You guys are 100% getting played. Did you REALLY think you stumbled across some secret doc when you found the PUBLIC LLC info?? For real? You didn’t think they knew exactly what they were doing when they used the name Steven Giardino as the ONLY named member? That with just a little effort you AMRN flongs would find it? Lol, I mean cmon.. This is clearly a well planned campaign. They obviously used my analysis, at least on the study. Maybe that is a real person listed as a member that was paid, I don’t know. But they’re doing exactly what I did--fooling you. I don’t and never did own Finishedworks or live in Albany. I met AVII once for dinner and drove back down to NYC. I even use an Albany proxy IP address on these sites. The best way to keep yourself from being found is to pretend you are someone else, not hide yourself. But as I posted before, which was supposed to be my last, I realized something--I have better things to do with my time.

I just realized something profound.

This will be my last Ihub post. Actually, my last stock message board post. And I don’t mean I’m gonna create other aliases and badger you all lol.

I hope AMRN makes it. I hope the mineral oil issue is a non-issue, and that EPA works fab. I hope this turns out to be something great, and maybe AMRN can rack up some dough and acquire the small private co that owns this synth EPA analogue:

https://www.ahajournals.org/doi/10.1161/circ.136.suppl_1.16580

Or grab EPA from GMO crop, as Sonam pointed out.

I’m in a great spirit, and can’t shake it. Life is amazing.

Cheers all

Oh, well hey good luck, hope you make bank.

Cheers

Stacc, ask your cardiologist if it’s bad if the followed occurred:

-While on moderate intensity statin therapy your LDL-C dropped from 106 to 86 (Hopkins) and your hsCRP went from 3.2 mg/L to 2.1 mg/L. Your apoB also went from 95 mg/dL to 83 mg/dL. It was stable there for years

-Then you started taking this supplement with your statin and at 4 months had blood work done and noticed your LDL-C went up to 93 mg/dL. You didn’t check your hsCRP or apoB at that time.

-You maintained your regimen, taking this supplement with your statin, and one year in you got your bloodwork done again, this time with hsCRP included, and noticed your LDL-C was 94 mg/dL and your hsCRP was 2.9!

-Undaunted, and because you loved the supplement so much, you kept taking it. 2 years in you had bloodwork done and saw your LDL-C was now 95 mg/dL and your hsCRP was 2.8, and your apoB (tested this time too) was 89 mg/dL.

What would he say about your increased risk? And what would he say about the supplement?

What if you also got a full panel done at month 4, and realized your LDL-P had jumped 11%, oxLDL went up 11.3%, and VLDL-C went up 15%? (changes in MO group in ANCHOR).

Ask him/her and report back please and thank you.

Sincerely yours,
Pyrr

Sorry KCSVEN, once again I am forced to correct you :)

The meta-analysts you are referring to primarily examined all-cause mortality and CVD in high vs low statin therapy trials. It also included other studies that were add-on to statin therapy (PCSK9 and ezetimibe). They found a sig diff in favor of greater intensity therapies. Then the performed a subgroup analyses and found those with a baseline of 100 mg/dL or greater achieved significance, but those less than 100 mg/dL at baseline did not.

Look at what they found for MI though:



https://jamanetwork.com/journals/jama/fullarticle/2678614

Note that all cause mortality is rarely very significant, or sig at all, in CVOT studies, and I won’t go into all the reasons why. That list includes R-IT btw.. On CVD, the problem is the presence of the massive ezetimibe study skewing data to the negative in low LDL-C quartiles examined. It and the PCSK9 studies they included are irrelevant to our discussion. The only relevant studies here are pure statin trials, in particular high vs low dose. I hope you get why.

Lastly, I am actually contending R-IT subject technically had LDL-C > 100 at their pre-statin baseline. Not much more of course, but more ;)

Cheers

(Ps a 2010 study is not “old”, lol..)

Lots of things can cause an outlier effect, that’s why it’s best to view data as a whole, especially if the group is robust in size. It substantially controls variability.

As a whole the placebo group saw very significant jumps in all inflammatory markers. And it appears their mean LDL-C was probably ~106 mg/dL before statin therapy, which became approx 86 after therapy, and then retraced to 95 mg/dL on avg due to (imo) mineral oil inhibiting statin absorption. Based on this it appears ~50% of the effect was lost. But it in fact is more than that, as there is a substantial amount of diminished returns with LDL-C reduction from low vs high dose. For example 80mg atorvastatin results in a 50% drop on average, while 10mg (1/8th the dose) results is ~35% drop. It has a lot to do with the already low bioavailability of the statin.

What you do notice though is a very large diff in hsCRP reduction from low to high dose atorvastatin. 10% vs 40%, roughly. It tends to match the mg more closely. 10mg = 10% drop, 20mg = 20% drop. 40 and 80 however are similar in effect on hsCRP, which can be 40% or even much higher.

Then we look at R-IT data and ANCHOR data and it follows this theme.

And what do you think? Will FDA ask for a DDI study to be conducted to rule out interference with statin absorption, like they have requested be conducted for Lovaza and Vascepa pre approval? If they do, do you think that will impact the pps of AMRN’s stock? And what would happen if the study produced data that showed mineral oil in fact did adversely impact the AUC or Cmax of exposure to various statins? What would happen to AMRN stock then? And would FDA not care and go ahead with the approval anyway?

Oh, well now all you need to do is find lots of low, moderate and high dose studies where end of treatment LDL-C is = to baseline R-IT values (range is fine), then record the baseline in those studies, then proportion these based on the ratios in R-IT (6% low, 62% mod, 31% high), calculate the mean, and voila—106 mg/dL.

Innnnncorrect sir!



(I mean, just look at the title of this well known paper):

https://www.jwatch.org/jw201012160000001/2010/12/16/statins-sharply-lower-cardiovascular-risk

I did all that one handed while feeding a baby btw :)

The rest of your post is irrelevant due to your incorrect premise, unfortunately.

Cheers

HD, you probably don’t know that atorvastatin 20 mg is considered moderate dose, 10 mg or less is low, and 40 mg is considered high. But you do now.

70% in R-IT were on on atorvastatin 20 mg/d or its equivalent, or less. 30% were on some mix of 40-80mg and its equivalents. And more on 40 than 80, considering current guidelines.

Cheers

That was all a very fun walk through the weeds, but they already stated after the study reported results that compliance was surprisingly high. That likely means > 85%. So...

SVEN, you’re way off. I already cited the data, go back and read it. For example, low to moderate dose statins have ~30% LDL-C lowering capability on average. 70% of R-IT was on this intensity. Only high intensity can cut it 50% or more. And only certain patients are prescribed these. There is a definite protocol to all of this.

When LDL-C levels are already <100, the effect of statins is lessened, but still impactful. Low-moderate cuts about 20% in these. Also, given the high number of T2D patients in the trial, this makes further sense. They are all required to take statins if LDL-C is > 70 mg/dL. So, doesn’t need to be very high to have the scripts written. The average baseline LDL-C of the R-IT population prior to their taking statins, all things considered (which may have been a few months before R-IT or years before) is therefore calculable. And is probably no more than 110 mg/dL. Thus the drop to 87 mg/dL (Martin/Hopkins) represents an approx 20% decline, and the retrace to 96 represents a massive loss of the statin efficacy, in avg.: a 40% retrace.

Also, you conveniently said nothing of hsCRP. Did you notice in CANTOS (which, btw, had a very stable LDL-C in both groups with an ~85 mg/dL baseline, well controlled LDL-C, just like R-It, and remained unchanged all the way through the study—a much more relevant example than the Odyssey one you guys like), hsCRP was well correlated with MACE risk, despite everyone having well controlled LDL-C? A diff of 37% between groups with treatment group just barely achieving hsCRP of 2.0, (placebo in mid 3s), correlated with a 15% RRR?

So let’s put it all together. The LDL-C retrace of ~40%, but still < 100 mg/dL LDL-C, confers anywhere from 8%-12% difference in risk, and elevated hsCRP in placebo group confers an additional 10%-15% increase in risk, on TOP of the LDL-C increase in risk. Net net this study may very well have failed if not for the adverse impact of mineral oil on statin absorption in placebo group.





Jmo

Yeah, I had guessed > 85% based on those comments.

I doubt that shows anything compelling, otherwise we would have seen it as an excuse, rather than the lame post hoc “patients with increased LDL didn’t do worse” nonsense :)

Cheers

One thing is very clear to me after reading your posts—you do not have a good understanding of the FDA, their review process, or their tendencies. And that’s fine, most have no need to be, but if you are going to hold AMRN shares through their PDUFA in early 2020 (or late 2019 if priority review), you’d better familiarize yourself.

GL chuck :)

One more for good measure:



I think the only way you’re going to get such huge RRR (25%+) with anti-inflammation or additional LDL-C lowering therapies is... if you block statin absorption in the other group ;)

AVII, another point on log-transform. I don’t know that FDA will accept it. Recall the Epanova data, the percentages in the study using log-transform, and they just threw it right out.

You might also find this interesting:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120293/

It’s also compelling to me that there was so much stability in the values through years on in the R-IT study. This to me flies in the face of the “massive variability” claim. With so many subjects, I’m sure that helped. Reminds me of the stability of hsCRP data in JUPITER:



Note this interesting mention in the paper:



https://www.nejm.org/doi/full/10.1056/NEJMoa0807646

Also of note:



Later data would confirm this. Among subjects with low LDL-C but elevated hsCRP >/= 3.0 mg/dL, the risk of MACE jumps over 40% vs lower levels of hsCRP.

Note that FDA expanded the label for rosuvastatin after this study for subjects with hsCRP > 2.0 md/L. They did this using figures from the study, regardless of what log-transform might show. In R-IT, and I think because of mineral oil placebo, that group’s hsCRP rose to near 3.0mg/L. V arm remained near 2.0, and EPA probably did have a modest positive impact on it. But as seen in JUPITER, the values for a very large group remain mostly constant over time. That should have been the case in R-IT placebo group. Instead they saw a massive 32% jump through year one, and it remained approx that elevated til the end of the study.

I’m back to thinking R-IT really may have been non-significant had it not been for that placebo choice! Lol.

Ah well who cares?

Cheers

Oh I see it there, the mention on 2g/d group. Interesting! Wonder why FDA only focused on the 18 in 4g/d group..

Still think the size is too small to draw any conclusions (of course, right?). At least admit you’d say the same about conclusions drawn on DC therapy with an n that tiny lol.

You’re most welcome lol. Ah reminds me of the jmlogan days..

Could you elaborate on that? As far as I can tell there was only one placebo group and those given 2g/d EPA knew they were only getting 2g/d. FDA confirmed only 18 also when they said:





No I meant the mention I just quoted above. Sounds like FDA isn’t compelled or assuaged at all by the MARINE trial example.

Wrt Odyssey the changes affected both groups and took years to come about. That looks like classic regression to the mean. In ANCHOR and R-IT however the jumps occurred only in MO group, were highly significant, and immediate. That looks much more like a treatment effect of some kind.

Rats given 1-2 mL is a lot relative to their GI track size, but it does show cause. And dose response cause. Everything starts there.

I’ll admit it’s probably the best anyone who is seeking to prove MO doesn’t block statin absorption can produce, but I don’t think it’s a strong case. It’s 18 subjects, and at least one did see a 32% jump in LDL-C (one had a 30% drop to be fair). Did you read what FDA stated when they viewed the same data? It sounds to me like they’re saying no conclusions can be drawn about the small sample.

On the other study the 7% jump in LDL-C was insignificant. The study was also only adequately powered to show 20% change in LDL-C or greater. The 60% jump in hsCRP is large, but again the sample is small. Hard to draw any conclusions from the 80n arm.

Compare that to the massive R-IT with extremely significant changes in inflammatory markers in short order in MO group, and the relatively large ANCHOR that showed the same (very similar % changes also), very significant (p<0.001 across board) jumps in inflammatory markers in MO group. And then the small study I just dug up. Plus this data:



Inhibited in a dose-response manner too.

It’s really hard not to conclude there’s an inhibition of statin efficacy.

I think AMRN will be required to run a DDI by FDA. I think it’s unavoidable really.

Jmo

AVII, you know I love ya buddy, but is this it?

It has nothing to do with being a gentleman. It’s just savvy not to. Whether it’s discussing AMRN or any other company.

I remember a guy who works for Merck (low level position) that posted an article negative on NWBO’s DCVax-L. He wasn’t savvy enough to use a fake name, thinking he could just engage in good ole honest discourse. Well, when people have money on the line they get weird (suspicious, paranoid, etc.). The longs harassed him and harrassed his employers about him. Calling his work, etc. Lynch mob stuff. He actually could have pursued criminal charges against them, not sure if he ever did.

Anyway, best to just avoid all that headache.

FDA is plenty concerned already. They charged the DSMB with monitoring levels in mineral oil group (even though they ended up just the same as in ANCHOR, which data concerned FDA to begin with lol), stated treatment effects with Vascepa may be overestimated, and now we have REDUCE-IT researchers saying it may have in their study too—to some unknown degree.

If it’s one thing FDA absolutely cannot tolerate it’s ambiguity. I think they’ll request a DDI study. It looks like they required it before approving Lovaza or Vascepa initially anyway. Why won’t they ask for one to prove mineral oil didn’t inhibit statin absorption? I think they may actually view it as a necessity from a public health standpoint.

Ok my friend, I’ll hold off.

Interesting counterpoint, though no one is taking issue with MO impacting lipid/lipoprotein levels in and of itself, but rather its potential to inhibit statins, thus affecting levels indirectly (I know you know that, but the quote spends a lot of time “missing the point” imo). The relevant part and I think best point was:

That caused FDA to say they were “somewhat reassured,” though with caveats:



I do agree in general investors should stick to investment forums for debate, and leave the medical community, and especially patients, alone.

That’s not correct. Actually I cited a study in a previous post that accumulated data with thousands of patients per arm and showed very predictable avg % drops in those on various doses of various statins. There is a paucity of data on LDL-C reduction in those with levels around 100 at baseline, but it is out there. Comparatively it is a less robust decline on 10-20 mg doses of atorvastatin and other low doses of other statins. It’s simple deduction from there. 70% took equivalent to 10-20 mg atorvastatin and 30% took 40-80 mg in R-IT. That’s not debatable. All had to have LDL-C between 40-100 mg/dL at baseline. The median and mean around 75. Also not debateable. Boom. It’s easy from there. Pre-statin their LDL-C mean is near 100, and hsCRP somewhat > 3.2.

Thank you! Exactly. That’s what I’m asserting is normally the case.

Okay, I don’t have Twitter, but I’ll sign up and direct some questions to him. How do I do it? Do I just go to his account?

That’s true, but we know from ANCHOR SPA rescindment just how “binding” that is. When new data come to light it can and does change FDA’s opinion about things. Plus, when you say “FDA agreed to the MO placebo” you really mean (whether you know or not) that the reviewer(s) given charge over examining their SAP and in granting the SPA had no issue. The approval of drugs is far more arduous and involves many more FDA personnel and higher ups. Just because one less arduous process said “MO okay” doesn’t mean the much more arduous process will also say “MO did not inhibit statins to any meaningful degree.” In fact there are multiple examples of FDA taking issue with a trial design after allowing a study to commence. They have even put holds on trials due to problems with design even tho they allowed them to commence after one or more FDA reviewer had examined the design, lol. When saying “FDA” we’re not referring to one king or anything. Lots of moving parts/levels of review.

Btw, it was only in late 2013 after FDA really dissected and agonized over ANCHOR data that they made this statement:



But at the time 6,000 subjects were already randomized into the study. So they decided to just charge the DMC with monitoring lipids. But DMC wasn’t likely to raise any flags unless they saw something incredibly obvious like > 40 mg/dL jumps in LDL-C. And too, just because the DMC didn’t recommend the study be halted for safety doesn’t mean FDA won’t take issue with data. Think of all the studies that the DSMB rec continue but that during review FDA said no bueno due to excess SAEs in treatment group.



It seems that MO may block 50%-70% of the absorption of statins. In which case the REDUCE-IT study becomes effectively a “moderate to high-dose statin therapy + 4g/d Vascepa vs low-dose statin therapy” study. Even if Vascepa is totally ineffective, a study like that would be expected to show a 10%-20% RRR for the group given higher intensity statins. You don’t necessarily need to see a 1 mmol/L LDL-C difference either. In a number of those studies the diff was closer to 0.6 mmol/L. And as I showed, patients with lower baseline LDL-C see less of a drop than those with higher baseline LDL-C, but hsCRP usually remains as dramatically impacted in CVD patients.

Actually the 11 point jump in LDL-C at peak in mineral oil group in R-IT was probably much higher in high-intensity statin subjects with higher baseline values. But even the 11 point spike could mean a 50% retrace for patients that saw their baseline LDL-C of 100 go down to 80 with moderate intensity statin and then back up to 90 due to statin inhibition. When you look at ALL of the values it tells a bigger story (and FDA will have the complete breakdown):

ANCHOR mineral oil group changes vs baseline:

TG: +5.9%
LDL-C: +8.8%
LDL-P: +11%
oxLDL: +11.6%
Non-HDL-C: +9.8%
VLDL-C: +15.0%
Apo B: +7.1%
hsCRP: +17.1%
LpPLA2: +6.7%
Tot. Chol.: +9.1%

REDUCE-IT mineral oil group changes vs baseline at next blood panel:

TG: +2.7% (note that subjects in R-IT had lower avg TG levels at baseline than those in ANCHOR)
LDL-C: +8.7% (very similar!)
LDL-P: ?
oxLDL: ?
Non-HDL-C: ?
VLDL-C: ?
Apo B: +7.8% (very similar!)
hsCRP: +32.3%
LpPLA2: ?
Tot. Chol.: ?

Also relevant is that when statins are given in high dose there is an initial drop in hsCRP in just a couple months, which grows and then stabilizes after 6 months. See that 17% jump in ANCHOR after 12 weeks? Then the 32% jump in R-IT after one year? Makes sense if in effect the mineral oil group subjects had their statin dose cut by 50%-70% due to malabsorption. You’d likely see a similar change and then stabilization over time.

Also note the various established recommendations now for hsCRP to be <2.0 mg/L. There is a great increase in risk of MACE in those with hsCRP near 3 vs under 2, regardless of LDL-C differences. FDA is well aware, and are perhaps going to be even more concerned about that. And look how consistent the value stays! Just like in JUPITER...



FDA will definitely ask tough questions, but they will be directed towards Amarin, the sponsor. And I personally think they will require a DDI study.

Maybe I’m wrong, but I think I’ve got a point here.

GL

I know two people that did (very respectfully) and he blocked them.

Here we go—a study like this except testing concomitant administration of mineral oil w/ statin:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281350/

Why wouldn’t FDA require that of AMRN? Appears FDA made GSK and AMRN already do these studies with Lovaza and V pre approval. Makes sense they would request one be done with mineral oil before expanding the label for V.

Don’t worry, FDA will inquire and get all the data I’m sure ;)

Subjects with established CVD and > 50% stenosis are definitely on statins.

I found another study in CVD subjects that showed 4g/d mineral oil placebo caused a significant jump in LDL-C and hsCRP (not to mention a drop in apelin):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175591/#!po=1.13636

LDL-C jumped 9.43 mg/dL and hsCRP jumped 0.68 mg/L. Very similar to R-IT placebo group, and it happened in just 8-weeks and after a washout period. That’s another confirmation FDA will probably look at.

Patients prescribed omega 3 that are are also on statin medication are told to take them with the statin. There is evidence of some additional benefit when taken together (see COMBOS trial).

This is interesting btw: numerous studies were done to determine if 4g Lovaza taken with statin would inhibit the absorption of the statin, and showed no inhibition:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021654s041lbl.pdf

I still think FDA will require AMRN to conduct a similar study as the above but replacing Lovaza with mineral oil. That’s why I’m gonna straddle/strangle options through PDUFA.

“In-vitro” lol. Do you know what that means?

Here, I’ll share another in vitro study on EPA and oxLDL:

https://www.ncbi.nlm.nih.gov/m/pubmed/21822944/

If you don’t know, that’s bad.

My credentials do not matter. My writings are always based on A&WC studies. They are all the credentials I need.

Still the most commonly prescribed statin, especially where low-moderate statin effects are desired. Rosuvastatin is next in line, but tends to be reserved for patients that need high intensity therapy. And 70% in the study were on low-moderate doses. Also, the move in hsCRP looks a lot like atorvastatin (or rosuvastatin) low vs high dose. For example simvastatin 20 vs 80 shows no sig diff in hsCRP lowering.

Ask yourself, is it annoying because of the content, or because you have money riding on AMRN? If I was at a racetrack and looked over the racing form and decided on horse 7, and was talking with a buddy about it who also agreed, and we both went and placed our bets and were watching the telemonitor, and then some guy came over and began to diss the horse and jockey and tell us all the reasons he was going to lose, would we like that guy or what he was saying, even if it ended up all being true? No of course not. We’d get defensive and probably even exaggerate why #7 is great—maybe even lie—to defend our position. And the whole reason is because we possessed a belief. Or maybe better, the belief possessed us. And the belief was confused to determine our reward. So we needed to believe it, because we needed it to be true to obtain the reward. Therefore we interpreted the guy’s admonition against the horse and jockey as saying “you don’t deserve the reward.” We took it personal. But in fact he never said anything about us. He just talked about horse #7 and its jockey.

This is also why retail investors very commonly lose in the market. Here, feelings, including hopes, and things like loyalty, which are benefits in society, should come last. They will ruin you.

The cold, hard fact. The cold, hard fact...

Lol, you guys are too much. On the one hand, you acknowledge they are nearly always taken together and so why not a combo pill? On the other you don’t like the idea that MO can block statins so now you want it to be true that they are taken at vastly diff times.

No they’re taken together. Almost always. Read the labels, some even require you to take at night with food (lovastatin). And even if some were taking their V or placebo with dinner and then taking a statin and going to sleep 2-3 hours later (unlikely they would separate them when the label says you can take the statin with food), it would still interfere with absorption, having coated the GI track.

It’s actually most probable that subjects just took all 4 pills at dinner with a statin. And you really shouldn’t do that with MO, even despite the statin. I’ll bet their serum vit E, D and K levels were significantly lower than V group as well.

That’s silly. One small St Johns Wort capsule can block it just fine. The bioavailability of most statins is poor already.

EPA does nothing to oxLDL. The only reason you think it does is because it went up so much in mineral
oil group in ANCHOR, and they say “compared with placebo, oxLDL...”

Right of course compared with placebo.. lol.