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I think they have some reason to plan it as 5,2% (if it is the overall rate, then placebo rate is 5,62%)
All we know that AF was negative / bearish regarding the AdCom well before the meeting and he was right.
By end of July he wrote a „bullish” article (“Jenkins might also chicken out and kick the appeal decision up even higher into the FDA's top ranks”) around (or after …) the official delay that was available to public one week later …
But the most surprising thing (for me) that on July 10, 2014 he wrote “Timing an FDA response to the appeal is tricky but we may hear something late summer or early fall”. I was surprised since he is familiar with the FDA process, so I am just wondering at that time why he predict this and not end of July / early August or middle fall (Oct / Nov) as next level. It is not a question now.
He has right
1 time – he is lucky, good guess
2 times – hmm … (and the second projection was strange for me)
3 times ? - hopefully, but WTF
Hi Kiwi,
The app. 5.000 (as May 2013) is my calculation based on the enrollment data from AdCom presentation.
The data as Oct 4, 2013 and the categories were 3/6/9/12/15/18 months follow-up (5.535/4.451/3.043/1.756/5.75/108 patients).
Agree, however just partially. Do not forget if ANCHOR approved it will be different world.
Independently from ANCHOR, we will be screwed earlier if we have to wait for final result and R-IT will not stopped based on interim data.
Why they launch it? Their science is outdated … Acc. to new science less than 500 mg/dl TG should not be treated …
The new science: "one size fits all" ... use statins (c) BH
Hi Ajax,
1.) More than 2.000 (app. 5.000) was enrolled before criteria change in May 2013 (due to low event rate). However the 150 (and 200) mg /dl was the minimum level and not the real level. I am not remember exactly where (maybe GS conference) Thero said that the median and the mean TG are north 200 mg / dl.
2.) The planned Power is 90% (at 15% eff.) and total event is 1.612, however if eff.% is higher the same Power could be reached (see: #28220) with less event. The enrollment is totally as planned originally, it was not slow down after AdCom. Current enrollment is over 7.000 and will be 100% in Q1-2 2015.
3.) Timing of result (both interim and final): It depends on the real event rate vs planned and real eff.% vs planned. We do not know any of them, but it is "funny" that higher eff.% will be lead to later result.
Interim definitely will not reached before 2016 Q1 and final before 2017 Q3. It is just the "date" of the last event and analysis will take - at least - additional 6 months.
So if real (placebo) event rate is lower than planned and / or eff.% is excellent 2018/19 is possible as final.
Not exactly. The placebo arm(s) is hurting the Lovaza /statin results while helping the Vascepa /statin results. The "strange" lipid-change in the placebo arm could be a result of a lot of thing, not just the corn / mineral oil.
AMRN slide (CM-14) listed several studies (with different mineral oil quantities 2-5g) and the lipid-changes were different: ie: TG some times up, sometimes down, HOWEVER if we see the same dosage (ie.: 2g in 4 studies) it is the same: TG some times up, sometimes down.
Nobody (inc. FDA) knows the exact reason behind the lipid-changes in placebo arm
Every long term study has at least one interim analysis (IA) and IA has a stopping rules. IA is not equal with stopping rule, so AMRN's stopping rule is not the 60%. It (967 events) is the "time" of interim analysis.
R-IT's DMC has a meeting on a quarterly basis and they could recommend the early stop anytime, but usually at interim analysis, just like in case of Jupiter trial, which was stopped early, after the second interim analysis with 328 events and a median follow-up of 1.9 years at the recommendation of its Independent Data and Safety Monitoring Board.
Lovaza study was referred as other omega-3-acid study, not as a minerail oil placebo study. Lovaza decreased TG levels by 26% to 47%, whereas corn oil placebo increased them by an average of 6.7%.
Furthermore FDA did not attack the mineral oil as placebo, does not penalizing AMRN for it. They checked the placebo arm (due to strange lipid changes) and during this analyzes among with other possibilities, they check the mineral oil also.
"Thus, the review team sought evidence that might help explain the changes observed in the mineral oil group. These included considering the plausibility that treatment assignment could have been unmasked due to physical differences in study drug appearance or manufacture; reviewing the literature for mineral oil-specific effects on lipid parameters or absorption of fat-soluble vitamins; evaluating whether the statintreated subjects in the placebo group from MARINE demonstrated a similar pattern; and considering elements of the ANCHOR study design that may have contributed. Finally,the Division reviewed lipid changes observed in the placebo groups of other lipidlowering trials."
Everybody has to decide itself, which is worst: "a stupid soothsayer or a clever liar" ... (stupid means wrong)
It is not possible. Too much elements in a lot of study should be determined for placebo (ie.: I do not know the color and exact smell of coconut oil, but I assume it is not good for Vascepa’s trials as a placebo).
FDA (and every authority) has to be proactive as issuing clear guidance for new issues, and acting fast and according to laws, rules. FDA is not top of it.
btw: Meanwhile they did a lot of unacceptable, unrealistic action in case of Vascepa they handled the placebo “issue” correctly. They done their job when analyzed the possible effect of mineral oil (placebo arm was the basis of eff., doubt is exist regarding mineral oil, lipid changes were atypical) and I have to say they were totally correct: check all possible reason (not just the oil) and come to the conclusion: strange, but ok. I do not think that anybody could criticize them for this. Furthermore, maybe they could set-up a better argument based on the placebo arm (mineral oil) to screw AMRN than the referred studies, but they did not use this “issue” against AMRN.
We do not have to speculate. The sealed info is AZN’s plan regarding commercial launch of Epanova (the details were sealed). It is not speculation, it is in the filed documents. It is still sealed for the public, however maybe unsealed for AMRN. If it is still sealed for AMRN, we have to wait till the judge issue the order to AZN to unseal the info.
Summary:
July 29 & 30 (Based on Document #20 filed 08/25 in support of #18): AZN’s counsel shared info (“regarding Defendants’ plan for Epanova”) with AMRN’s counsel (John D. Adkinsson) as “Outside Counsel’s Eyes Only”
Aug 18: AZN filed #18 as “…filed under seal pursuant to Local Rule 26.2 and maybe viewed by outside counsel only”.
Aug 25 – AZN filed #17, AMRN filed #18, #19 and #20
#17 – It’s the „Redacted – Public Version” of AYN’s #16. (Some line, sentence disclosed (black out) in the available doc for the public, but maybe it is for the public only and not for AMRN, so AMRN – again maybe – know the details of AZN’s plan.) AZN’s new argument – LDL increase is greater than 20% compared to baseline in Epanova arm - raised for the first time.
#18 – AMRN requested “(1) strike the “Outside Counsel … “ designation …. (2) …grant … to file a surreply” and an attachment “”[Proposed] Order …]. They (AMRN) worded the proposed order as “The “Outside …” designation … will be stricken … file a public brief within three days of this Order …”. It was not a judge’s order it was a proposal from AMRN. This is the reason why we did not see any unsealed doc on 08/28.
#19 – Support of #18: AZN improperly filed #16 under Local Rule 26.2 and to file a surreply. This doc includes AMRN’s reaction to AZN’s new argument, as the patent is “as compared to a baseline or a placebo arm”)
As I see we have to scenario:
a.) #17 was blacked out for AMRN also (not for public only) – waiting for Judge’s answer to #18
b.) #17 was entirely available to AMRN (blacked out for public only) – AMRN has to file a reply
Both scenario are due on 09/08 (using BioBill’s 2 weeks)
JL,
I know that the mineral oil is not an undisputed placebo. Since I am not a physician I judge the issue as a manager (the best interest of the company, what and when has to be done):
It is not heads in the sand. Without detail the current situation I think (hope) we could agree that no urgency. (My) reason to do not run a trial:
- they does not have to “help this public relations issue”, until it is not their real and not just theoretical interest
- the DMC pay a special attention to this during the R-IT (at least in the last 2 years) and no issue was raised (as we know)
- based on the fact that 8-17 weeks studies showed different results (AMRN AdCom slide CM-15) it will / could not be a small and short trial
- as R-IT is the longest trial with mineral oil placebo, maybe it will give the answer (no dedicated trial will be necessary / requested)
- “If we do not run the trial, then the possibility someone else does and if there is such an effect it will hurt Amarin.”
a.) maybe never. It is “if” / theoretical, but if AMRN run the trial it will be fact
b.) at least not their cost
c.) they still could start a second, own trial
- they are in “cash freeze” mode
I do not say that they do not have to run this trial at one point in the future. However it’s not sure and definitely not now.
Central European Time
Exactly, glad to see your agreement.
But the "news" was that on Friday (btw: the same day, January 17, when FDA officialy informed AMRN about no reinstatement ... FDA was so quick to write down and send it on the same day ... Maybe the quickest action in FDA 's history) FDA negotiated with AMRN the SPA. Not sNDA, label or something else.
I just would like to point that the "news" is not logical.
Wow, they are working during weekend ...
-----------------------------------------
Saturday, August 30, 2014 9:19 AM
Dear Amarin,
Please inform me how you will inform shareholders about OND’s decision.
a.) Will you release a PR “immediately” in both case (reinstatement of SPA; uphold of rescission) or
b.) release PR in case of reinstatement / announce uphold during the next quarterly conference call
Kind regards,
HDGabor
shareholder
-----------------------------------------
Sunday, August 31, 2014 7:38 PM
From: Investor Relations
Hello and thanks for your question. I cannot get into specifics on how we will disseminate information, however, when there is a material update we will issue a public announcement at that time.
Agree, it is history, we have to concentrate on the present and future.
The current situation is a non-sense, it is over a normality and very frustrating to all long (including myself). Most of the posters try to add something useful (facts or assumptions). Sometimes the assumption is not good, but supported by something.
Just an example:
BB expected the unsealed document on 08/28 based on a document submitted on 08/25 contains „… file a public brief within three days …”. So his assumption has a background. The reason, why he was wrong that the document was submitted by Amarin and it was a “Proposed Order” not a Judge’s order.
Regarding the “all FDA wanted, saving face and revising the SPA” in 2014, everybody has to make own judgment. It’s logical or not, realistic or not. I have my own based on facts, as:
SPA: it’s about the study (size, design, etc.) and nothing else – ANCHOR SPA: 19 May 2009
SPA sometimes modified before and during the study – ANCHOR modification: 10 March and 27 May 2010
ANCHOR start and end: 16 December 2009 – 21 February 2011
Study result (database unbliding): 29 March 2011
FDA accepted the study as it was according to SPA
My conclusion: revising the SPA in 2014 will not change the study (it was finished), the result and anything else, since it’s about the study only …
However, I have an open mind, so if anybody has any idea how could be the SPA revised after the study finished and result released to affect anything, let me know.
LMAO
SPA rescission and ANCHOR approval comes together.
Regarding "Amarin got a chance in January 2014 to "negotiate"." and FDA "blew the whistle at the end of Friday negotiations, it was Game Over".
It was January 17, 2014 (Friday).
I do not know it happened or not. I do not know that FDA would like to agree or not.
I know one thing only FDA was well prepared for the outcome of the meeting since "On January 17, 2014, the Company was notified by the FDA that it does not intend to reinstate the ANCHOR SPA agreement."
ps.:
Gents - Stop to attack each other.
JL,
Not as a physician, but as a manager:
Current situation: Some doubt is exist regarding mineral oil, based on ANCHOR study. However other studies suggest that mineral oil does not have clinical effect, especially in this dose. FDA accept the mineral oil as placebo and they concluded that the best measurement of Vascepa is to compare to placebo arm. “Because no strong evidence for biological activity of mineral oil was identified, ultimately it was concluded that the between-group differences likely provided the most appropriate descriptions of the treatment effect of AMR101 and that whatever factor(s) led to the within-group changes over time in the placebo group were likely randomly distributed to all treatment groups.”
I do not see any reason now, to come to different conclusion in case of R-T. Based on this I do not see a necessity of the trial now. Based on current situation it will not necessary ever.
If anytime in the future – after interim / final result of R-IT or based on any other study - it will be necessary they will have enough time (before sNDA submission or AdCom, if any) to run this type of study.
My view: The real gamble is to run a trial now (result could destroy R-IT), meanwhile FDA did not request it, did not stated that eff. is definitely overestimated in ANCHOR due to mineral oil.
The result of the trial is ‘the answer for a never asked question / request’.
Yes patents are often bought and sold and yes AZN is interested in buying one or more patents from Amarin (since they could not launch it legally / claim free now.)
However I do not think that AMRN will sell / license any of the patents to anybody. AZN will not offer high enough royalty or fix amount to off-set the disadvantage of marketed Epanova.
It looks like the best option for AZN if they write-off the purchase price of Omthera or ...
I try to summarize the key point regarding the mineral oil.
Let’s start with the final sentence of FDA: “These results suggest the changes in ANCHOR are atypical, but the etiology of this remains unclear”
Choice of Placebo - Corn oil, which had been used as a placebo in other trials of omega 3 polyunsaturated fatty acids, contains triglycerides and has a distinctive yellow color different from icosapent ethyl (colorless). Therefore, Amarin proposed to use light mineral oil, NF, in the placebo capsules for the pivotal studies. The FDA agreed that light mineral oil was acceptable as a placebo as long as the amount per capsule did not exceed the amounts in FDA-approved products given by the same route of administration.
FDA already noticed during the review of the MARINE data, that several lipid parameters increased from baseline to week 12 in the placebo group, treated with mineral oil (and earlier in case of Lovaza trials also, and these trials did not use a mineral oil placebo), however no strong evidence for biological activity of mineral oil was identified. (Note: The LDL-C change in the placebo arm was -3,0, -8,0% w statin, 0% w/o statin).
FDA analyzed the placebo group in their BD (PDF page 57-59 / Page 53-55 of 94, 5.5 Placebo Group Effects) and Amarin presented mineral oil related slides Amarin Presentations ((PDF page 99-103 / CM14-19)
All AdCom Materials (scroll down the page to find as October 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee)
My view: Since the result was atypical it’s normal that the FDA raise this "issue". However, meanwhile the FDA definitely screwed AMRN, they did / could not come to the conclusion that the mineral oil is not inert. The strongest that they could say was: “These results suggest the changes in ANCHOR are atypical, but the etiology of this remains unclear”
The issue already discussed with sponsor, relayed concern to DMC of R-IT. I think it will be analyzed again for R-IT, however they will not have any evidence about “not inert” and if – as expected – eff.% will be greater than 20-25% it will not affect the approval.
115-125 that different than 175-190
No, it's not possible and I agree w Kiwi no BO before ANCHOR approval.
But hey, it's just two weeks left till SPA reinstatement and after that few weeks till ANCHOR approval.
If ANCHOR approved, BPs will not let AMRN to reach R-IT interim as an independent company, somebody will BO (before 2016)
BB,
Take a breath.
The company was not destroyed, it's still exist. After SPA reinstatement, which is equal with ANCHOR approval (we have a good chance, so I increase my previous 60% to 61% ) the chance of the BO will be much higher than ever before.
Hi Kiwi,
1.) I do not think. It's not realistic and I guess technically not possible. (Not enough time to organize a shareholders meeting).
2.) My guess - $20+ in case of yes, $10+ if no from the current level
3.) no: below $1,60, yes 28417
AZN / Epanova: I just pointed that it is not too simple to raise the DHA quantity as you suggest, I do not think that they will change the composition and I do not think that they will launch Epanova ever (without pay penalty to AMRN or before BO AMRN).
They need to add enough DHA to to raise the LDL level in trials from what 15% to 20.1% to avoid any infringement ....is roughly my take
BB,
We do not have to speculate what was sealed since, from #17, #19 and #20 we know that the Sealed Part is AZN’s plan regarding commercial launch of Epanova. Sealed part contains the exact info about it (and as AZN said it’s not imminent), so we know the topic, but not the details.
Other reasons why it could not be “the intension to Aquire Amarin”:
- I never heard any acquisition where the intension was hidden from the target company
- if they are talking, they submit a joint (or separate) request to the Judge to suspend the case
No BO will happen before JJ’s decision, since it is not makes sense for any parties.
AMRN: do not accept any offer below – let’s say - $15
Buyer: do not offer at least $15, since the answer still could be no
Regarding timing / dates (I do not know the local rule so I use your 2 weeks / 14 days):
09/01: Why the Judge has to reply anything regarding #16 (08/18)? The answer to AMRN request (#18) is due on 09/08, since it was filed on 08/25.
09/11: how did you get it? Nothing happened on 08/28. If you get 08/28 as 08/25 + 3 days it is false, since on 08/25 AMRN filed a proposed order, but it has not issued yet by the Judge
I think TRx is interesting. NRx "just" predicts future.
It's within the 1,15-1,25 range since January 2014 (except 1 week w 1,4). The reason given by mrmainstreet makes sence for individual week, but still strange for this long period (why in case of V only and not at other drugs)
3,5% vs 2% - the reason is refill change was +0,7% only (4,801 vs 4,767).
Since January 1 2014, the Net Revenue is not based on reported script number, it's based on delivery to wholesalers.
10-q: "The Company commenced its commercial launch in the United States in January 2013. Prior to 2013, the Company recognized no revenue from Vascepa sales. In accordance with GAAP, until the Company had the ability to reliably estimate returns of Vascepa from its Distributors, revenue was recognized based on the resale of Vascepa for the purposes of filling patient prescriptions, and not based on sales from the Company to such Distributors. Beginning in January 2014, the Company concluded that it had developed sufficient history such that it can reliably estimate returns and as a result, began to recognize revenue based on sales to its Distributors. The change in revenue recognition methodology resulted in the recognition of previously deferred revenue. At December 31, 2013, the Company had deferred approximately $1.7 million in amounts billed to Distributors that was not recognized as revenue. This change in revenue recognition methodology resulted in the recognition of such deferred revenues in the three months ended March 31, 2014."
The 97k is not an estimation, it was based on 10-Q
97,554 “120 capsules” were delivered to wholesalers and the net price (after allowance, discount, etc.) was $129.22. – Method: (Revenue + allowance, discount, etc from 10-Q) / $195.04 (wholesale price)
Thx, makes sense.
Maybe my request / question was too sophisticated ... – “who has an idea … why?”
So, let’s try it as simple as possible:
If anybody has an own idea (not a fantasy), please let me know, since I do not have.
JL (or anybody else who has an idea),
The Q2 weekly reported script number (96k) is matching with my calculeted number (97,5k based on 10-Q numbers).
However I still do not understand why the refill / Nrx ratio is so low: 1,15-1,25. As I know the "normal", usual rate is 1,75 - 1,9.
The current number suggest that only 60% refill the script (or 20% refill it only once, not twice).
Why?
Hi Kiwi,
The AMRN vs AZN / Omthera case is about 662 patent.
The 662 patent: which requires that treatment with claimed formulation not increase LDL-C by more than 20%
AZN's noninfringement argument is that Epanova had an LDL-C increase of greater than 21%(2g) and 26%(4g) relative to baseline within Epanova arm.
However the patent is "against a baseline or a placebo arm".
Epanova had an LDL-C increase of 13%(2g) and 15%(4g) relative to placebo arm within Epanova study.
The case / claim not related to Marine, to Anchor or to statin.
The R-IT study design is 5,2% event rate and 15% eff. It's not 100% clear for me that the 5,2% for the entire study or for the placebo (statin only) arm.
If it is for the entire study than the estimeted placebo arm's event rate is 5,62% as (5,62 + 5,62*(1-0,15))/2 = 5,2%.
They modified the TG criteria in May 2013 (min. from 150 to 200) due to lower than expected event rate.
Yes
Epanova / LDL-C:
- compare to baseline higher than 20%
- compare to placebo arm lower than 20%
If mineral oil effect statin absorption and Epanova had used it the difference - compare to placebo arm - is lower and not higher since the change in LDL-C within placebo arm is higher.
AZN's actions re infringement lately have been all about the placebo effect in Amarins trials