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Cardio - Quote "I myself used to prescribe Vascepa based on Reduce it criteria. However since patients with triglycerides of 135 benefited the same as patients with triglycerides of 300 i now prescribe off RIT label for any patients with known CAD/CVD ... with any triglyceride level. ...
I believe EPA goes beyond triglycerides"
I'm very glad to hear you say that. I hope other doctors agree. My cardiologist does, enthusiastically. I don't know if the FDA will see it that way and include on the label those with at least somewhat lower trigs (say 100 or so) if they have other elevated risk factors. A similar case can be made for those not on statins. Even if the FDA doesn't see it that way, off-label sales will continue. It just makes too much sense.
I appreciate your posts.
LBL - Couldn't agree more re level heads and whining. Re pharmacoeconomic analysis, until the detailed analysis is complete, pretty good indicators are NNT and price, both of which are quite good. Bhatt commented when he said a pharmacoeconomic analysis would be forthcoming eventually that he thought V was likely to come out looking good due to the great efficacy and relatively modest cost. So I don't see much to worry about in that regard. Even if it were pricy, which it isn't, a lot of people have money and very much want to live.
The fact is, there are many millions who could reduce their biggest risk by about a third, right now, off label, often for $3/month, as I have done for years. As word gets out, sales will take off even more. We've barely scratched the surface.
FYI - Ken Fisher is very bullish, for both US and Europe. He says it's bullish when the market over compensates for a small problem. He says that happens a lot, and Brexit and tariffs are classic examples. He says we're late in a bull market, and strong markets are typical at that point in the cycle. That's not a guarantee, but it's the best guidance I know of.
FFS - Quote: "IMO, the FDA will not allow label expansion before these new results are revealed"
FDA was very clear that successful completion of RI would satisfy requirements for label expansion. I'm not saying they always keep their word, but they had a reason for wanting to rescind the SPA in 2013 (other failed trials shook their confidence, and they wanted to avoid another embarrassing post-approval failure). I see no reason now, and if they didn't approve there would be a riot that would not be good for them.
Thanks berryfit. That's helpful.
I'm very happy about today's Cardiology Today article for several reasons. Thanks for posting the link gozips, I hadn't seen it.
It's a positive article from a specialized magazine that reaches just the right people, and the advertising supplement re RI and Vascepa is a very good idea. I especially enjoyed the complete lack of any mention of mineral oil from a presumably cardio-savvy reporter, given the magazine's title. Bhatt said MO didn't really merit discussion, Fuster didn't raise it, and now Cardiology Today omitted it from an in-depth report, which I assume will reach a lot of rank and file cardiologists. I also take this as a sign Amarin is conducting an effective marketing campaign. Frankly, they have made some bad media moves (apparently denying Herper access to a scientist for the Forbes article, and not being more pro-active re the MO and MOA issues). JT said he wouldn't distract his staff from the SNDA, but one guy for 15 minutes on the phone might have made a huge difference. Missing info and ruffled feathers.
I've got a good feeling about sales going into the summer.
Thanks DITD - So, does that mean a pork chop (3.1% contribution to AA intake) is healthier than chicken breast (26.9%)? Is this per ounce, or is the high number for chicken because people eat a lot of chicken? I've heard pork called the other white meat, but I figured that was probably from the pork growers lobby.
Seriously, curious what to think here. I try to eat healthy, and always thought lean skinless chicken breast was healthy. I guess it makes sense if the chickens eat seeds with AA they accumulate it like anchovies do with EPA.
If I understand correctly, at noon today there's an Expert Advantage piece on Amarin, but it costs $500 for a one year subscription (for 12 such events, $42 each). I'm not paying. There's far more expertise on this board. I expect we'll hear about it. If I've got that wrong, someone straighten me out.
JL - Great post. Thanks for summarizing so clearly even those of us who aren't doctors can understand.
Steer clear of MTNB IMO, see one of my recent posts
jk - I wouldn't touch MTNB with a 10 foot pole. They have been coattailing Amarin, and that could continue for a while, but there is no there there. They have a centerpiece graph showing better EPA absorption vs Vascepa, but they did that by trickery. (V needs fat for good absorption, and Matinas' tiny, unblinded, unpublished trial gave the entire daily dose after an extremely low fat breakfast, in violation of label directions.) They showed plasma EPA levels for V much lower than reported in much larger real trials. They did hire a top shelf science advisory committee (including Ballantyne and Kastelein), but it's not at all clear it's more than an attempt to sell the rights, and I don't see how it sells without more merit. They would need 8 to 10 years to get approved for CVD, assuming it works well, which is not at all clear, and V goes generic in 2029. I wouldn't be surprised if MTNB insiders were selling (I haven't checked).
The current MTNB price relies on investor ignorance, which may well continue for a while, but I sure wouldn't rely on it. Amarin is a much, much, much better bet, even if it sags occasionally as BO rumors come and go. I think just that Cardiology Today article with advertising will make a noticeable impact, and sales will increasingly accelerate. (I didn't notice any mention of MO BTW, unworthy of mention.) The evidence is simply too clear.
Thanks Jerry
ranjo - "What is normal is under tremendous revision" (re trigs) - I like that quote and may use it. Is that verbatim, or a paraphrase? I remember that discussion, but not the exact words, and don't have time to listen again. TIA
I figure V will conservatively prevent over 800 events a day, over 300,000 annually, about 18% of them fatal. In 10 years that would be over half a million lives saved, and that's probably very low (US only).
Redberg didn't seem to understand RI was double blind or that it had great hard MACE performance. You don't even have to read the paper to know that, the topline results or abstract should be enough.
Nice Reuter's article. No mention of any worries, all positive. That's what my wife would call tier one coverage. At my house, when she gets a nice tier 1 hit, it's an excuse to tip a glass. (She's a media/analyst relations pro.) It will get picked up and widely circulated.
There art we happy.
Reuters re Vascepa
"Stupidity is the strongest force in society..."
That is so true so many ways.
A quote from the link about ARNA investors suing AF, from a note from a shareholder to AF:
"These facts are readily available and have been presented to you many times. I'm frankly baffled about why you refuse to acknowledge them."
Sounds familiar somehow.
Kiwi - You were a very slow learner about RI as I recall. Glad you're a believer now. Kind of humorous when you take a tone as if you were teaching me, when you for so long refused to learn from me and others who understood the science. If you'd gotten your way and required low HDL, it would have cut the V market down by about half or more for no benefit I can think of. HDL lowering had proven ineffective somewhere around 2011. The low HDL hi trig subgroup has much higher RRR, but 2 or 3 dozen percent is already enough to capture most of the addressable market, no need to try for 50% at huge cost to market size. Small incremental marketing benefit for increasing past 25% RRR.
Epanova is likely to work at least fairly well because it's mostly EPA and EPA works great. The DHA isn't a great idea for those worried about LDL-C, and would necessitate a higher statin dose for many, and most people wouldn't consider that a good thing. And, there's also the AMRN patent.
Don't get me wrong, I'm about as bullish on Amarin as anybody, and I'm not worried about Epanova for several reasons, but they picked a small subgroup (hi trig, lo HDL) where their odds are best. V set the bar high there with 38% RRR, before any possible total events enhancement. Trigs are one piece of the puzzle, and generally not the most important piece, but STRENGTH picked a subgroup where it's probably more important than usual, and they don't have a lot of DHA, so they'll probably have some benefit. That's OK, V is probably better even in that subgroup, has a head start, and will probably sell all they can make once they get rolling. But, STRENGTH will likely have decent RRR (V got 38%). JELIS had mostly low trigs, but got over 50% RRR in the hi trig, low HDl subgroup (small N, so imprecise RRR, but 53% with half dose is impressive).
My SA article is still waiting for an editor to get around to looking at it. Yesterday I sent a near final draft to AF and MH, and MH got back to me with a very nice email. I had sent both of them material several times over a period of weeks, and no reply. I assumed they ignored it. Maybe imminent SA publication got their attention.
Here's the email:
Charlie,
Thank you for your emails. I have read everything you have sent, except for some Google Docs that did not open. I really do appreciate feedback.
I'm not going to revisit my Forbes stories here, except to say that I spent a considerable amount of time trying to get further response from Amarin, including asking to be put in touch with more experts. I don't think the company's decision not to offer a substantial response affected the direction of any story. Researchers quoted were fully aware of the results, and I did not exclude positive comments about the study. The quoted sources were experts in the field, almost all without relevant financial conflicts. Many of your arguments, including the word "historic" and the 4% figure for a mineral oil effect, are included in that original article.
Thanks again for your comments. I am listening and they will inform my future coverage.
Best,
Matt Herper
Senior Writer, Medicine
Editorial Director, Events
STAT News
PE - STRENGTH enrolled subjects with high trigs and low HDL, which has always been a higher risk subgroup that is easier to get high RRR.Trig lowering trials that failed (fibrates?, not going to take time to look it up) had excellent performance for that subgroup (ACCORD maybe?). DHA lowers trigs better than EPA so they do have a chance of doing well for a very small subgroup. On the other hand, there's all that Dr. Mason stuff DHA can't do, so hard to know what to expect from STRENGTH. We also know fish eating populations have less CVD, and they get both DHA and EPA. But, the bar is set high, because RI got 38% RRR for the high trig low HDL subgroup. And, RI had 4.9 year duration vs ~3 for STRENGTH, so we should have several benefits related to the startup period. For them, it around half the trial, vs just a bit under a third or so for RI. If they do a total events analysis, I'd expect slightly less improvement related to the shorter duration.
Epanova is mostly EPA with a little DHA. Dvidson seems loyal to Epanova. So, he'll want EPA to be seen as effective. So, unlikely to bang the MO drum (which is indefensible anyway, when the facts are easily available as they are now). Likely to muddy the waters re MOA and make the case for waiting til STRENGTH. That extra wait would kill a lot of people, and to start saving lives it's not necessary to know exactly how or why something works. What matters is that you know it's safe and effective. We'll have to see how far Davidson tries to push it. Very tough sell to suggest V isn't confirmed safe and effective. I don't think Nissen and Krumholz helped their reputations last November. (Recent Krumholz tweets are focused on policy more than science.)
Ziploc - I agree about 9 of 10 biotechs fail. I would add that more like 19 out of 20 don't have a big breakthrough. And a very high fraction of breakthroughs that are claimed by CEOs are not really breakthroughs. Skepticism is a prudent default position unless there's very compelling evidence that you're very comfortable with. Amarin is an exception. It's going to take a while for more people to get comfortable with the facts. Step one is to hear the facts properly presented. Headway is being made, but it may take a while. Cardiologists get it (mine did) and they'll be the tip of the spear, off label, until approval.
MH was much, much worse, clear negative bias, AF was disappointing but probably honest. AF's biggest mistakes were endorsing the MH article and saying RRR could possibly be as low as 15%, which is categorically false. Af left out some key things like SPA.
Hadn't heard of Davidson until now. Not sure what to expect. MH and AF have been thoroughly provided relevant info, not sure if or how much they looked at it. Probably not much, they have a lot of other things to do and don't focus on AMRN like we do. They know they're being scrutinized. That could either help straighten them up or tick them off so they double down. I tried hard to be diplomatic. When that didn't work, I got a bit firmer. We'll have our day no matter what.
Script numbers are going to fluctuate. Don't fret, things are going well.
Thanks everyone for the kind words. I'm trying to rush it through, editors can take several iterations and are sometimes slow. Conflicts of interest are included.
iwfal - If you read the Herper Forbes article, you will find that it is in fact a hit piece. I'm publishing a media fact check piece in Seeking Alpha very shortly. An excerpt (links omitted):
"The Forbes article seemed to have a strong negative spin that went to the next level by saying lipids in other trials “do not budge,” and “mineral oil had not behaved as a placebo at all.” That was very damaging and is false. (See the Deep Dive Into Mineral Oil section in my previous article, and the Amarin MO FAQ page with 54 scientific references.) It is generally known that comparable or larger increases are routine. Among many others, the ODDYSSEY, EVOLVE, Frovocimab, and DESCARTES trials all had larger LDL-C increases without MO.
Herper said MO “seriously bothered five of the six cardiologists I spoke to,” but he quoted seven, apparently not counting Dr. Bhatt, the Harvard Medical School professor and leading cardiologist (1100+ publications) who led RI. Bhatt and Kaul were not bothered. Kathiresan had “a little bit of doubt.” (Later, for the update article, he retracted his doubt and called Vascepa a major advance.) Weiss seemed less concerned in Stat. Stein was bothered. The Krumholz and Nissen quotes gave a very negative impression without actually saying anything practically relevant.
Dr. Krumholz said the results were surprising and another trial was needed to understand them. He asked “Is this a one-off chance finding, or … an amazing addition to our armamentarium?” A question is not a fact or even an opinion. He seemed unaware of the extreme statistical robustness (p<0.00000001) and special protocol agreement (SPA), which very thoroughly preclude any possibility of a one-off, not to mention the very similar JELIS trial which would make it a two-off.
Krumholz’s insulting implication that RI could be a “one-off” was inconsistent with the laws of mathematics. It was prominently featured, unchallenged, near the top of the Forbes story.
…
Dr. Nissen said “It [mineral oil] is a potential factor … that may result in an exaggeration … compared to … if there was a [true] placebo,” “It’s about the magnitude of the result. It’s not that the result would completely disappear.” These thoroughly hedged quotes essentially say MO impact on RRR was less than 25%. That’s true, but not really enlightening. MO impact over 4% is implausible (Bhatt video, after 10:00), and there’s strong evidence it’s much closer to 0 (the Bhatt video again, and my previous article)."
AVI - Thanks for that. You dug deeper than I did on that, and I'll reel back that talking point. I was basing my remarks on Amarin comparisons of NNT of 21 to other numbers between about 50 and 100, confirmed by multiple other sources for statin 5 year NNT of ~50-100 for 5 years for subjects at elevated risk, but, it looks to me now like their risk was probably less elevated than for RI. (I also saw statin trials with 5 year NNT well over 200 for low risk subjects, so the NNT numbers really are all over the place.)
V is wonderful, but we don't want to lessen our credibility by overstating anything. No need to. Comparable to statin with better tolerability is plenty good enough. (I still have a hunch if V dosing were optimized for each patient, as statin is, and statin were tested as an add-on to V, V may well outperform statin, but that trial is unlikely to happen.)
There are 3 to 4 year statin trials with NNT between about 50 and 100, so pretty clear V beats them, not to mention serious statin tolerability issues. Not that V competes with statins, it doesn't. JUPITER pretty short trial, results less precise compared to later trials.
D I t D - Seems like the bar ought to be reset higher. That doesn't mean it will happen. The STRENGTH folks should be worried about that. My best guess is they show benefit, but substantially less than V. Their short trial duration is not in their favor, on top of the DHA, not to mention IP issues. One more thing for them to sweat.
zz1 - Thanks for that, I hadn't been aware (re greatly increased risk for total events). In my mind that does make an additional case for expecting more improved performance compared to the initial results. I still believe in restraining expectations and still believe what has already been proven is already enough for blockbuster sales, but RRR does tend to increase for higher risk, and NNT gets much better too.
My enthusiasm for March 18 has ticked up a notch.
It's simple to adjust NNT to different time periods. 1 year NNT is 5 times the 5 year NNT. A lot of the trials are around 3 to 5 years long, so not a huge difference. That's one reason to give it as a range (50 to 100). For healthier subgroups, statin NNT can actually reach around 200 or more.
Statins (among the most successful drugs in history) have ARR ~1-2%. V reported 4.8%, amazingly high. My expectation based on all events performance being less influenced by the startup period is an improvement in maybe the 10% or so range (maybe a bit more for hard MACE), i.e., maybe ARR of 5.5% or so for MACE. Not clear to me how to justify ARR near 20% just because of what another trial did. Haven't spent a lot of time thinking about that, am I missing something? Frankly, what we have proved already is enough, if we can just get people to notice it and believe it.
With modest expectations, the inevitable surprises are more likely to be pleasant.
Search engines like Google, or Wikipedia, can be very useful, and I use them (or Bing), but it is important to keep in mind that anything with a political or ideological aspect will be very strongly slanted. For example, try to learn that about 95% of Earth's greenhouse gas is natural water vapor. Or that North Korea is a nuclear power because Jimmy Carter gave them a breeder reactor that produced plutonium as a by-product, relying on video monitors and promises to restrain the murderous dictator. Years later they had a big pile of weaponizable plutonium and just removed the cameras. Virtually impossible to learn that now. I suppose this post will be deleted too. I wish it were that easy to delete the Korean nukes.
NNT (number needed to treat) is the inverse of ARR (absolute risk reduction), which is the difference in event rates between control and active arms. If there were a mineral oil effect, it would influence NNT, and make it appear slightly better than it really was.
For many reasons, we know the MO effect is somewhere between zero and very small. A recent version of my take on that is included here: Facts About Vascepa
TRX up 30% year to date (two months, from week ending Jan 4 to March 1). Pretty good considering the Q1 headwind. At that rate , by mid 2019 it would be up 120% from 31k Jan 4 to 68k end of June (with compounding). Could easily go even higher than that, with seasonal headwinds winding down and more acceleration likely as the word spreads. I'm hopeful for positive reports from AF and maybe even MH, believe it or not. (No promises.)
stone - It's a bit hard to directly compare statistics for Vascepa vs statins, because they depend on risk level of the subjects and trial duration etc, but certainly V has much better tolerability and V benefits are better (prevent more events), arguably much better, depending which statistics you look at. Statins were among the most successful drugs ever, so anywhere in their ballpark is wonderful.
The overall market certainly doesn't get it yet, with a few exceptions (e.g., Baker Bros). But, our time is coming.
Typical statin NNT is 50 to 100 (up to 200 or more in lower risk subgroups). V is markedly better at 21.