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BB - Which brings up an interesting pragmatic question:
For a patient meeting R-It label criteria (e.g., TG = 160), would an insuror pay slightly more for V because the patient is "on label", or would they force the patient to get a slightly cheaper generic that is "off label"?
TTE - But if we settle with the two generics in the next month, future patent trolls will likely be someone else's problem.
Thanks Kiwi. I had not seen these details.
Based on my experience (limited) in pursuing patent challenges, obviousness has to do with what was in the "prior art" at the time the patent was filed. So, if the published literature and other public sources available at that time did not clearly indicate that ethyl epa would lower trigs and other biomarkers specified in the patent (apo B?) without raising LDL levels, then the "invention" described in the patent was not obvious.
HDG - I saw a very good analysis of this case by a patent attorney. He stated that Amarin only has to prevail on one of these two issues to be able to stop the generics. Amarin's inducement case seems very strong, with the judge already clearly leaning their way. I am sure the defendants' attorneys know this, so I would assume they will prefer a settlement before trial to risking being locked out of the generic market until after TEVA enters. Just my two cents though.
STS - Check the language in the FDA response again. They quite clearly referred to the sNDA as being approved (past tense).
Thanks. They didn't get reduction in CV death risk on label...oh well. I still think this is about as good as could have been expected.
I totally do not get the people now claiming in news reports that Amarin "did not get the primary prevention label" they wanted. WTF - Diabetic with no prior CV event and no known CV disease is absolutely primary prevention by any definition. No way that group could be called secondary prevention. I am just happy that BP understands the implications.
Age was a risk factor in the R-It inclusion criteria for diabetics, so you can assume that will be listed as a risk factor on label.
I think the "secondary prevention" CV disease group does not have to have any additional risk factors, just the "primary prevention" diabetic group.
They got the original (TG>150) reduce-it inclusion criteria label. That is secondary and primary prevention, but must be diabetic for primary. Still a BIG population.
Thanks Rose. I invested in Amarin due to an "accident" that I think must have been something guiding my hand at the computer. I won't question it though because it has been life changing for sure.
Thanks JL - You too, I appreciate your good information over the years.
I am psychic!! Check this out from November 15:
TTE - Amarin doesn't even have to win on obviousness. One very good analysis of the patent case recently made the point that Amarin only has to prevail on one of the challenged claims to be able to stop generics. I think the other claim (that generic V would only be for use for 12 weeks or less) is easy to beat, and the judge was already leaning in Amarin's favor as this idea is absurd for a chronic condition. I think this is why a settlement will be reached, and honestly, if JT is planning for a BO, why not pay fairly big bucks to make the generics go away? It will be BPs problem after that (of course, the BP involved may be the one that wants Amarin to go to trial).
Thanks Chas - Good stuff by Budoff and Bhatt. MO makes no difference in plaque progression in any analysis.
Raf - I suspect they will not release any results that they want to publish eventually, unless it is as a poster/talk at a major conference. Avoids giving information to potential rivals and insures there are no hiccups in publishing (if it is released formally by the company, a journal in theory could argue that it is not new information, although this is unlikely).
Cal - Thanks for the clarification.
CDEC does not evaluate drugs for approval, only reimbursement. Health Canada is the FDA equivalent.
TTE - I think it sometimes may be hard to distinguish well-intentioned incompetence from a scam.
Makes perfect sense - If I had $50 calls and and the BO was at $40, why would they have any value?
My reading suggested that if there is a buyout, the options with expiration after the buyout get converted to shares automatically once the deal closes, based on the difference between strike price and buyout price. So if your calls are ITM, you will get shares/cash. I would like someone in the know to confirm this though.
STS - Ha Ha. I had not even looked at the magnitude of the move! Someone on the board implied it was "up big." Maybe that IS a big move for MTNB.
How much do you want to bet that MTNB announces a secondary soon. Seen the same kind of unexplained jumps both here (July) and in other stocks right before secondary.
OBR - Your comments get at a gray zone with regards to Amarin. Is it an established business (like a BP) that should be evaluated solely based on actual earnings, or is it more of a "Bio startup" that can demand a very high valuation due to its predicted potential? We are established in that V is already approved and has been sold for multiple years generating income (so P/E can be evaluated), but we also are kind of a startup in that the expanded label would be such a sea change in prescribing, almost like a new company. I think it is very hard to decide which rules apply here. My guess is that we get treated more like a high value startup in Q1 of 2020, and the longer we go without a BO, valuation tends to move more towards treating it as an established BP. This could cause disappointing PPS performance later in 2020 after the initial hopes of a quick BO wear off (IF they are not bought out). I think a quick BO happens though, with news breaking in mid-January.
When the board gets really chippy, its a sign that big news is about to break....every time. Just relax and wait for it. My prediction is late next week
North - Settling now does take care of the current generic problem and future generic problems, at least from one perspective. IF Amarin has been preparing for a BO, it doesn't matter if there are future generics that could come in a challenge the patents. That will be BP's problem, not Amarin's.
Raf - I looked it up at the time (can't recall now). It was a nonprofit that used to focus on women's health issues, that has expanded its mission somewhat. I think their mission focus is why the woman was so insistent that more data was needed in women. She came in for a specific agenda and said her piece, but I did not think that anyone on the panel thought there were real issues in this regard.
Excellent summary of the patent issues. Looks like Amarin has the upper hand, but not a slam dunk. Seems like the perfect situation to encourage a settlement advantageous to both sides.
TTE - Do you know of any examples of drugs approved earlier than the PDUFA when an adcom was required? How soon after an adcom is a reasonable early approval date based on past experience?
Eight -
Atom -
Jamaal - I totally agree that the "more natural" aspect of V is a positive to the public, and probably many MDs. I just think the investment community is biased to look at "natural" as being lower in value (despite the data). I remember Pyrr using that argument, with the rebuttal being examples such as aspirin, morphine, and Taxol, all of which are natural derivatives and very effective. With so much of the trading done by retail, all you have to do is look at all of the idiotic comments on StockTwits to see the bias against a more "natural" product such as V (although I totally understand that icosapent ethyl is a manufactured molecule).
CBB - JMHO, but Amarin suffers in part from having a product that seems "too natural." Just look at all of the "fish oil" comments. The companies with high tech (e.g., RNAi) products look way cooler, and traders incorrectly assume they must be better drugs and of higher value. In the end, I don't think BP will care though - a dollar is a dollar.
STS - P values for interactions work the same as for main effects, as you suspected. In the tables in text, the single p value is for the overall interaction, and it then lists all of the multiple categories for the variable involved in the interaction (e.g., different levels of baseline TGs). There are no separate p values listed for each level of the interaction variable.
GG - In the full R-It sample (USA and outside), RRR for the primary outcome (soft MACE) was 27% in the secondary prevention sample, and 12% in the primary prevention sample. For the hard MACE outcome, comparable values were 28% and 19%.
In the USA only study (from the supplemental materials), it looks like RRR for the primary outcome (soft MACE) was 36% in the secondary prevention sample, and 16% in the primary prevention sample. Comparable info for the hard MACE outcome is 34% primary and 22% secondary. Based on the error bars presented in the forest plots, it looks like neither of the primary prevention group RRR values is statistically significant in the USA only study (due to much smaller sample size).
In follow-up to my post yesterday, the interactions between drug condition and primary/secondary prevention status were NOT significant for hard MACE or soft MACE in the USA only study. So, results can be interpreted as indicating both groups got the same risk reduction benefit with V. Showing statistical significance individually within the primary and secondary prevention samples is unnecessary - they did not differ statistically
HDG - I think you are correct on this. I do not expect any serious BO offer before mid-January at the earliest (JP Morgan conference is my prediction), and that will likely be after the patent settlement. My main point in suggesting no BO until Q1 2020 was that this is largely driven by inability to value the label yet rather than the pending litigation.
Rose - I think the issue is that with an approved drug and known label, the value for BP of acquiring Amarin can be estimated much more accurately. If rumors of past lowball BO offers are true, it could be that JT is the one who has held off on entering into serious BO negotiations because he realizes that it will be easier to get top dollar once he has hard data (the label) to support what he is asking for. Given how narrow the patent case is now, and how unlikely it is for the patent challengers to prevail, I doubt that the patent litigation is a major barrier to a BO. A settlement of this is very likely from everything I have seen, and a BP would be happy to just pay these patent challengers to make them go away.
Resting - ADA and FDA are completely unconnected. If the label says TGs>150, then that is what insurers will likely use to determine coverage for V. With the ADA recommendatiobn being TGs>135, it means that some diabetic patients who are hoping to receive the ADA standard of care may have to pay out of pocket fro V. I think the R-It data can support a label of TGs>135, as Bhatt has argued, but based on the adcom discussions, it did not seem like the panel was in favor of that interpretation. Maybe Amarin can give up the TG>135 requirement in label negotiations to get something else they want on the label. But I am not really sure how much of a real negotiation this process is.
STS - Sure, but it is a bit complicated. When doing a statistical analysis there are two types of effects you can look at: Main Effects and Interactions. Main effects are straightforward effects of X variable on Y outcome. In R-It, the effect of drug condition (V versus placebo) on MACE outcomes is a main effects analysis. Interaction effects are a bit more complicated, and refer to situations where the effect of X on Y depends on the status of variable Z. In R-It, the interaction that everyone is discussing relates to whether the beneficial effects of V on MACE outcomes depend on primary/secondary prevention status. If an interaction is significant, you then have to see where the interaction is coming from, so you examine the effect of X on Y outcome separately within each category of Z variable. In R-It, this would mean that if the Drug Condition by Primary/Secondary status interaction was significant, you would then have to examine the effects of V on MACE outcomes separately in the primary versus secondary prevention subsamples. These so-called "simple effects analyses" are then interpreted based on the pattern of significant findings within each subgroup. So, hypothetically, if the interaction was significant, and the effect of V on MACE was significant in the secondary prevention subsample but NOT in the primary subsample, you would conclude the the interaction resulted from a significant effect of V on MACE outcomes in the secondary prevention subsample that was absent in the primary prevention subsample. This is how all of the negative commentators are interpreting the R-It data.
In the actual R-It results, the interaction between Drug Condition and primary/secondary prevention was not significant for the most clinically important hard MACE outcome, so there was no obligation to go look at whether effects of V on MACE were significant in the individual primary and secondary prevention subgroups. The lack of significant interaction they reported means the effects of V on MACE were not statistically different between the primary and secondary prevention subsamples, and THAT is the end of the story. V worked for everyone studied in terms of hard MACE outcomes. I think the one stats reviewer at the adcom made her positive comments about approval in both the primary and secondary prevention populations based on this absence of interaction.
Now, with all of that said, I will admit that technically, there was what the investigators considered a barely significant interaction for the soft MACE outcome, with V working better in the secondary prevention than in the primary prevention subgroup. So technically, for the soft 5 point MACE outcome, the commentators are correct in saying that results support V being effective in the secondary but not the primary prevention sample. It is important to note that the sole reason they got a significant interaction for soft MACE was due to their a priori choice to have a VERY lenient criterion for determining significance of this interaction (p<.15). This is atypical in my experience, but I am sure they must have had some reason to be so lenient. I honestly do not know what that reason was though. If they had used the traditional p<.05 level of significance for testing this interaction, it would not have been significant, and again we would conclude that the benefits of V on soft MACE were statistically similar regardless of primary vs. secondary subgroup status. I think what I have described above is the source of some of the confusion on how to interpret the results.
For the soft MACE situation I described, the lack of significance of V effects on soft MACE in the primary prevention group was very much influenced by the relatively smaller sample size for the primary subgroup. They did not have the statistical power to show that the effect they got within this subgroup, which is likely clinically meaningful, was statistically significant. If they had added another 1,000 patients to this subgroup (estimate), the exact same effect they actually reported would have been significant and we would not be having the conversations that we have been having.
My take on all of this is to pay more attention to the most clinically important hard MACE outcome, which found that primary vs. secondary prevention did not make any difference in the benefits of V. We will see if the FDA agrees, but my hunch is that they will. I think we get the R-It entry criteria as the most likely label scenario, with the best case scenario being a label that includes patients with "existing CV disease or with multiple risk factors for CV disease." I think statin use and having TGs >150 will also be on any label we get.
CardioMD - No - You are missing an important issue that I think a stats person made in the adcom. The lack of significant interaction between V and Primary/Secondary on hard MACE (and only p<.15 or so for 5 point MACE) means that they are NOT required to even investigate the magnitude of effects of V on MACE separately in primary and secondary groups. It was not powered to examine separately in subgroups. No interaction means the effect did not differ between groups, and that was the point the stats person made.