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I wish they saw it as such.
What if Amrn / its BoD or interested large stakeholders are parties to a pre-agreed legal agreement such that in engaging Covington or other legal counsel they may not sue the legal representation either directly or by proxy for "incompetence"?...Would this even be possible? It might explain why Amarin cannot be seen to be aiding or abetting a Rule 6o motion that alleges precisely this by inference. It might also dredge up evidence that could be used in a class-action suit for a malpractice case against Covington.
Kiwi,
While the associations between thrombotic vents and mortality have been well recognized in the early phases of this pandemic in the USA and China and Europe, the associations mostly reported are venous thromboembolic events. Though arterial events such as strokes were reported previously as increased, now comes a retrospective case series showing an association of SARS-CoV 2 infection with spontaneous arterial thrombosis. It is no surprise that D-DSimer, CRP Ferritin sed rate and many other acute phase reactants are up in this disease--D-Dimer is a marker on thrombosis though the causality link between the D-Dimer and CRP levels and thrombosis remains unknown. But yes the Cardiolink-9 study demonstrated that Vascepa reduced all these markers- and yet with Vascepa the reduction in inflammatory markers may be a concomitant effect of drug action without being necessarily directly related to the actual mechanism of action.(reference R-IT TG and serum EPA levels)
HK
CBB,
I agree EPA levels are key. We also have to ask if taking oxidized fatty acid by products and DHA along the way is good either?
Nissen like all physician prescribers are free to punt based on judgement. One would have to prove gross disregard of accepted guidelines and practice eg a physician failing to lower a BP of 220/120 with symptoms in a patient presenting for evaluation who then succumbs to hypertension and stroke). Not easy to prove if the ACC and AHA have not yet finalized Vascepa in their lipid and CV risk prevention guidelines...
sts
CBB,
No one can sue an academic author for slander for publishing peer-reviewed or editorial material in the spirit of academic discussion in a scientific journal. That said, there is clearly a group of doubting Thomases that want to point the finger at mineral oil or a least raise the possibility that some effect of R-IT was due to the mineral oil. The evidence is heavily against it in my opinion. However, one of two things will have to happen to lay this to rest: (1) A separate independent randomized trial of Vascepa against corn oil reproduces R-IT type effects or (2) A mechanistic trial of some sort showing comparable inert actions of mineral and corn oil is needed--olive oil is considered to be lipid changing so not used---though at a dose of 1g/day in 15,480 diabetics (primary prevention) there was no difference in outcomes between an EPA-DHA Omega 3 mixture and olive oil in the ASCEND trial. In my view, a comparison of corn and mineral oil directly is a more efficient and doable construct than redoing R-IT with a corn oil placebo. I would suggest the randomization of high-risk (including diabetic) secondary CV event prevention cohort to either corn oil or mineral oil capsules and seeing whether the two event rates differ longitudinally across time (minimum 2 years+ based on the R-IT event curves). This would be ethical, given the equipoise in beliefs regarding mineral oil and the lack of mandated CV guidelines by the ACC or AHA regarding Vascepa use, and the trial enrolees should be offered Vascepa on completion of the trial, and followed for event rates thereafter...this will yield an answer a lot quicker. An imaging sub-study would seal the deal. If the event rates were no different in the corn oil and mineral oil arms, and then reduced in both arms, after switching to Vascepa, the evidence would be conclusive.
HK
Jasbg,
These listings are very "informative" and the warning is quite ironic if not hilarious: It warns about the illegal online sale of unauthorized generics..
I put my own warning in:
As to the other site, it clearly identifies Greg Curfman the deputy editor of JAMA as being the editorial instigator of this mineral oil hand wringing and 'deleterious" effect criticisms. This is interesting because he was co-author with Bhatt on the Nature bIotechnology article, criticising the statistical methodology in MORI at the Nevada trial:
HK
DAR,
Text can be copied using the conventional functions CTRL C and CTRL V. The images you will have to upload. Go to settings and click my pictures. Then under the image upload function that appears, click choose file then upload. Once uploaded, there are options to embed or insert a direct link. Let's say you wish to embed the image into a post, simply copy the embed link (CTRL C ) starts with/ends [chart]...[chart] and paste (CTRL V) into the spot in your post where you want it located.
Hope that helps. If not let me know and I can do it for you.
HK
DK
Working at it feverishly.
HK
AGREED
MARINE WAS INFORMATIVE BECAUSE IT DEMONSTRATED UNDER CONDITIONS OF LPL ENZYME SATURATION AT TG'S >800-1000 THAT VASCEPA COULD STILL REDUCE TG'S AND LDL AND APOB (UNIQUELY AT THE TIME OF PUBLICATION OF MARINE AND THE REASON FOR THE MARINE PATENT ALLOWANCE. CONTRARY TO WHAT WAS ACCEPTED AS SCIENTIFIC FACT IN THE NEVADA COURT NEITHER MORI OR KURABAYSHI ESTABLISHED THAT THIS WAS ACHIEVED PRIOR TO MARINE. THE PATENT EXAMINER RECOGNIZED THIS BUT NOT THE COURTS
So unlike Judge Du, she is not a complete scientific illiterate judging complex patent issues. Must be a positive in there somewhere, if not for Amrn then for society.
HK
Here is the article that makes the point that whether you reduce LDL to below 100 mg/dl or not ( IMHO a good thing to do anyway), IF you don't correct the remnant cholesterol (VLDL) elevation through Mediterranean type diet, exercise weight loss, control of hypothyroidism, diabetes, etc or use of medications (VascEPA), then MACE events continue to escalate. It fits with R-IT and the high TG elevated VLDL risk story, and is categorical proof of the deleterious effect of elevated uncorrected remnant cholesterol over a prolonged period of time...Since the world is exploding with morbid obesity and diabetes and inactive lifestyles with carbohydrate and lipid-laden processed foods, there is trouble awaiting down the road.
Ralphey--all true but they say "take a statin" if you don't like the LDL rise. I know its crazy!
DAR
I am not sure about the dynamics of rep activity to be perfectly honest--I was giving you my gestalt. But I do think they are in a bit of a bind because many offices are closed, some are not receiving reps (ostensibly due to covid), and virtual access to MD's is a very limited affair even with a free drug lunch. So it the best of a bad job scenario. I think direct to MD/prescriber email about Vascepa work if they don't hit the spa, box and Tv ads DTC may help also. At the end of the day, a DFAW on a script from an MD /provider goes a long way to preserving Vascepa dispensation to the public.
So yes, efficiency and efficacy of rep work have been eroded along with morale, especially seeing generic IPE or Lovaza, being substituted willy-nilly across the board where API constraints in supply allow.
HK
Zman
The Amrn reps are hard at it. I see it at the medical office level. They are truly up against it with mandate substitution policies for gen V at the state, insurer/PBM/pharmacy level. The only reason the figures aren't worse is the API constraints of the generics. But, why generic Lovaza is substituted for Vascepa (prescribed for R-IT indications) is interesting. Since the genIPE script is allegedly prescribed/substituted for a MARINE indication of a "12 week period to treat TG>500 to prevent pancreatitis"....it could be argued that Lovaza should do that job (with/without a statin added to fix the LDL problem). But we know therapeutically this is a horrible idea, just as bad as taking Fish Oil-->No CV benefits, some AFib risk and unnecessary long term DHA/contaminant exposure.
We need a separate patient-directed campaign of what I tell all patients and my local pharmacists:
"Better to Loosa than Lovaza".
Good point sts,
The same is true of the Indian generic companies including Dr Reddy's Labs:
https://www.aboutlawsuits.com/dr-reddys-solvent-inspection-167886/
HK
If we think these generic API bulk manufacturers or their HIKMA type redistributors are going to do due diligence for the patient in the USA we are very much deluded and fatally mistaken.
HK
Raf
I think the capsule is likely one of the the secret sauces. I think the method of separating out EPA from crude fish oil extract and then purifying by liquid chromatography and then esterifying may also be important for absorption characteristics. BUT,I cannot help feeling that two things are critical : (1) Achieving a high dose of pure esterified EPA at the brush border of the small intestine without acid degradation or oxidation and the consumption of some fat to promote lipolysis of IPE and absorption as EPA. The importance of this is exemplified by the results in STRENGTH for the EPANOVA which was a carboxylic acid form and was touted as being free of absorption hinderance with ideal absorption characteristics. Even allowing for half the 4g EPANOVA dose as being EPA the serum EPA levels on therapy in STRENGTH was not even 70% of that achieved by the pharmacokinetic studies in MARINE/ANCHOR with the 2g/day dose of Vascepa. So the IPE formulation matters.(2) Avoiding oxidative degradation to peroxide byproducts prior to ingestion --these products may be assumed to have less efficacy or deleterious consequences biologically.
As to generic IPE smell-->I can confirm by smell test blinded of 5 people in my office that it is clearly discernible as "different" if not "fishy". This is discernible immediately on cutting the capsule. Two possibilities: (1) Fillers and contaminant accompanying the IPE product in the HIKMA capsule are responsible for it OR (2) The standard issue type 2a gelatin capsule has a porosity to the atmosphere and a predisposition to rigidity and cracking that is avoided by the Vascepa capsule and hence oxidation by products exceed within the HIKMA encapsulated IPE product.
HK
We could do an ANCHOR type study with generic IPE vs Vascepa--this may OR may not show lipid change differences BUT since R-IT therapeutic effects were not linked to lipid changes which were regarded then as surrogate ancillary bioactivity markers; Can we then say if lipid effects were similar in such a trial that the drugs are biologically equivalent for CV efficacy? NOT. So there are complexities and subtleties in establishing the differences between generic IPE and Vascepa. That said, the thought of a double-blind prospective crossover trial of GenIPE vs. V has me salivating...
HLK
EPA, EPA:AA and red cell EPA
Will do DK
He is right, these basic invitro tests do not protect against toxic contamination...witness the NDMA contamination scandal with so many HTN Rx generics that originated abroad.
HK
Good point: No gain and perhaps some pain also (AFib and oxidized product consequences...)
I agree PDude. The FDA is nothing if not measured and considered in weighing all evidence before giving its response to anything (with the possible exception presently of COVID therapeutics or vaccines). Consequently, the response times are what you and I would consider SLOW, since the wheels of bureaucracy turn slowly if at all. I think proving deleterious consequences in-vitro or in-vivo of oxidized byproducts of generic Icosapent Ethyl will be a long drawn out process. However, proving that the generic IPE and Vascepa are dramatically different in their susceptibility to oxidation and hence in their oxidized byproduct content should be easier. It should also be possible to show that drug levels achieved using standard HIKMA generic type 2a gelatin capsule technology are a far cry from those achieved by the Vascepa capsule technology. This would allow (1) Showing they are NOT biologically equivalent by FDA classification criterion AB and (2) That sustained therapeutic 24 hour plasma EPA levels e.g. >100 mcg/ml or similar obtained by 2g twice daily dosing of the PROPRIETARY Vascepa capsule protected by patent 10881632 are intrinsically related to achieving R-IT like clinical outcomes.
Personally, I look forward to more detailed publications from Amarin investigators outlining the nexus between the pharmacokinetic studies produced at the time of MARINE and ANCHOR and the plasma levels achieved and documented in EVAPORATE and REDUCE-IT and the connection between these and clinical benefits observed. Therein lies the secret sauce and at least 50% of the real reason STENGTH and OMEMEI FAILED (the other 50% being the presence of DHA)
HK
OK I SEE
sstyles
I believe exactly that --I hope that Amrn has already initiated detailed oxidation testing on the HIKMA generic IPE PRODUCT AND ITS packaging
Congratulations Pdude!
thank you jasbg
This is a supply constraint API war. they are full of bravado but privately are standing nervously with fingers crossed that the supply chain for API catches up to their ambitions.
BofNW
I see this as but ONE claim in a series of claims NOT definitive in and of itself but logical. A court would say use the same logic that the defendants did in the Nevada court for Hayashi...what's good for one is good for all, and the overall "pattern", not the specifics matter. So, they will argue that IF you have Afib or not, you still have TG>500 and for reasons specified ad nauseam in the Judge Du bench order, TG<500 is to be considered the same therapeutically as Tg<500 (and thus pts with or without Afib who are but a subset) and also because prior art said all of this was obvious pre-2008....Mori Kurabayashi Hayashi etc...
Yes BUT one more pills+ less compliance and IF peroxidation product levels go up with plasma EPA levels (consuming more pills with more peroxidation product) we are still short of a therapeutic goal and definitely NOT therapeutically or biologically equivalent even for FDA purposes...
HK
There is some method in the madness .. I sense something but cannot yet clearly grasp it...
Ralphey
It is like the Pharmacology of any drug you can take a high loading dose and spike the levels supratherapeutic for a few hours but the maintenance doses have to come in if you are to maintain steady-state levels...
HK
not sure
In a perfect world this might be one construct:
HIKMA RELEASES generic product IPE that has a gel encapsulation technology that fails to protect against significant lipid peroxidation degradation with peroxidation levels >20 meq/mg. Also, it is shown that levels of plasma EPA achieved by HIK Gen IPE are inferior and unsustained in comparison to Vascepa and that this is demonstrated in a peer-reviewed independent scientific publication. Time passes and scientists show for varied applications of Vascepa IPE including Cv disease, COVID disease, NASH etc that a critical level of EPA is needed for the therapeutic effect the first actor that shows a nexus between levels formulation and clinical benefit wins. They also have the means to claim that HIK gen IPE CANNOT be biologically equivalent to Vascepa. QED
HK
I think we have to wait for OB zman I am afraid...
This I have no expertise to comment on