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Zum - Great figure - Maybe our worries about R-It effects being reduced by patients being on "optimal statin therapy" are misplaced in some cases? Could actually be a benefit if this synergistic effect occurs with other statins.
Thanks BC - nice confirmation.
Raf - Don't know, but I would similarly wonder whether beating the Repatha 15% RRR by at least 5% (or whatever) might be part of instructions. That is their competition to beat now, and if they can beat it at much lower cost, they are set.
Zip - Possibly. AVI recently reposted a meta-analysis from January that showed in clinical trials of EPA/DHA in secondary prevention studies, there is about a 25% RRR in those with high trigs (>150, compared to R-It median TG at 200) receiving a high dose (> 1g day compared to 4g day pure EPA in R-It). Having more diabetics in the sample (their cutoff was 30%) nonsignificantly increased the RRR, which should help R-It which will be approx 50% diabetic. Interestingly, the length of the trial was not associated with differing effects (which maybe JL would like to comment on). Similar effects were found among clinical cohort studies in a companion meta-analysis, so there is consistency between highly controlled and "real world" studies. Those who have talked about JELIS here have sometimes dismissed the strong effects of EPA in the secondary prevention subgroup of that study because the MACE definition included a subjective angina definition, and imply that that was the sole reason for the big 53% RRR effect. This is not really accurate. If you read the details, subjective angina was the most common event, and was significant by itself, but the effects on several "hard" MACE outcomes, including MI, had the same size effect (RRR %) as for angina. The numbers were just smaller (they did not happen often) so they were not significant on their own. The effects on the different MACE components were fairly consistent (less for stenting if I recall correctly). R-It is more than twice as large (N=~8,000) as this JELIS subgroup study (N=~3,000), with sicker patients. I agree a 25%+ RRR might be expected based on this which might be enough for a stop at 80% IMHO.
Not to be argumentative, but in defense of FFS, he did identify almost perfectly the shift in the market from the post-Trump election bull mode to the neutral mode it has been stuck in recently. While there has been no large sell off (yet), one is certainly conceivable given the high valuations right now in the U.S. market - time will tell. FWIW - I have had my retirement money for the last couple of months in bonds and emerging markets (which are not overvalued right now), and have been outperforming the U.S. markets despite having the majority of my funds in somewhat safer investments (bonds).
STS - You make a reasonable point, although there are several large insurance providers (e.g., BC/BS) that might have nationwide data in adequate numbers for analyses. I also know there are companies that aggregate similar types of data across multiple institutions and sell to to willing parties. For example, the Cerner Health Facts database. This could be used to do the same type of real world study linking V to outcomes. The Cerner database in marketed to pharma for exactly this type of study. It has data on more than 84 million acute admissions, emergency and ambulatory visits, including
detailed pharmacy,laboratory, billing and registration data.
Thanks AVI
Avi - I think this was posted previously, but I appreciate the reposting and interpretation re: 25% RRR, effect moderators, and dose response. I certainly hope to be "farting through silk" come July (or next March). You imply that the high EPA dose effect and high trig effect are additive (vs. overlapping effects). Is this correct or can you tell from what they report?
Pyr - You are way behind the times in your thinking. Big data and precision medicine are THE thing nowadays in medicine. The NIH just awarded $71 million over 5 years to do multi-site, big data precision medicine work (the Precision Medicine Initiative Cohort Program). Having messy data is not a problem when you have 10 million patients in which you can detect the signal. This high patient variability works in your favor in some research contexts.
Bfost - I agree that Insurers might not initiate this, but quotes in my recent post on analytics (#103842) indicate that pharma companies can, and do, initiate this type of analysis sometimes, and can take these "real life study findings" to insurers as part of their arguments for coverage. I certainly hope Amarin has done this.
Great analytics example (from consulting company report I found): "After German payor G-BA rejected coverage for premium priced Lantus, a form of insulin, Sanofi leveraged real-world research to counter its exclusion from the formulary. It conducted a comparative effectiveness study of Lantus vs. human insulin using data from IMS Health's Disease Analyzer and proved that use of Lantus results in a 17% higher persistence and may delay the need for higher-priced intensive conventional therapy. Using the real-world evidence, G-BA reversed its position. Sanofi has now secured contracts with more than 150 individual payors in Germany covering about 90% of the German population."
Also relevant from this report: "In 2011, AstraZeneca established a 4-year partnership with WellPoint's data/analytic subsidiary HealthCore to conduct real-world studies to determine the most effective and economical treatments for chronic illnesses and other common diseases"
Substitute AMRN for Sanofi....
Not saying it has happened the same with AMRN, but with their CMO Granowitz speaking on uses of big data in healthcare, it would not surprise me in the least. As I have said before, it is possible the company already knows what R-It will show based on big data findings.
Zum and Bfost - Here is a short article from a couple of years ago about the increasing need to use data analytics in the health insurance industry for cost reasons: http://www.insurancetech.com/2015-outlook-analytics-in-health-insurance/d/d-id/1318241
Only question seems to be whether to do it in house or contract out of house.
Bfost - You may be correct, but I do know for a fact that they are doing this type of analysis regarding chronic opioid use. Maybe V is too small a fish to do this on though.
JL - They clearly could look at these all cause cost benefits of V quite easily. Something clearly changed between last year and this year in terms of insurance coverage for V (including preference over Lovaza). Without new trial results to justify this, one has to wonder what changed the "bean counters" minds??? I do not think insurance companies make changes like this for no reason, especially when (on the face of it at least) the change costs more money up front.
Interesting - Thanks Zum. I work some with informatics people and I am amazed at how they are able to pull meaningful data out of messy medical records. Insurance records, while more limited, are much more standardized so are much more amenable to rapid big data analyses.
VN - I don't know that insurer data are available to the company (maybe we'll know more after Granowitz speaks), but if they are, my guess is they are using those data to see whether things they already expected in R-It can be seen in the clinical data. For example, do people with lipid disorder diagnoses who are on V have fewer procedures associated with cardiac events than similar patients not taking V (or who are taking Lovaza)? Or, do diabetics on V have lower CV-related costs than diabetics not taking V? I doubt they would change what they are looking at in R-It based on big data findings (they are very messy and broad brush), but I am sure they would hope to see some evidence of R-It like effects in the big data.
CBB - I think PPS may have been down yesterday because of publicity over new and very expensive drugs that raised the specter of price regulation again.
FFS - Love the single subject study you just did. Nice results.
Zum - "Big Data" implies either insurance carrier info or massive medical record data bases. Wonder whether the company has been working behind the scenes with insurers to analyze their claims data and show the value of V outside of R-it?
That is a big IF given how fractious congress is. I am not betting on anything happening as proposed.
Any omega 3 drug that is not exactly the same composition as V (pure EPA) is going to have to run a full scale R-It style trial to get FDA approval for reducing MACE. That would be at least 6-7 years from now. Any drug that is exactly like V in composition, violates Amarin's patents, and cannot be marketed without winning a lawsuit. Assuming R-it is successful, nothing to worry about for a few years.
STS - I think HDG just meant that there is only one PE, not multiple PEs
HDG - Agree. The company certainly would not have embarked on the huge expense of R-It if they only expected a 15% RRR as in their power analysis. I think we can assume that their projections for tracking events are based on an assumed RRR higher than this, but no way to know what that was.
Kiwi - Approx 50% will have mixed dyslipidemia in R-It. Per Feb 2017 IR presentation:
Kiwi - What effect new stents have depends on when they came out, and how many patients were implanted with old style vs. newest stents when they entered R-It. First patient was enrolled in November 2011. Patients already enrolled would not be able to get the new stents unless they had an event, which would remove them from the study anyway. Not that wikipedia is the best source of info, but here is an interesting quote about drug eluting stents (DES):
HDG - My mistake. Thanks for correcting. I for some reason thought that the sample size increase happened around the time of the increase in TG entry criterion. They were just hedging their bets by powering it for a lower placebo rate before the trial started. So, when the company says "events are tracking to predictions," they are referring to how the event rate should look if V worked and the placebo rate was only 5.2%. For some reason, that makes me feel more comfortable with where we are.
Raf - It was actually Kiwi that made the point of lower event rates due to changes in the CV medicine field. The company did increase their sample size by 1,000 patients mid-stream to address a possibly lower placebo rate of 5.2%, but I have no idea what that change was based on.
STS - If the EPA being sold as DS fits within the % of EPA vs. DHA in Amarin's patents, Amarin could sue the DS makers for patent infringement. If R-it is approved, this course would not be surprising. Barring a lawsuit, nothing can be done to prevent people from just buying the DS version of EPA.
Raf - I agree that no stop at the 80% tells us nothing either way in fact, although the temptation is (for myself included) to see this as bad news. I just have to keep going back to the strength and breadth of the EPA science to feel better. One image I saw in an animal study publication stands out - showed the inside of an artery in a animal on EPA for an extended period vs. one not on EPA. It was very different in appearance. Clear and dramatic EPA effect (and assume this would translate to human CV health outcomes).
Kiwi - I get your point and agree that your 2 phase model is a reasonable possibility. I don't think that at about 1 year into the trial when they increased the TG requirements that they really had enough people for long enough in trial to get a reliable idea what the eventual event rate would be. I agree that what you said is certainly possible though.
Also re: your statement:
GRB - I think Anchor indication approval is the whole point of R-It. The patent issue is totally separate from the trial results. You can patent drug concepts that don't actually work, but you cannot get FDA approval for it unless it works.
Kiwi - I have always heard that Mill Valley is very nice but have never been there. Is this on road or off road biking? I got hit by a car when I was a kid, so am not very keen on biking on roads with cars. I have a nice 10 mile trail near our house that goes along a river, through open fields, and through some forested area. It connects to a great uphill trail that winds around a big hill if I am feeling ambitious.
Kiwi -
FWIW - Having 2 follow-up time points (60% and 80%) is enough to see a trajectory. If they do stop, I would guess they are seeing a clear divergence of the groups that would be hard to argue with even with an early stop. If there is no clear pattern, or there was no divergence at 60% but there is at 80%, then I suspect they would elect to continue to further solidify the effects.
Ferret - I totally agree. I started biking at age 50 and love it.
I find it interesting that with the biggest news in months occurring nearly 2 weeks ago (that the 80% IA trigger event has occurred), daily volume has pretty much dried up and the wild up and downdrafts of recent months have disappeared. Seems that the short sellers and manipulators are gone (too risky now?). Strangely enough, Pyr is suddenly posting much less. Hmmm. What do people on the board think about time frame for start of a run-up prior to the 80% readout? Based on the pattern prior to the 60% readout, my guess would be mid-May. Are we looking at 3 months for a readout this time or closer to 6 months like last time? Right now the stock seems stuck in neutral.
Raf - Controversial I think because Amarin was the first to sue the FDA over free speech rights. That's a big deal.
Century - I agree that the cost of developing drugs is way too high. However, I think you have to look at the economic flipside of basing approvals only on high safety without adequate efficacy data. If the economic incentive is to market safe drugs, then you will get many new safe drugs with no proven efficacy. There could potentially be a huge amount of money spent by the public (and insurance companies) on drugs that don't even work, so this change would simply shift the cost burden from drug manufacturers to individuals (who also get no health benefits from the ineffective drugs, potentially risking their health). Is that really an improvement?
BaaBaa -
FWIW - My guess is that the individuals or institutions who have been manipulating the stock between $3 - 3.50 for repeated small gains (the lather, rinse, repeat cycle that has happened repeatedly over the past 6 months) are going to stop doing this. The closer we get to June (3 months post announcement of 80% target being reached), which I see as the earliest that we may learn something about R-It results, the more risky short bets become. No one knows exactly when the 80% IA DMC decision will come or what it will be, and the risk of betting wrong could be huge. In the absence of manipulation (or any new news), I would think we might see smaller fluctuations with a slight upward trend in the near term, and then when we get to late April-May, a significant ramp up. Looking back at the time before the 60% IA, it looks like the 1st amendment win announcement was at the beginning of March 2016, with no major impact on the PPS. However, between the end of March and August the PPS went from $1.43 to $3.32, with the only "news" being the pending 60% IA results. I do not expect a >100% PPS increase again for the 80%, but I think $4-$5 is totally realistic. Unless the broader market is tanking badly during this time frame, I would be very surprised given history if it does not reach at least mid-4's. I think the "squeeze" pattern that FFS has talked about in his charts may be reflecting the reduced manipulation, and the PPS is now more free to float wherever it's going to.
Sam - Thanks. I suspect the lower numbers this week were in part due to many cardiologists attending the American College of Cardiology annual meetings (started on 3/17, so many probably shut down their practice on the 17th or even 16th). This would be the largest single group prescribing V. This should be treated like a holiday week.
Agree - these population differences in MACE reflect other things beyond EPA levels. Those things do not have any bearing on efficacy of EPA in a controlled trial though.