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BB & sts66,
I think no direct relation between labeling and patent use code.
I am 100% sure, that Epanova label will be for >500. Something like this (or exactly):
Epanova is a combination of ethyl esters of omega 3 fatty acids, principally EPA and DHA, indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (=>500 mg/dL) hypertriglyceridemia.
Limitations of Use:
• The effect of Epanova on the risk for pancreatitis has not been determined.
• The effect of LOVAZA on cardiovascular mortality and morbidity has not been determined.
Patent use code: The brand manufacturer submits the use code to the FDA as part of Form 3542, and the FDA accepts the code without verifying its accuracy.
The description of the patent use code itself means nothing (just see Lovaza's PUC: U - 822: USE IN LIPID MANAGEMENT) it's just a description.
Look, this unbelievable situation put in my mind of the film from 50's '2 times 2 sometimes 5' ... however at the end it have to be ok, maybe at court, maybe after 2 years, but FDA has a great 'exit point' now.
- dosen of drugs approved for the same indication WITH false studies
- clear safety profile
- FDA broke ALL protocols and own guidances (if somebody know any protocol or guidance which was followed by FDA during ANCHOR process please let me know)
- met all endpoint (events was not an endpoint !)
so, in real life - sometimes not immediatelly - 2 times 2 is 4 ...
ziploc 1,
Nice thought, however it's 'for profit' company and Vascepa is already the cheapest within category (including OTC products - if you calculate the same EPA dosage)
BB,
Done.
I do not understand your logic: why Vascepa's price should be decreased? It's cheaper than Lovaza and generic Lovaza. I did not check it, but I do not know any other case where brand is cheaper than generic.
BB,
Your CP could be supported by U.S. citizen only or by anybody?
HDGabor
I did not / could not check all, but use 'FENOFIBRATE' or 'NIACIN' in search field.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
They are for mixed dyslipidemia ... as Vascepa was denied they have to change the label for all ...
From BD.
Maybe, but their label at approval (12/15/2008) and now (09/05/2012) is the same. The bold 2 was included from 09/30/2011 and underline was deleted by 09/05/2012. So "funny" to read this label ... Studies 'with Trilipix' enough to deny Vascepa indication, but not enough to withdraw Trilipix indication ...
Trilipix is a peroxisome proliferator receptor alpha (PPARa) activator indicated:
• In combination with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and CHD or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal (1.1).
• As monotherapy to reduce TG in patients with severe hypertriglyceridemia (1.2).
• As monotherapy to reduce elevated LDL-C, Total-C, TG and Apo B, and increase HDL-C in patients with primary hyperlipidemia or mixed dyslipidemia (1.3).
Limitations of use: No incremental benefit of Trilipix on cardiovascular morbidity and mortality over and above that demonstrated for statin monotherapy has been established.
General Considerations For Treatment: Fenofibrate at a dose equivalent to 135 mg of Trilipix was not shown to reduce coronary heart disease morbidity and mortality in a 2 large, randomized controlled trial of patients with type 2 diabetes mellitus.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022224s007s008lbl.pdf
birzinho: I could not comment, it's a calculator
stangish,
DMC check the eff. and safety data on a quarterly basis. These data / results available for them only. DMC could to stop the study for safety reason ANYTIME and they could propose to the sponsor to stop the study ANYTIME.
'We recommend that any part of the interim report to the DMC that includes comparative effectiveness and safety data presented by study group, whether coded or completely unblinded, be available only to DMC members during the course of the trial, including any follow-up period—that is, until the trial is completed and the blind is broken for the sponsor and investigators.'
'the interim analyses prior to the first analysis of unblinded data to develop a template for the interim reports.'
read this:
http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127073.pdf
Feel free to download and use it: https://drive.google.com/file/d/0B88p2VqeOjMGdkRsREhELU1RN1k/edit?usp=sharing
correction for #28949. It's about HPS2-Thrive
I found it on YMB:
"I received this email today from the group conducted this study:
I am able to let you know that the paper has now been accepted by a major journal so the next stage is the checking of the proofs when they arrive, etc.
Again this process can take some time and we are unable to predict how long this will take.
Thank you again for your continued interest and patience, I hope to have more positive news for you by the middle of July."
I found it on YMB:
"I received this email today from the group conducted this study:
I am able to let you know that the paper has now been accepted by a major journal so the next stage is the checking of the proofs when they arrive, etc.
Again this process can take some time and we are unable to predict how long this will take.
Thank you again for your continued interest and patience, I hope to have more positive news for you by the middle of July."
BioChica: yes, the DMC are the only ones that have access to interim data DETAILS. General number (ie.: enrollment data, events number, etc. – only as total and not separated by arms) are available for the sponsor.
Kiwi,
I don't know we have to rely on public info and our assumption / calculation.
- DMC did not stop it (nor safety nor eff.)
- mean and median are nort of 200 TG (a'la Thero)
- median folow-up: app. 20 months (based on enroll.)
- total events: 394 w 15%, 351 w 35% (based on enroll.)
but we do not know the early stop's conditions (min. events number / power / eff.).
sts66 & BioChica
sts66,
Theros said yesterday 'I mentioned that the mean and medium baseline triglycerides in REDUCE-IT are north of 200.'
I do not know, whether laugh or cry: ’add-on study ... Efficacy is, of course, established by such studies only for the combination treatment’
You will never find out where I found it ….
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073139.pdf
JL / sts66: read the above doc (1) and this one also (2) – specially
7.2. Accessing Interim Data
7.2.1. DMC Recommendations to Terminate the Study
7.2.2. FDA Interaction with DMCs
http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127073.pdf
‘double-blind (or double-masked), meaning that both subjects and investigators, as well as sponsor or investigator staff involved in the treatment or clinical evaluation of subjects, are unaware of each subject's assigned treatment.’ from (1)
Birzinho / Ajax133: Birzinho has right 150 (and later 200) is the minimum TG level, so we do not know exact TG of enrolled patients (except Thero’s statement ‘mean and medium baseline triglycerides in REDUCE-IT are north of 200'.)
I listened again: Thero said 'north of 200' (two times) - the poster 'mixed' it w Jelis subgroup
'...north of 200s, so at risk population. If one wanted to look at the results of an outcome study done with EPA, which is the active ingredient in Vascepa; (went to) [ph] look at the JELIS study in Japan which is 18,600 patients (being seen) [ph], on the left which is the overall cohort of the trial that compared to statin alone, it was a 19% reduction in cardiovascular events or relatively low risk population.
In our REDUCE-IT study where we are looking at a more at risk population, I mentioned that the mean and medium baseline triglycerides in REDUCE-IT are north of 200. The subgroup analysis for JELIS showed triglyceride levels above 150 adding a 53% reduction ...'
Hi,
I know, but it's too complicated to detaild here (ie.: loss related to set-up of the company usually could be carry forward forever. (The private stock loss carry forward is 2 years in Hungary)
ggwpg - eff.% - events YTD (app., V / placebo))
15% - 393 (180 / 212)
35% - 350 (138 / 212)
sts66 - John Fuson Lovaza CP: as I remember he filled February 13 and FDA answered Jan 2014
Positive. A tax loss carryforward takes place where a business reports losses on a tax return. The logic behind this is to reduce tax liability during a year where the profits are positive if losses were previously. The tax loss carryforward reduces the overall tax liability during the positive year by incorporating the earlier loss as a reduction to taxable income.
So they could use it in 2015 ...
It's good, that drugs.com included it, however I could not count it as a special step:
'Has been used to reduce residually high (200–499 mg/dL) triglyceride concentrations† in statin-treated adults at high risk for cardiovascular disease despite adequately controlled LDL-cholesterol concentrations (40–99 mg/dL).4 5'
References:
4. Ballantyne CM, Bays HE, Kastelein JJ et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012; 110:984-92. [PubMed 22819432]
5. Amarin Pharma Inc. Vascepa (icosapent ethyl) AMCP dossier. Bedminster, NJ; 2012 Oct 17.
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It's already included. It's not in the 'INDICATIONS AND USAGE' section, however you could find it as 'WARNINGS AND PRECAUTIONS':
Lovaza:
- LOVAZA may increase levels of LDL. Monitor LDL levels periodically during therapy. (5.1)
- There is a possible association between LOVAZA and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first months of initiating therapy. (5.3)
Epanova:
- In some patients, EPANOVA increases LDL-C levels. LDL-C levels should be monitored periodically during therapy with EPANOVA. (5.1)
Omtryg:
- OMTRYG may increase levels of LDL. Monitor LDL levels periodically during therapy. (5.1)
- There is a possible association between omega-3-acid ethyl esters and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first months of initiating therapy. (5.3)
All of them (and Vascepa also) contain in the same section:
- In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy.
- Use with caution in patients with known hypersensitivity to fish and/or shellfish.
BB,
Sorry BB, but still could not find it:
Indication is the same since approval (with some wording change):
11/10/2004: 'Omacor® is indicated as an adjunct to diet to reduce very high (>= 500 mg/dL) triglyceride (TG) levels in adult patients.'
05/14/2014:'LOVAZA is a combination of ethyl esters of omega 3 fatty acids, principally EPA and DHA, indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (>=500 mg/dL) hypertriglyceridemia (HTG). (1)'
and Limitations of Use was included at least since 09/16/2009:
'Limitations of Use: The effect of LOVAZA on cardiovascular mortality and morbidity in patients with elevated triglycerides has not been determined. (1)'
tha last change was on 05/14/2014 as detailed in #28802
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist
Where did you find the referred label update?
BB,
What do you mean exactly?
The last changes were on 05/14/2014 and the deletion of 14.2 was discussed on this board.
Main changes:
(Deleted the bold part):
Limitations of Use:
• The effect of LOVAZA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. (1)
• The effect of LOVAZA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined. (1)
Deleted sections:
- 14.2 Other Clinical Experience
- 17.1 Information for Patients
- 17.2 FDA-Approved Patient Labeling
Fasten your seatbelt!
'because the indication had already been granted based on numerical improvements and supported by regulatory standards of the time, this should be honored until further information on clinical outcomes were available'
Trilipix withdrawal - it was discussed during Trilipix's AdCom after Accord-Lipid (the citied part is from Vascepa BD, Accord-Lipid part, reviewer comment, page 85)
KOWA/Horizon - Agree. I just want to point, that BP are not always good as a partner.
No, as I remember they cancelled only one presentation in January waiting for Division's decision. They were presented on Leerink Conference in February.
These 2 presentation are nothing special, just business as usual.
I do not expect any news regarding the appeal before end of July as the earliest.
So if ANCHOR approved and R-IT stopped for eff. 'tomorrow' we will not see pps increase? Due to the balance sheet and debt?
AstraZeneca CEO (Pascal Soriot ) On His Predecessors, Rivals, And Pfizer
by Matthew Herper
Fish oil: “We didn’t pay a lot of money for this thing, right?”
Matthew: One thing you purchased was the fish oil product, Omthera. If there is such a thing as great fish oil product, it looks to be a great fish oil product. Do you have NCE (New Chemical Entity designation) on it?
Pascal: Not yet. The problem is because Amarin has launched a legal case. Basically, I don’t think we’ll know about the NCE status until that Amarin case is settled.
Matthew: What makes you confident that a fish oil will do well, especially given all the meta analyses and the flood of data saying that at relatively good doses, you’re seeing no benefit on heart attacks and strokes?
Pascal: First thing is to keep in mind is we didn’t pay a lot of money for this thing, right? The upfront money was limited. Essentially, the idea was it’s going to pay for itself if we market it only in the high triglyceride patients. If we actually get an indication and show benefit in the lower triglyceride population, so mixed dyslipidemia, then it’s going to be big. If I start with the high triglyceride, more than 500 milligrams per deciliter, there is a very strong synergy here because most of those patients are treated by endocrinologists, lipidologists. Those are physicians we visit for our diabetes franchise. I think we can certainly do relatively well in that population. Of course, it’s limited. Now if you move to this mixed dyslipidemia… It’s a scientific question of course, so there is a lot of debate around whether it’s going to work or not.
Matthew: Are you committed to doing the outcomes trial to prove it can prevent heart attacks and strokes? You’re not going to pull funding for the outcomes trial? You’re going to do it?
Pascal: I happen to believe it has a good chance of succeeding. I’ll tell you why. It’s that first of all, people look at triglyceride studies across the entire population. They look at fish oils, if you want, at different doses. First of all, you have to have the right dose of omega-3, you have to have the right mixture and secondly, you need to have the right patient population. Those patients, they have to have triglycerides at least above 150 milligrams per deciliter. It’s clear that you can’t show a benefit below this level.
If you look at the analysis the FDA did, and that is a public analysis, if you look at the patients that have triglycerides above 150 and low HDL. They have to have a low HDL and triglycerides above 150… there is reason to believe that it would work on that population. If it works, then the opportunity is quite large.
Let me some thought (without medical background):
- expected event rate in R-IT placebo group is 5,2% / year
- we know that the event rate was around 1% / year in Jelis (without or with low dose of statin) - 80% lower than R-IT placebo group
- it looks like that statin does not decrease AA/EPA ratio (based on the citied study it increase)
- EPA decrease AA/EPA ratio significantly
I do not say that we will see the same event rate in R-IT Vascepa arm, but I believe the group will be 'transformed' to Japanese and the eff.% could be around 40%
Nobody said it should be $20 at this point ... 'If these problems get cleared up and Amarin gets the 35 mil man cohort the stock will go to $20 plus'
Regarding sales force:
'We remind investors that on November 19, 2013, Pozen announced that Vimovo commercialization partner, AstraZeneca AB, has entered into an agreement with Horizon Pharma USA whereby Horizon acquired the U.S. rights for Vimovo.'
'As a result of the acquisition of the U.S. rights to Vimovo, Horizon began the expansion of its sales force to approximately 250 primary care representatives and 40 rheumatology sales specialists. The company completed the hiring and training of the expanded sales force in January 2014 and began full promotion of Vimovo in early February 2014.'
'After all, 2013 U.S. Vimovo royalties totaled only $2.1 million on sales of $21 million. Well, based on the breakdown of royalties in the first quarter alone, Horizon will crush that $5 million minimum payment by the end of the second quarter. For 2014, we think it is likely that Horizon does over $100 million in Vimovo sales, putting Pozen's royalty at greater than $10 million from U.S. sales alone'
con’t:
Based on FDA' logic I changed my mind and I think we have to stop Reduce-IT (however it will be successful), since it will not provide enough evidence relevant to the specific Vascepa coadministration indication to warrant grant of the indication, however R-IT demonstrated unequivocally additional cardiovascular benefit from non-statin lipid-modulating drugs, so FDA will allow the indication for other non-statin lipid-modulating drugs (ie.: Lovaza and Epanova), but not for Vascepa ……
I see your approach, however the target population is indifferent until they not include ‘to reduce risk of coronary heart disease.’
The FDA’s problem with the indication is the TG level (=200 to <500 mg/dL), since according to their view ‘FDA has historically considered granting approval for lipid-altering drugs based on favorable changes in the lipid profile, with the assumption that these changes would translate into a benefit on clinical outcomes.’
‘Dr. Colmam: I also think that if ACCORD Lipid and AIM-HIGH and THRIVE were positive, I think we would have a different discussion today.’ (October 16, 2013, AdCom).
I think that if ACCORD Lipid and AIM-HIGH and THRIVE had not been done we would have a different discussion today.
We have a problem due to the (citied), three negative studies’ interpretation, not because of indication or safety.
Don not forget, since 2008, Trilipix is FDA-approved for use in combination with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and CHD or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal.
The debate is about that ACCORD Lipid and AIM-HIGH and THRIVE result could be or not extend for Vascepa.
FDA said yes, while I could not find any parameters – except that patients were on statin – that match with ANCHOR.
Parameters / ACCORD-Lipid / AIM-HIGH / THRIVE / ANCHOR
TG > 200 mg/dL / no /no /no / yes
HDL-C < 39 mg/dL / no / no / no / yes
contains EPA / no / no / no / yes
on statin / yes / yes / yes / yes
CD risk reduction / no / no / no / ongoing trial
Furthertmore ‘some members felt there was not enough evidence from the ACCORD-Lipid trial relevant to the specific Trilipix coadministration indication to warrant withdrawal of the indication. Others felt that with no additional relevant clinical evidence provided by ACCORD-Lipid, and because the indication had already been granted based on numerical improvements and supported by regulatory standards of the time, this should be honored until further information on clinical outcomes were available.’ and if we see the subgroups – TG and HDL-C parameters were comparable with ANCHOR’s – ‘we .. have a different discussion today’
It’s unacceptable that the 3 studies – with different parameters - enough to determine that substantial scientific issue essential to determining the efficacy of Vascepa and were not enough to withdrawal of other drug’s indication (specially where they found a safety issue.)
Top of it, it’s also unacceptable that they determined the issue in the BD only, not ANYTIME since the publication of Accord-Lipid or since March 2013 when the latest FDA’s reason was published.
Thx BB,
Anybody could check the exact status: 'PATH FORWARD: Appealing to higher level, John Jenkins, MD, Director, Office of New Drugs in mid-’14'
Was it submitted or not yet?
Yes and no.
Yes: Vascepa could be THE anti-inflammatory drug, but it's a new sNDA.
No: The problem is the FDA determined that a substantial scientific issue essential to determining the safety or efficacy of the drug in the BD on Oct 11 2013. Not in 2010 (Accord-Lipid), not in 2011 (AIM-HIGH), not in February 2013 (sNDA submission), not in March 2013 (HPS2-Thrive). It is fact and not interpretation.
Of course – top of this – their background / reason – is wrong due to several reason (other studies’ target group / type / side effect, etc.) as it’s discussed on this board, so I am not repeat it again.
So the FDA 'has to' protect both the background and the timing, 'as a matter of public policy and fundamental fairness to the sponsor, FDA should be accountable for continued diligence in identifying issues that bear on the continued enforceability of a SPA agreement and in notifying the sponsor of such issues within a reasonable period of time after FDA becomes aware.'
You have right.
For everybody who is still saying that AMRN indicated CVE reduction:
Please, do not it as attack, but if you do not understand it, you have to blind or has dyslexia:
Since John King misunderstood the indication, he 'challenged' its wording:
‘On February 21, 2013, the applicant, Amarin Pharma Inc., submitted an efficacy supplement seeking to substantially expand the treatment population of AMR101 to include patients with mixed dyslipidemia who are at high risk for coronary heart disease and who are already being treated with HMG-CoA reductase inhibitors (statins).’ (BD by FDA)
Bruno said (something like this): ‘it’s not unusual to include the TARGET POPULATION in the indication’
and as I wrote the FDA said: ‘Although the indication strictly speaks to reduction in lipoprotein levels and improvement in numbers, this indication for this population certainly implies that one should expect cardiovascular benefit from treatment.’ by FDA / Mary Roberts, Oct 16 AdCom
They already started deferring (x instead of y):
0,8M - 2,5M for Q313
1,0 - 2,5M for Q413
1,1M - 8,0M for Q114
Thx for Budapest.
Zsa-Zsa: yes
I am really Hungarian, did not take Vascepa. 'Sleepless' is the sideeffect of AMRN/Vascepa pps ...
I took - just as suuplement - OTC product (Vegepa - 'pure' EPA, but only 280mg) and will try Lovaza/Omacor now since L/O is OTC product in Hungary (as I know the only country in the world w/o prescription)
Definitely not. It's not usual and as mrmainstreet wrote (#28558): 'I spoke to Mike in IR today and he was not able to confirm the congressional scrutiny was generated from their legal/lobbyist teams, and said company would not speak on the matter publicly.'
I think the upcoming 2/3 months will be really exciting , since if we will not see script increase with KOWA and positive answer from OND we will not have significant event till R-IT interim data (mid 2016).
I am not sleepless, it's just side effect of Amarin/Vascepa
Hungary.
Yes I know, however I am using the number as 2 weeks 'old' (since 04/18, when short week was significantly higher then the previous and the next full week was lower than short week), so it will be the week 05/23 (for me).
But we will see.
btw:
Anybody knows the source of the weekly number. Is it Symphony or IMS? Always the same every week?
Any updated table (link) for scripts?
We agree. I just said the the CAP is not enough: more control on cost and increase script #.
Based on available info, forecast, etc. currently guess +/-0 CF in Q215.
R-IT: Meanwhile hope that JL has right, I agree w u: it's not a simple math.
2 small piece for R-IT:
- 'All DMC meeting to date have recommended continuation of study as planned' (page 69) and
- I know it's a small chart without data (and we do not know the reason for it), however check the blue line position compared w pink ... (page 73)
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM371763.pdf
(Since last week I missed NRx by -4 and Refill by +100, my bet for this week: NRx - 3,672, Refill - 4,260, TRx - 7,932)