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I don't want the Stat article as an information source (they aren't reliable), just want to keep tabs on them. May do a critical Seeking Alpha article about their coverage if they persist with the inaccurate hit pieces.
MH just tweeted that he's proud of his Forbes article last year which had multiple blatant negative falsehoods. He closed with:
" if you're tweeting that raising concerns about a drug or a study of it means people will die? You are the problem with everything. Thanks. Have a nice day."
In his defense, he's had some less than civil tweets fired his way (not from me. I pointed his errors out to him, civilly, not sure if he really read it. He said he did, but it didn't seem to take.)
I'm also very interested in having the full Herper/AF Stat article but am determined not to subscribe. I believe a free 30 day trial is offered. Anyone?
OT - Kev - That's one example of at least several dozen funded by George Soros as an apparent attack on the United States. He's had a lot of success and still at it. He just picked radical activists to be commonwealth attorneys in my county and the adjacent one (cost him about a million dollars). It's quite scary actually, very much under the radar.
Soros 1
Soros 2
For Amarin's 2013 adcom, FDA defined the question so it was virtually impossible to vote yes. Even strong supporters of Vascepa and Amarin voted no.
FDA is unpredictable. If I recall correctly, in October 2013 they didn't post the Vascepa ADCOM briefing documents until early afternoon the second day before. I believe they wanted to minimize the amount of reaction time Amarin had, while still more or less being able to claim they had met their goal of providing them two days in advance.
I believe the situation is different now, and FDA recognizes it is in their interest to approve Vascepa's label expansion. I expect them to want to make it clear that they thoroughly investigated every issue, including MO, AFIB, blood thinning etc., and expect those to be reflected, possible aggressively, in briefing docs and possibly specifically mentioned in voting questions, but end of the day I think FDA knows it's a no-brainer for approval and they will approve.
The big open question, of course, is label breadth, and any of the plausible options will be very broad. Off-label will remain an option for those who don't get on. The evidence seems pretty strong V significantly benefits pretty much anyone at elevated risk of CVD, whether or not they were explicitly represented in RI. That doesn't mean they'll all get on the label, but a big pile of them will.
dmlcento - The 90 page document you looked at us the applicant briefing material for the Nov 13 panel. Links to the FDA voting questions and briefing document for that are the 4th and 5th entries below that in the table.
The Amarin briefing material not posted yet.
Dancing - I meant not dying.
Dancing - If you've been taking V for a couple years and have not had prior CVD, then after adjusting the trial result for the 2 year primary prevention subgroup startup period before benefits kick in, your odds of dying are actually more like 50% better than comparable Americans not taking V. (30*(4.9/(4.9-2) = ~50)
I still recommend looking both ways before crossing the street.
Next they'll complain that half the results were below average.
The concern about primary prevention possibly being omitted from the Vascepa label is unfounded. All SPA requirements have been met, and there is no reason to expect this SPA to be rescinded.
Note that, as Prof Bhatt mentioned in his recent video, primary prevention subgroup had 2 year delay before benefits kicked in, vs about 1 year for secondary prevention. Adjusting for the trial underestimation of RRR due to startup effect would increase the primary prevention RRR from 12% to about 20% (factor of 4.9/(4.9-2)). Secondary prevention RRR was also underestimated, but not by as much. And, as Pharmacydude pointed out the other day, RRR of 6% was approved and is in wide use for Ezetrol.
We're in good shape.
Good point, I'm sending my friend the link to new Bhatt video.
A friend asked me about that MF article too. Lots of misinformation in it. RI primary and numerous secondary endpoints were carefully specified in advance, and primary prevention cohort RRR > 12% wasn't among them. Because of fewer events for that healthier subgroup, confidence interval is quite large. If it had been considered crucial to measure it precisely, FDA would have required more primary prev subjects, but they didn't. Not an issue IMO. MF got several basic facts wrong in that article, not a serious analyst, no one should lose sleep over that IMO.
BTW, 12% is quite good. It just looks less impressive next to the kick-a$$ overall and secondary-prevention. I recall JT saying in spring of 2018 his market research said RRR of 7 or 8% would be marketable.
The study is relatively small and based on correlation only, but indicates good benefit for EPA, neutral for DHA, and those with higher DPA did substantially worse (for stroke for seniors with AFIB). DPA is what Matinas MTNB dilutes EPA with to try to get around Amarin's patents. Study is small and for a niche group of subjects and not conclusive, but still good for Amarin and bad for MTNB, which already wasn't in a very strong position.
Great post
I wonder if Sharma covered his short and went long. His Seeking Alpha blog recommended going long AMRN. No mention of mineral oil.
JL - I agree AF is overrated. I guess it's relatively easy to be a big fish in the relatively small pond of biotechs, less widely followed than higher cap sectors. Easier to get away with not doing much homework, like not bothering to report on Amarin's Nov 10, 2018 Saturday night technical presentation. In fairness to AF and MH, before Gwen Fisher, Amarin lacked media relations savvy.
It's disappointing AF dropped the ball on Amarin because he's done some good work. E.g., his October 2018 Matinas article exposed some of their bogus claims of superiority over V, and called V a likely blockbuster. In November he seemed overly influenced by unfounded negativity from Herper and others. It was AF's disappointing complete disinterest in correcting the record that was the real sign of a second rate reporter IMO. He seems mostly back on track now as far as I know.
Montana - If they measured stain level in the blood (is there such a test?), it would not be essential for the trial subjects to be particularly high risk, although it's obviously desirable to match the RI subjects as closely as possible. In any event, for a 12 or so week trial, not a lot of risk to omit V, which doesn't reach full benefits for a year or two anyway. Currently, most of the target market unaware and not on V anyhow.
I suspect it's mostly a moot point anyway. There is no perfect placebo (certainly not corn or olive oil), and FDA signed off on MO and stayed signed off when revisiting the issue around the time of the last interim look. The 72 day letter was required by law in mid-July. We heard nothing, so presumably it was clean. (I know, FDA omitted their policy change from the 2013 72 day letter, but I don't see a parallel situation now.) If a small, short trial were required, I don't think it's likely the FDA would be irresponsible enough to wait until Nov to first mention it if there were any possibility of requiring its completion pre-approval, when they could have mentioned it months ago so it could have been about done by ADCOM.
I expect MO to be prominently and even aggressively addressed, as part of the extra diligence appropriate for a large market, but I think FDA has known for years MO is not a big deal. The facts are too clear too many ways, as we've discussed for months.
Sidestepping the BO/GIA issue, I don't take AF very seriously after his major fumble post-RI and his refusal to pick up the ball and make obviously needed correction when the facts were spoon-fed to him. With or without big pharma, I think it's a safe bet V will take off soon in a much bigger way than the very solid gains we've already seen.
Here - Good point. Any holdeovers still clinging to fibrates or niacin (I think there may still be a few, believe it or not) should dump them, and a case can be made for reducing statin dose a bit, based on the argument that some of the statin benefit is from inflammation reduction, and V does that with fewer adverse effects.
If a giant trial were done to compare event rates for various combinations of statin and V doses, I suspect the result might favor partial replacement of statin with V, as a better means of inflammation reduction, with statin still needed to control LDL-C. I don't see how such a trial will happen, given the huge expense and time required, with statins off-patent and just a decade of V patent life left.
After quickly scanning the article recently posted by Burn Sanderson focused on how insurers and other health care providers might view Vascepa, I choose to focus on this quote:
"ICER’s estimates suggest that Vascepa is currently priced at least 75% below a theoretical cost-effective maximum price."
I don't doubt that bulk purchasers of V will try any available means to try to maneuver the price down, but at the end of the day they'd be stupid not to pay up and encourage as many as possible to take it. When people have their own money at stake they generally end up doing the right thing at some point after it becomes obvious, and ICER is helping make it obvious that V is a win-win for providers and patients.
Kiwi- 1981 was at or near a major historic low for bonds, so I believe your bond performance number is on the high side. Currently, total return of muni bonds over last 10 years is under 5%. It had been higher before that.
I suspect that in the long run that investor cut his portfolio at least in half compared to stocks. For example, 8% vs 12 % compounded for 20 years multiplies holding by 4.7 vs 9.6, so a switch to bonds eventually cuts the portfolio in half (less by over $700 million in the case of the CEO, ignoring taxes).
As I said, he was fine either way, but investment timidity can be very costly.
BTW, doubling 5 times, reinvested and compounded, multiplies the holding by 32 ($100k becomes $3.2M). If you have a calculator with a y to the x key, you don't need the rule of 72, although it did pretty well in this case. 1.096^38 = 32.57. After 38 years, a 12% return turns $100k into over $7M.
Fisher gives presentations to people who are already clients, not to prospective clients like many others do, so not a marketing ploy.
Ken’s story about the nervous exec was from many years ago, and his timidity cost him many millions. But, he needed his peace of mind and didn’t need more money, so good advice IMO.
Invest - Ken's point about gridlock being good for the market at least in the near-term is backed up by empirical observation and by explanation that market above all dislikes uncertainty and change. Also, long term positive policies (like trying to stop Chinese theft of our IP) can involve short-term negatives, like the tariffs Trump is using to help motivate progress.
Another Ken core belief is that whenever a consensus starts to form about what the market is expected to do, that is the one thing that is quite certain to not happen. Also, when people more actively manage their portfolios to try to account for anticipated market moves, that almost always hurts their long term performance. Also, one of the biggest risks in the market is missing big upswings by trying to avoid downturns.
He has analyzed all this in great depth with extensive analysis of historical data. No one knows for sure, but Ken is the best I know of.
Kiwi - I attended a presentation by Ken Fisher last week, and he specifically addressed tariffs and other issues that could influence the outlook for the stock market in the US and globally.
Ken continues to believe the tariffs are a small negative which the market perceives to be bigger than it is, which is bullish. (Max possible tariffs ~$161B, global economy $80T, and tariffs are often avoided by moving goods through a third country not subject to them.)
Ken remains bullish, only slightly less so than he has been for the last 3 years we've been with him. He gave convincing reasons, touching on the yield curve, politics (gridlock is bullish, and there's piles of it, in US and globally).
This overall market perspective applies to Amarin, of course, on top of the other expected catalysts.
BTW, Ken told a story of a retired Silicon Valley CEO with $300M. He lived a simple lifestyle (drove a beat up old car wearing blue jeans etc.). He had half his $300M with Ken, the other half in municipal bonds. Stock market volatility kept him awake nights, even though he only needed a very small fraction of his bond income to maintain his lifestyle. The obvious explanations and reassurances didn't provide peace of mind, so Ken eventually advised him to put it all in bonds so he could relax and enjoy life.
Most people worry more about losing what they have than they do about missing out on an available gain. That's irrational and costly, but very real and very common. I see right now as a crazy good time to buy Amarin, perhaps the last of the seemingly endless series of "last chance" opportunities to buy at a bargain price. One of them really will be the last, and I think it's at hand or very close. Of course, I thought that a while back too, more than once.
Thanks for sharing the link. Agree JT coming across very well. I suspect some coaching from Gwen Fisher. Good to hear him say there’s lots of stock price appreciation to come and he’s confident of ability to execute, and expect approval this calendar year.
Seems pretty comparable to me, except for what's already been discussed.
Thanks for looking it up.
Re STRENGTH, there can be a big difference between extending by a year the end of the trial and extending by a year the median or mean duration a subject spends in the trial. I didn't look at it in great depth, would be interested to read and adjust if someone looks it up. Don't know if they had a very long recruitment period like RI, or if they increased their target number of events. If they did (and it would help them), they should have to pay a price like Amarin did for their interim looks. The far bigger factor in my analysis was the reduced EPA level, more than duration. Also, it might help them if STRENGTH avoided Ukraine (only half joking, I don't trust their compliance, worse health and inexplicably less RRR).
Wouldn't expect the bottom line to change a whole lot from duration, which is why I didn't spend more time chasing the details. There are other factors too (different subject profiles etc).
My original post we refer to, estimating STRENGTH performance, is # 210571.
JL - So glad you're on the path to recovery. We hope you'll be a bit less stoic regarding future warning signs. Sounds like they gave you a thorough going over so hopefully no more surprises anytime soon. Belated condolences for the loss of your brother, and welcome back.
marjac - I believe you are correct about the side effects. That wasn't included in my analysis.
VuBru - I meant the benchmark for non-inferiority assuming V approval, which I consider virtually certain. I'm sure they had a different benchmark in mind when they started out, but non-inferiority is a moving target. We learned all too well a few years back that other trial results can move the goalposts mid-game.
VuBru - Thanks. Agree with your points. Recall too that STRENGTH is limited to the high trig and low HDL subgroup, and they won't be able to make much of a case for comparable benefit without low HDL. That greatly reduces their target market (probably by at least about half).
They seem likely to get low 20s, which will likely lead to a headline that will seem more exciting at first, until word spreads that the MACE RRR benchmark is really 38%, not 25%, due to the low HDL restriction. There could be initial market confusion for both stocks when the STRENGTH news hits. Hopefully Amarin gets ahead of it when the time comes, as they did with other omega-3 trial results last year.
Monday morning quarterbacking, Epanova probably would have done a lot better if they'd upped their dose to 5g, to get a competitive EPA level. Frankly, V would probably also benefit from larger dose. I supplement my prescription with a bit of extra DS EPA. There's strong evidence for substantial benefit for increased dose, especially for older western males.
Mets - There are any number of subtle differences between V and Epanova and the RI and STRENGTH trials that will have subtle impacts. And, even if the trials were absolutely identical, results could come out significantly different due to statistical aberration, even for fairly large trials.
I didn't take a very hard look at a lot of factors, including bioavailability. I'm not too worried about it, since RI had quite good increases in plasma EPA level, and, obviously, strong cardio-protective benefit. Don't know if there's available data for Epanova's impact on plasma EPA level. That would be interesting. They're starting from a considerably lower amount of EPA. I do know that MTNB's claims of much more plasma EPA are bogus.
Even in the unlikely event Epanova came close to V performance and overcame patent issues, I don't think that would be a disaster for Amarin, anymore than Pepsi stopped Coke from having immense success. (I think JL made that analogy a while back. Epanova is really more like RC Cola or Mr Pibb. Worst case, Dr. Pepper.) Amarin has a big head start building market and tying up suppliers. I see no scenario where Amarin is not very successful.
Kiwi - If you want to look that up and estimate an adjustment, I'd be interested to read that. This was a quick rough estimate, I'm on the road and it's my turn to drive.
STRENGTH Rough estimate of likely upper bound on performance
Looking for a quick rough estimate of the maximum likely RRR we should expect from the STRENGTH trial of Epanova. Epanova capsules are a gram each, at least 850 mg of which is PUFA. They are 50-60% EPA and 15-25% DHA. We’ll look at the 4 gram dose (I believe they study 2 and 4). The trial specifies a low cholesterol diet, and subjects are on statin, so presumably LDL is well controlled.
To give a best case estimate (for Epanova, worst case from Amarin’s perspective), ignore the likely LDL-C increase from the DHA and any negative effects of extra material and assume DHA has 1/3 the benefit of EPA (due to good trig reduction benefit but lacking many other benefits of EPA). So, 4 Epanova capsules have 4x0.60=2.4g of EPA and 4x0.25=1g of DHA which we’ll call equivalent to a total of 2.4+0.33=2.73g of EPA. Vascepa is 96% EPA, so a dose is 3.84g of EPA, and the Epanova dose has 0.711 as much EPA as the V dose.
Next, we’ll consider the difference in trial duration. From the RI and JELIS trials it is reasonable to assume a startup delay of between 1 and 2 years before full benefits, let’s conservatively call it 1.1 years. If I recall correctly STRENGTH duration was expected to be 3.5 years but they may be running a bit long, so let’s call it 3.7 years. RI was 4.9 years. So, STRENGTH had a startup degradation factor of (3.7 – 1.1)/3.7 = 0.703. V’s was 0.776, so the ratio is 0.703/0.776 = 0.906. Assuming local linearity of RRR vs EPA dose (which is reasonable based on JELIS and RI), with RI reporting 38% RRR for the high trig, low HDL subgroup, our estimate of maximum likely STRENGTH RRR = 0.711x0.906x38% = 24%. Allowing another 2% for statistical aberration (with possible placebo effect), I would say that STRENGTH seems fairly unlikely to exceed 26%, and very likely to be under 30%, although no one ever knows for sure with clinical trials.
If we do a best guess estimate instead of a likely upper bound (using 20% DHA, 55% EPA, and duration 3.6 years for Epanova, 1.25 years for startup delay, and DHA benefit 0.3 as much as EPA) that gives 21% (not adjusted for active placebo).
BOTTOM LINE: A rough guess at STRENGTH MACE RRR is about 21% after adjusting for EPA dose and trial duration. It seems fairly unlikely to exceed 26% and very unlikely to exceed 30%, which is well under Vascepa’s 38% MACE RRR for the high trig/low HDL subgroup.
The corn oil placebo is active and will likely exaggerate performance at least a little. I don't know how to predict the impact, this analysis focuses on the more predictable dose and duration effects. Placebo impact will be estimable after the trial from the K-M curves.
Herper moved from Forbes to Stat a month after writing the Forbes hit piece on Amarin. AF is at Stat too. Maybe they’ll join the bandwagon after the rest of the world is on board and there’s no choice. They certainly declined to correct their gross errors when given the facts.
Yes, I could have phrased better, corn oil and high risk subgroup will exaggerate STRENGTH performance, the DHA and shorter duration will pull it down.
Nice DD. I heard linoleic acid raises AA level, directly impacting (negatively) AA/EPA ratio, one of the better causal CVD risk factors. Corn oil is an interesting choice for STRENGTH placebo, with the supposedly fussy about placebos Dr. Nissan.
I trust the FDA to do what they perceive to be in their own interest. In 2013 a reasonable case can be made for requiring the outcomes trial pre-approval given other trial failures. The inexcusable part was concealing it and avoiding an informed open discussion. Now, there’s no reason for FDA to not approve, and in fact it would be very much not in their interest given the superb trial results and huge eager market. I expect them to cover their a$$ by raising all questions (like MO and hs-CRP) even if they already know the answers. I don’t expect a major FDA problem, perhaps a minor jab because Amarin had the nerve to defend their legitimate rights. IMO the big question is between a broad label for a huge market or an even broader label for an even huger market.
I expect STRENGTH to show benefit, but less than RI, because of highly active corn oil placebo and also subjects are all in easy high trig low HDL subgroup (for which RI reported 38% RRR), plus they’re using mostly EPA, and EPA works great. The DHA lacks key benefits, as JL has told us for years, and will likely increase LDL. The shorter trial duration will hurt them due to delayed benefit, and there are patent issues. With very probably substantially less benefit (than V’s 38%) and likely LDL elevation, not to mention a real placebo issue, it’s not clear to me FDA will approve it.