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Interesting quote from that Suzy Cohen article:
" if statin medications raise AA, and EPA lowers that, it makes you wonder how much BETTER the study trial results would have been ... if there was an arm of the trial that was EPA only, without a statin.
The statin raises AA, and EPA reduces it. They argue with each other in yet another way.
EPA is an inhibitor of delta 5-desaturation which reduces inflammation. Statins enhance this pathway according to THIS STUDY.
The ratio of EPA to AA in your body is very important – that’s the message I’d like to get out there."
She seems to make some sense there.
"forbidden from doing work during the time of furlough ...technically she can not even check her email "
That seems crazy. Whose idea was that?
Kiwi -Thanks for contributing toward our drinks. I had a couple very nice Marlborough Sauvignon Blanca (from Kiwi country).
IMO, AF was overly skeptical and gave a very disappointing report, omitting crucial facts (like the max possible MO effect couldn’t possibly be enough to matter muck, so V is a confirmed blockbuster). It was Herper who crossed the line to fake a couple different ways. He said lipids don’t budge and 5 of his 6 cardiology were seriously bothered, which was not supported by his quotes. He also didn’t mention Bhatt was from Harvard, but listed critics credentials. One of AF’s biggest mistakes was endorsing MH’s article.
TerraPharma has been actively tweeting positively about AMRN and Vascepa. There are a few of us doing that.
biobill - ".this delay is giving me an ulcer;) "
I share your impatience, but, for the sake of your ulcer and blood pressure, I hope you can relax and take a deep breath and take comfort in the fact we are making good progress, even though frustratingly slower than it needs to be. Millions with good insurance could pay $9/quarter to reduce their risk of heart attack and stroke by about a third if they'd pay attention and get a prescription off label. More fair reporting would help.
Be at peace, I think our time is coming soon.
Once we make it to 35k scripts, then it will be just 9,965,000 more til 10M. With at least several tens of millions of Americans who would clearly benefit greatly, and many more globally, 10M shouldn't be the final peak but it would be a good start.
FM - Agree completely we don't know what the outcome will be, certainly not with much precision, but we'd have a rough idea what to expect and very likely there would be benefit substantial enough to be worthwhile.
Frankly, if REDUCE-IT were re-run, same as before, the results would come out somewhat different. That's just how the world works.
ferretmoney - V has numerous modes of action, and we don't know the details about how much of the benefit comes from the various modes. Benefit varies pretty widely also based on type of event and the subject. High trig low HDL gets much more benefit (38% RRR vs 25% overall). CV death is reduced less than heart attacks. So, if anything is changed, we don't know exactly what the benefit will be.
But, it's pretty clear there are modes of action that are largely independent of the statin, probably most of them. If RRR or ARR were plotted vs statin dose, and that curve were extrapolated outside the range spanned by RI subjects, it seems very likely to me substantial benefit would be clearly indicated for statin dose of 0. Ditto for trig levels outside the RI range (say down to 100 or lower). It's not the same as proof by a trial, but people with flexible minds and common sense who care about preventing human suffering and death should support extending V to the wide range of people who seem certain to benefit substantially. Trials take many years, and unclear to me how more big ones would be funded given Amarin's tribulations and generic coming in 2029. I think either of the populations you mentioned would benefit. I suppose whichever is larger is more likely to get included in a trial in sufficient numbers for conclusive results.
I'm not counting on FDA making the well-being of Americans their top priority, but we can hope, and thank goodness they have not yet succeeded in their attempt to further tighten their grip by ending off-label prescription.
dan - I recall those posts, but it was not my brother.
Biobill - " The RRR of R-I rivals the results of Lipitor or ANY statin trial!!!"
At the risk of riling you up even more (which might not be good for your blood pressure), I'll point out that it may be more appropriate to look at absolute risk reduction (ARR), which is the inverse of the key NNT (number needed to treat) metric. Statins have ARR ~1%-2%. V has 4.8% ARR, more than double. So, while some say V is biggest thing since statins, a case can be made V is more impressive than statins, and with less severe side effects IMO.
BTW, if statins were tested as add-ons to V, it's not clear their performance wouldn't be lower than previously measured.
RAF - Not anonymous, but they absolutely didn’t say what he said they said.
PE - EVOLVE, and also ODYSSEY, had LDL rise, and lots of others. From Amarincorp.com FAQ page on mineral oil:
" It is, in fact, generally understood that variability in blood-based lipid, lipoprotein and inflammation values is a common ccurrence in clinical studies of statin-stabilized patients, and many long-term studies of statin-stabilized patients have observed increases in biomarkers with time, including LDL-C. "
Not to mention, DMC checked RI for MO effect quarterly for 7 years and reported no effect attributable to MO. And a bunch of other indisputable arguments why 2 grams of MO (1/14th of an ounce) didn't have a big effect on 20+ foot long intestines.
PE - I suppose they were following orders, but there are definitely some FDA staff who did things they should be ashamed of.
PE - I forgot to mention, Herper gave no source for the bogus "do not budge" remark. And Kastelein, to his credit, said V should be used, but later there may be others proved useful also (from his trial).
PE - A band of shysters indeed. Nissen and Krumholz are well-informed and parsed skillfully - giving a negative impression without actually saying anything untrue. Nissen said more than once, in effect, that V benefit is more than 0, which is certainly true, but he presumably knows it is certainly more than 20 or 22% and probably more than 24% (RRR for primary endpoint), where 20% is a home run. I found no Nissen quote actually saying MO effect was more than tiny.
The Krumholz quotes MH printed came across very negative without actually saying anything negative. He said he was surprised and wanted another trial to understand why V works. He also asked whether this was a "one-off". (He knows it can't be with p<0.00000001, and very consistent across subgroups not to mention JELIS, but no one can ever say a question is a falsehood, so he stayed clean on a technicality.)
BTW, Herper said 5 of his 6 cardiologists were seriously bothered by MO, but neither Nissen or Krumholz actually said MO was a significant problem, and Weiss, also counted among the 5, said he could convince himself MO was not a big deal, but it was "messy and a little disappointing." MH had no report of any of them quantifying the MO problem. The Nov 10 Bhatt AHA video quantified it as less than 2% or 3% or at most 4% RRR impact if you believed in it, which he didn't for good reasons he explained in clear un-parsed terms.
BTW, it only requires mastery of 6th grade math (fractions) and a brief online search to do a ballpark sanity check on the MO issue. The LDL increase in the placebo group was 7 mg/dl. The total LDL decrease by statin is ballpark 10 times that, and absolute risk reduction (ARR) for statin is 1% to 2%, well-under half the RI ARR of 4.8%. So, the fraction of RI benefit that could be questioned is roughly 1/20th (1 or 2% RRR). And, for several good reasons, the MO effect is actually considerably smaller than that,
sts - Herper made that lie up on his own as far as I can tell. Nissen parses and gives a negative impression without saying anything false he can be held to account for. For example, anyone slightly competent who has thought about it would know min oil effect can't possibly be more than 2-4%, and much more likely between 0 and 1%. Nissen condemns with faint praise, saying he believes RRR for V is more than 0, which is true, but he knows it's more than at least 21%.
Bouf - Having lived through the 2013 adcom and having gone through the transcript and recordings multiple times, I think the FDA will probably approve the label expansion promptly. They do what they perceive to be in their self-interest. After some other CV outcome trials failed (niacin/fibrates), FDA decided to rescind the SPA and avoid risk of another embarrassing post-approval trial failure.
RI results are a grand slam home run, and FDA knows it is in their interest to approve promptly. Nothing's ever ever completely certain with them, and they may find a way to make it a bumpy path, but I think the RI SPA will be among the 98% that are honored.
rfj - "he [Herper] didn't cherry pick the KOLs to be negative)"
I don't know that. If you have information about that, I'd be interested to hear about it. How would anyone know whether he contacted more people than he used, and omitted some he that didn't fit his agenda (a very common tactic), or chose people he thought would support his position? I make no assumption about bias in his selection of cardiologists, but I can see the falsehoods he reported. MH went over the line, AF didn't quite.
In addition to a decidedly negative spin overall, and failing to mention the crucial and completely obvious fact that discounting for the maximum possible MO effect would still leave RI as a historic breakthrough blockbuster, MH also made the blatently false and unsupported statements that I mentioned before.
A problematic cut and paste from the Forbes hit piece: "what seriously bothered five of the six cardiologists I spoke to was that the mineral oil had not behaved as a placebo at all. In other studies of cardiovascular drugs, blood test results on placebo do not budge. That’s not what happened here. "
If you read the article, he does not have quotes supporting 5 of 6 seriously bothered by MO. And, he fabricated the falsehood that lipid measurements don't budge. Inexplicable and inexcusable. It didn't help his credibility with me that he thoroughly listed credentials of the critics, including the names of donors who fund their salary, but couldn't be bothered to mention prof Bhatt was a doctor or a cardiologist or a professor at Harvard Med School or director of CV something or other.
The modest LDL increase is easily explained by aging, regression to the mean, and natural fluctuation (mostly the latter, which is known to be greater for those with high trigs). Independent of why, it is also clear, for several reasons already thoroughly discussed here, the impact on RRR is far too small to matter much.
Reading the Nov 10 Herper article and the Amarin FAQ page on mineral oil confirms the Herper falsehoods I described, that Thero correctly called fake news.
Herper went out of his way to misrepresent the facts in his November hit piece. His follow on article didn't really fix it. What he did was demonstrably wrong and indefensible. AF at least reported the possibility or probability V is highly beneficial, albeit with overly skeptical spin. MH went over the line to fake news. He said lipids like LDL-C simply don't vary naturally, and that is well known to be false. He also misrepresented the views of the cardiologists he spoke to and didn't reveal the crucial fact that the max possible min oil effect was too small to threaten the breakthrough results. AF endorsed the Herper article and didn't report the full truth, so he shares the shame.
dml - Here’s some of what I have from AF recently:
The beginning of a Stat article (nothing much more of note in this short article):
“Amarin’s CEO drops enough JPM19 hints to know Vascepa sales driving higher
By ADAM FEUERSTEIN @adamfeuerstein JANUARY 9, 2019
ALEX HOGAN/STAT
SAN FRANCISCO — Amarin (AMRN) CEO John Thero used his Wednesday breakout session at the J.P. Morgan Healthcare Conference to not-so-subtly telegraph a stronger 2019 sales outlook for Vascepa than the company’s official guidance offered last week.
Thero, of course, can’t come out directly and say that Vascepa, Amarin’s heart drug derived from fish oil, will deliver significantly more than a 50 percent year-over-year increase to $350 million in 2019 sales. Like Fight Club, the first rule of sandbagging revenue guidance is not talking about sandbagging revenue guidance.
But during meetings with investors over three days here, and then on Wednesday during the breakout session, Thero dropped plenty of hints. …”
As a bonus, here’s some recent twitter action with AF, raf, and me:
Adam Feuerstein?Verified account @adamfeuerstein 23h23 hours ago
Help me with the logic here: $AMRN CEO John Thero just spent 4 days in SF meeting face to face with investors while ALSO negotiating a $PFE takeout? People, please...
Charles Crosby Lyon? @chas1232123 7h7 hours ago
Help me with the logic here Adam: after rock solid confirmation $AMRN ’s #Vascepa is the biggest #cardiovascular protection breakthrough in several decades, on top of not really reporting that, you now imply either $PFE is uninterested or would be stopped by JPM? Adam, please…
Adam Feuerstein?Verified account @adamfeuerstein 7h7 hours ago
Hi Charles — I can’t cure your stupidity. Apologies.
4 replies 0 retweets 4 likes
ra fun? @ra_fun
Replying to @adamfeuerstein @chas1232123
Poor little Adam has had his feelings hurt too many times, he has been on the wrong side of Amarin too many times.
Charles Crosby Lyon? @chas1232123 6h6 hours ago
Thanks for taking time to respond. Still want help with your logic. My engineering degrees and extensive DD led me to facts about #Vascepa and $AMRN I summarized here, with a deep dive on placebo: Seeking Alpha article on AMRN facts Why do you think Dr. Bhatt and I and many more are wrong?
PantherFan? @PickingMyOwn 6h6 hours ago
Replying to @adamfeuerstein @chas1232123
Charles I sometimes get irritated at AF too but I don't get what you are on him about? He's a fan of $AMRN and thinks a B/O makes sense. He is skeptical that JT was engaged in negotiating in SF. So why is that offensive?
1 reply 0 retweets 2 likes
Charles Crosby Lyon? @chas1232123 2h2 hours ago
If $PFE doesn’t buy $AMRN, it won’t be because of JPM. AF downplayed #AMRN ‘s confirmed #Vascepa breakthrough, severely over-stressing very minor placebo concerns. Understandable error, but instead of correcting he endorsed the indefensible Herper hit piece, and more jabs.
AF has a poli-sci degree. I'm guessing the poli doesn't stand for polite, and the sci doesn't have much to do with real science.
Several factual errors in the PMLive article. They say V rivals Repatha, when V clearly beats R (NNT 21 vs 67). They also understate RRR for heart attack and stroke as 25% (the MACE number, which is lower because it includes CV death).
KIwi - "for patients with a rare and fatal heart disease "
Not really relevant to discussion of protection against the leading killer of human beings.
"Not one word on MO"
It was never a real thing for anyone who did serious DD.
North - Thanks. I'll call that a typo, since they listed it as the number of enrollees and didn't mention the correct number.
PE - I believe the intent of slide 9 from the JPM deck was, as stated in the first line, to show that V benefit was largely independent of trig level, which strongly suggests V would benefit patients with a wide range of trig levels, including those below the RI lower limit around 135. JELIS results also support that, as do MOAs unrelated to trigs.
I believe similar reasoning supports V for those not on statins. That could be confirmed by plotting risk reduction vs statin dose and extrapolating beyond the lowest statin dose. Similar benefit for high or low dose statin would be pretty compelling.
Amarin has a lifetime total of 67 tweets, a handful of them on Nov 10 and only 9 since then (two of them retweets without comment).
Their media relations is pretty feeble.
mass - 19,212 enrollees? Typo?
gg - The idea of pitching a story to 60 Minutes and other media would not be to complain about past FDA actions (imperfect as they were, particularly in terms of keeping Amarin informed as required by law). The FDA is an 800 pound gorilla Amarin needs to work with, and there are certainly downsides to poking at it.
The idea would be to try to promote wider reporting of the very positive news about REDUCE-IT and Vascepa's proven ability to save lives and prevent suffering. It would be appropriate to mention how many lives can be saved daily/monthly/annually and the motivation to get that benefit started as widely as possible as soon as possible, by expedited approval, which there is every reason to expect, and by off-label prescriptions in the meantime. It would not be helpful IMO to point out how many lives the SPA rescission cost, although a bunch of us have opinions about that.
I would stress the strong benefits across all subgroups, which suggests benefits beyond the RI recruitment criteria (e.g., trigs below 135, and possibly those not on statins, although more data would make that clearer). Dr Bhatt just tweeted he expects benefit for patients beyond the RI recruitment criteria. I believe that's true, and confirmable pretty reliably by extrapolating from RI data. Dr B may be hoping for additional trial(s) I prefer not to wait for. (Not clear how major new trial would get funded with generic coming in 10 years.)
I also might try to get in a mention of the many potential benefits of the proven inflammation reduction, and it's tempting to mention the widespread convincing, albeit informal, reports of alleviating DES, although the proven RI results are by far the primary point, and it's important not to dilute the unassailable credibility of the RI results.
re smartkarma article - I'm way too cheap to subscribe to smartkarma ($7500 annual fee), but the first part of the article that they offered as a free teaser seemed pretty good and included an intriguing paragraph:
"Stock Plunges Due to Concern Over Placebo Used in Reduce-It Trial: Just 16 minutes into the Reduce-It trial results being revealed at the AHA conference last November, Forbes published a "kill" story on the trial outcomes. The Forbes article (here) claimed that results were not trustworthy (quoting doctors in charge of clinical trials for a rival drug), as the mineral oil used in the placebo arm of the trial impacted statin absorption. This sent the stock plunging by -26% in the following two days after the conference. Below we discuss why these concerns are misplaced"
The reasons why were not included in the free sample, but already thoroughly discussed here. Interesting to me they called it the Forbes hit piece (absolutely true, AF was disappointing but much less bad) and I hadn't realized MH published so quickly, without including the in depth Nov 10 evening Amarin presentation or Dr Bhatt's video interview recorded ~5 min after his presentation. Even allowing for the desire to release coverage immediately on Saturday Nov 10, it was inexcusable that MH didn't update and correct it before Monday. His follow-on article wasn't until Nov 20, and still didn't get it right.
dm - My opinion was that MO did not play a role in the Citi analyst, or any other diligent analyst, downgrading AMRN, because it is far too bogus an issue. I posted my disagreement with JM about why Citi might have downgraded.
bullish - Anywhere under $15 is crazy cheap IMO as a long term play.
JM - "Citi ... downgraded the stock in mid Nov from buy to hold because they heard about the MO in my opinion"
No analyst could think MO is a significant issue if they had a remotely scientifically literate junior staffer spend an afternoon taking a look at the facts.
Jeffries has had analyst articles very bullish on AMRN. The most recent one was quite extensive and I don't believe it even mentioned mineral oil.
My seeking alpha article summarized the MO info. Here's another similar article I wrote that's not paywalled:
Vascepa/AMRN article
Could - no response from AF, but I did end up having a nice chat with an enthusiastic Amarin long who gave me a call.
I'm not done with AF, and much more so, MH. The record needs to be set straight.
We’ll see how it goes. She has worked with reporters at Financial Times of London, the Economist, WSJ etc in the context of Fortune 100 companies, doesn’t really have contacts in network TV, but she has skills and we’ll give it a try.
The 50% growth is without counting on anything from the RI results, which are the primary reason to be exited about the stock.
For years I've thought the Amarin saga would make a great story for 60 Minutes or 20-20 or a news show. Much more so now. I'd love to see them interview Bhatt and talk about how many preventable events since 2013, and how many more every additional day that goes by. It would drive the point home to talk to a little girl who lost her dad a couple years ago, and a stroke victim struggling to get a few words out about how maybe V would have prevented it.
Besides increasing the already decent odds of expedited review, it would goose off-label use and stock price big time IMO, if they came anywhere close to getting the facts right.
Anyone got media connections? My wife is a media-relations professional. The key is subtlety, not being over the top and angry, coming across unbiased and credible, and doing most of the reporter's job for them so the path of least resistance for the show is to do the story. Hard part with a big show like 60 Minutes is they probably get a million proposals so tough to stand out and get a proposal even looked at by a low-level staffer who might hand it up to a decision maker. It's a long shot but I may give it a try.