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Thinking about AA/EPA and Jelis/Reduce-It and I have a question.
Saw a post by JL highlighting the fact that Reduce-It patients have a really high AA/EPA compared to Jelis subjects. Of course then the idea is that 4 gm of V can bring that AA/EPA level down to levels of the Jelis patients. But here is a thought.
Those Jelis patients had their AA/EPA low for most of their lives long before joining the study. In the case of Reduce-It where the ratio gets reduced during the study does that fully override or negate the fact that these people for most of their lives had high AA/EPA? In other words is there lifetime damage that is really not reversible in 2 or 3 years?
Who wrote that article. I know it gives a name Jason Shepard, but very poorly written.
He is certain that Amarin WILL GET label expansion and confuses the China deal by saying the company had to "add 15 million"..
ZU, no doubt you are right. See the rates amongst various peoples:
http://www.cdc.gov/cancer/prostate/statistics/race.htm
Not to mention that the vast majority of prostate cancer is slow growing and most will die from something else. Not a biggie.
As some often opine about the EPA/AA ratio, I believe that was not determined in this epidemiological study. So people could have also been eating a bunch of other types of oils that are possibly the culprit.
I think one can confidently say that Omega-3's and in particular EPA are good for people. Now whether they can show a significant decrease in cardiovascular events to really impact lives is what we are waiting for.
Of course this is not strictly related to EPA but omega-3s and it only showed an association and not cause. Too many variables to lay too much into it:
http://www.cancer.org/cancer/news/omega-3-fatty-acids-linked-to-increase-in-prostate-cancer-risk
While more nutrition education for physicians is long overdue for pete's sake just send them a cheat sheet so they can rattle off oily fish names.
Dan,
I think yours is the most cogent description of what transpired.
Whalatane,
Thanks for the link. Concerning your concern in relation to the lower LDL values in Reduce-It subjects, I follow your logic (even though it is but one factor) and think the situation sort of in relation to the law of diminishing returns. What I still have a hard time to sort out, is all this information has been out for some time so why could not the company and its supporters pound the table like this a year ago?
As to your idea that Reduce-It subjects more closely resemble the coronary interventioned group in Jelis, when do we find out (or has it already been disclosed) the breakdown of the type of patients in this study? When study results are released upon termination of study?
Such tremendous exuberance and confidence since yesterday is beginning to give me pause.
I have read and reread the Jelis study and a few questions or thoughts come to mind. First, can anyone elucidate as to whether there is any implication of the fact that Jelis was open label whereas Reduce-It is not?
My mind says that when considering that the subjects in Jelis - they consumed more EPA naturally in their diet than those in Reduce-It - would not have had as much of a bang adding 1.8g EPA to their already higher consumption as theoretically subjects in Reduce-It would be getting taking 4g.
On the other hand I am a little more cautious as in all cause mortality the EPA arm did not do better than placebo. Now taken as a whole the EPA arm did significantly show a 19% reduction in coronary events, but most of that was a huge improvement in unstable angina.
My bet is on Vascepa showing benefit in Reduce-It, but I am not as wildly confident as almost all the posts here the last couple of days. Even with great results in the trial there will still be a lot of work ahead for the company to make this a financial success.
Zu, don't know the full answer to your question but my first thought is that it would apply to the control group as well as the Vascepa group.
Of course we are just talking on a Sunday, but very few I know would complain with a triple overnight.
Not only would we still have to sit and wait for a couple of years before results, one truly never knows for sure the outcome of these binary events. If a positive result in Reduce-It was so certain we would not be sitting at the price we are.
And, some of us are up there in years so a quick payday works, rather than a big gamble albeit with potentially greater rewards.
Whalatane,
I think your guideposts vis-a-vis stopping the trial at interim are on target. Your point about the pps being cut in half if trial is not stopped at interim depends on what the stock price is at that time.
Don't think 1,50 would be cut in half. If pps was sitting at 8 to 10 then no question that would be a very strong probability.
But I think that is inherent in all clinical trials (depending on the phase obviously). Late stage trials will measure efficacy at interim so Reduce it is no different. The monitoring committee can stop the trial for safety reasons and also in conference with FDA and company the trial can be stopped because of either futility or tremendous success where it would be deemed ruthless not to put everyone on a beneficial treatment.
GG,
My english teacher may be really upset with me about my lack of comprehension, but when I read what you posted in terms of what Amarin said about Reduce-It I only understand it as a statement of timetables and facts concerning the study and don't see anything there that would speak to what type of confidence the company has with regards to the study results.
Maybe there is something I am missing and if so would appreciate you highlighting it to me. TIA.
Could, a number of reasons exist why they might not release preliminary data.
Actually a good discussion of things to consider here:
http://www.nature.com/news/fda-debates-trial-data-secrecy-1.15633
Zu,
Well, I hope it plays out that way but not that interested in a crap-shoot. I am sure data is being collected on all patients in terms of their medical conditions and medications that they are taking.
Just hope it does not come down to something like them having to do sub group analyses to show benefit in a subset and then everyone screaming - data mining.
Zumantu great piece. Now the question to Amarin is whether what is stated in their conclusion ("that this information will help reduce the flaws at the study design stage of clinical trials regarding the PUFA supplementation") was/is incorporated in the Reduce-It study or whether as the authors indicate in their paper results will be equivocal and hence not show the benefit this board expects?
Got meeting notices in the mail yesterday and not happy at all about the reverse split proposal.
Unless you are profitable the reverse split makes it worse. I wonder now if knowledge about this for the past few months has been one of the reasons the stock price has been so badly beaten up.
Good post Fishy.
Thanks. Interesting as it was not intended to show results of anything other than that 4gm of V does not affect the pharmokinetics of the statin.
Why not much discussion of various gene variants (some already found like 9p21, and unfound ones) that probably play a very big role in cardiovascular disease?
You are right, although I don't know if there exists some studies (obviously not done by Amarin) that have already shown HIGH trigs tied to CVD.
To add to my original post the first statins approved were for those who already had had a stroke or heart attack or existing heart disease. No proof of efficacy in those without existing heart disease.
But again as we saw with the Keys studies, valuable info can be omitted (like he did) and over the years we have heard about the fact that studies showing the opposite of what pharma wants to show are buried and never see the light of day.
You have to remember that the first statins that were approved were approved because they showed they could lower cholesterol numbers. They weren't required to show improvement in cardiovascular outcomes. Now as far as in the more recent years I will leave that up to others who are more knowledgeable than I in that regard.
HD, maybe a stupid question but
Is the P value affect by time? At the interim the study would not have been proceeding for as long as the end of the study obviously and would the aggressive value mentioned .001 be very hard to attain at interim?? but more attainable at end?? TIA
That is why I am long the stock.
As some posters have already noted in response to your post, there are very few leaked study results in blinded clinicals. Once the data is collected and compiled there is always a minuscule chance that someone finds a way to know the results (usually not us common shareholders).
On the other point you made, no one has really commented. That being price appreciation related to speculation of success. Obviously the largest part of the market does not believe Reduce-It will bear fruit or the readout is still too far in the future for people to stake out positions that would raise the pps.
But we here on the board have been regularly inundated with study after study that would lead us to believe that Reduce It will be successful, so if the inferences about these are correct you would think this should ultimately lead to some price appreciation speculation. Of course so many of these posted studies show how EPA works affecting various parameters, but will it change outcomes in humans?
Whalatane,
In one sentence (along with the couple after it elaborating) you have succinctly described the whole ball of wax here with Amarin.
Proceeding along a path with the blessing of the FDA that all that was needed was substantial enrollment in Reduce-IT only to have it snatched away with inkling.
Now there may be some truth to the NCE designation obstacle (in relation to GIA) but I personally would say I would be missing additional information to put too much into it. First, one would have to know that AMRN was interested and would have been actively seeking some partner or buyout (I know JZ stated he was exploring everything) and then I would have to know for a fact that big pharma would absolutely need exclusivity to join the fray. So yes NCE may have been a key but no doubt without question the nail that shut the coffin was the ADCOM.
Thanks Jesse,
That implies that it is the best marker yet found in relation CAD. Good thing Vascepa helps lower this guy for sure.
Anyone know how this marker ( Lp-PLA2) differs in terms of its predictive power compared to the C-reactive protein test? TIA
Agree fully with that methodology of PRs. Worry if sales people make the claim without prior FDA approval. But putting out the info via PR should be perfectly fine.
Agree in principle with both of you. However, do you think we should run it past the FDA first as they decide what are legal marketing claims?
I wonder if most of us will need them.
From the discussion it appears that there is a divergence of opinion among the decision makers about whether CV outcomes need to be proven before drugs are approved. In this case it appears that those who wish to see that were outnumbered.
As (luck, fate, etc whatever) would have it that was not the case with Amarin's Adcom and reading these kinds of stories just feels like someone is twisting the knife already plunged into our guts.
Sorry I got that backwards.
So am I right in saying that it is primarily or only the LDL particles that we need to worry about size?
Or does the reduction in size of the VLDL and HDL cause any concern? Can't they get stuck in and around the vessel wall?
Any concern with the increase in LDL particle size? Or is that offset
by the decreased size in VLDL and HDL???
under a buck is the line not 3 bucks.
You can say that again. Wouldn't be great if the government would force people to buy the stuff I sell. Would be great for business.. for sure.
Stupid situation where the rest of the advanced world has pretty much figured out health care but our entrenched system can't be changed. American exceptionalism on display.
Apologies if this has already been mentioned
But I came across an interesting post on another message board that highlights that in the
IMPROVE -IT trial triglycerides as well as LDL-C were lowered in the drug combo group.
The author's point (or at least suggestion for thought) is that possibly the benefits seen in the study could be not only due to the LDL-C lowering but also/or the trig lowering, which might bode well for Vascepa in the Reduce-IT trial. Anyway here is the post:
http://www.investorvillage.com/smbd.asp?mb=2294&mn=1662&pt=msg&mid=14398093
I am pasting the post below but unfortunately the paste does not show the graphs he posted.
The million (no, billion) dollar question
This week results from IMPROVE-IT were released. The trial enrolled 18144 high risk patients and observed over 5000 events. It was able to detect a very small (“modest”) outcome benefit by the addition ezetimibe to statin therapy.
This modest benefit, as measured by a decrease in cardiac events over 7 years in a huge trial, was attributed to the LDL-C lowering effect of ezetimibe. In addition, many claim the trial “confirmed” the LDL-C hypothesis: the lower the LDL-C, the better. Hard to argue with that conclusion (but I will) considering that the control group (just statin) had incredibly low LDL-C and the ezetimide group had even lower LDL-C. In the words of the lead researcher, Dr. Cannon: “We took patients from a clinically appropriate target LDL-C to even lower. We now have solid evidence that lower is good, and even lower can be even better”.
Seems like common sense that the reduction in risk is attributed to the further reduction in LDL-C that the ezetimibe group realized. But perhaps there is more to the story.
It is generally recognized that most of the benefit of lowering LDL-C is achieved in the population of those who have high LDL-C. The CTTC meta-analysis suggests a diminishing benefit with lower baseline LDL-C. There were very few (if any) data points on the lower end of the curve below to demonstrate that there is not a point, below which, further reduction in LDL-C is beneficial. Cannon’s statement is basically saying “we provided that point”.
But there is something else interesting (and relevant to AMRN shareholders) about the IMPROVE-IT results: Not only was LDL-C lowered in the treatment arm, but trigs were lowered too.
Yet the benefit of ezetimibe is attributed (by virtually everyone) to the fact that it lowered LDL-C.
How do we know it’s not due to the lowering of trigs?
Maybe, just maybe, there is no benefit to further reducing already low LDL-C. There was no enrollment requirement for trigs, perhaps the benefit is attributable to trig lowering in the high trig population. And perhaps that modest benefit was only observed because of the very large size of the trial.
One way to shed light on this, of course, is to look at a Forrest plot for different values of baseline trigs. Was the benefit observed in the high trig sub group? We don’t know because that data has not yet been presented.
When you look at similar subgroup data (high trig) from the 3 trials the FDA used to shoot ANCHOR down (AIM-HIGH, HPS2-THRIVE and ACCORD-LIPID) you see, in each one, suggestion of greater benefit (though not SS) in high trig populations. And, while it’s risky enough trying to interpret sub-group data, it is extra questionable when the subgroup data come from failed trials (trials not meeting their primary endpoint). The FDA, in particular, does not like to do that.
But here, for IMPROVE-IT, we have a trial that did indeed hit their primary endpoint. Unfortunately they have not presented the subgroup data to see what effect reducing trigs had on the high trig subgroup. Sure would be interesting to see.
Maybe its nothing.
You guys are both right. Something causes or triggers the inflammation. The body's response to the inflammation includes packing cholesterol onto the site which in turn narrows the clearance through the vessel. But, taming inflammation (even without knowing or attacking the "cause" of the inflammation), appears to reduce harmful CV events. As evidenced by Jelis and a reason for measuring CRP.
Can we easily agree that insurance companies do indeed deny claims?
If so my only logic is that they are in the business to make money for themselves (albeit providing a service like many other businesses in many other fields). I have yet to hear a plausible argument showing that denying claims loses them money, so denying claims must make them money?
The answer to your question is one word:
Money