision.
Given Amarin’s interesting past stock price behavior, with fabulous news often accompanied by weak stock price, I assume today’s weakness means in addition to CVD and dry eye, V must also remedy baldness, dandruff, and underarm odor. If it also turns out to be a great dessert topping and floor wax, we’re in real trouble.
STAT had an article by AF and Herper on Dec 31 that started like this:
"We dug through every drug that passed muster with the Food and Drug Administration starting in 2010 and identified ten — along with a dozen honorable mentions — that have had the biggest impact on the companies that sell them, on medicine, and on society as a whole."
Curious if Amarin made their list or was an honorable mention, even though it was approved so recently most of the impact is yet to be felt. I don't subscribe to STAT. Does anyone know?
I find it reassuring that Reddy’s law firm with over 180 patent attorneys had to go back more than 7 years for an example of defeating a patent. No mention of their presumably large number of unsuccessful attempts.
I believe JT mentioned that Europe pricing could be higher than US, contrary to the usual situation, because the US price was set low years ago to compete with generic Lovaza, and that is not going to be the case in Europe.
Not clear to me if it’s bad news or good. Could be Amarin felt their position is strong enough to not need to give up much in a settlement.
I don't pretend to have a crystal ball for short-term share price, but recall that price action at the open after top line results was relatively weak and built over time, in the afternoon of that day and on following days, as buyers eventually overcame sellers of the news and other factors.
A chart from November 2018 (the lighter parts are after hours):
TTE - That works for me. At one point I was one of those who declined statins, deterred mostly by concerns about their impact on mental acuity, and also by the belief that much of statins' benefit was anti-inflammatory, as explained by JL, and I'd rather get that with V. I did start taking a very low-dose statin recently after reports that feared adverse statin side-effects had likely been exaggerated, especially re mental acuity, and increased confidence in statin benefit, as reflected by remarks by Bhatt and others in a post-AHA scientific session video where they agreed evidence was strong for advising statins to drive LDL down to 70. (BTW, that same video also commented favorably on the continuing benefits of the balloon pump JL played a key role in developing years ago.
Jeffkad - I respectfully and cordially disagree with your opinion that:
"if a doc digs into the actual study, he/she will find nothing that supports use without statin."
RI results do support Vascepa for those not on statins. RI had subjects on statins of varying intensity. The degree of independence of V benefit (e.g., RRR) on statin intensity is revealed by the trial results and has strong implications for expected V benefit without statins. This can be examined scientifically and quantitatively by exptrapolation. Additionally, as JL pointed out, JELIS showed very strong benefit from EPA with low dose statin (even more per gram of EPA than RI), and there is further support from the fact that fish-eating populations with high EPA levels had lower CVD risk before the advent of statins.
A week or two ago I wrote a note making the scientific case for a broad Vascepa label that explored this in detail:
the case for a broad Vascepa label
Interesting fiercepharma quote:
"Vascepa has now been approved for a possible patient population that runs into the tens of millions, Thero said."
After the early morning top line results, in the very early pre-market trading, before most people could trade, I remember seeing Amarin trade for a while in single digits, $7 or $8 for a while. I remember adding a few shares when I was able to, at around $9 or $10. I don't think we're as vulnerable to bad reporting this time around. Next week should be good, no reason to think we're limited to the twenties based on low volume after hours trading so far.
On Pluto I think maybe it will be 3:30 in eleventy four and a half years, easterly southwestern FDA time, after adjusting for relativistic effects. Relax and it will come when it comes.
I don't see how the label isn't very broad if the FDA staffer who rebutted MRC was at the table. The facts point clearly to a very broad label, even broader than Amarin ambitiously asked for, IMO, if public welfare is a high priority.
KCSVEN - As speculative rumors go, yours seems pretty good to me.