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Canes
Nope. Pfizer or Novartis would have sent their top people who knew every stat, trial, subgroup, endpoint, would have been able to quote peer reviewed journals and government reviews etc.
I did not listen to the Amarin presentation but from all reports they failed to provide a qualified team capable of presenting the needed arguments and rebuttal.
Iryokabu
Just like in Canada with their CADTH report the NICE report was clearly meant to give the government leverage in renegotiating the price. I wouldn’t be surprised to hear that the UK government had invited Nissen to speak to give them something to create doubt. Without Nissen pushing his MO nonsense they wouldn’t have any counter argument against V already being part of the treatment guidelines of ESC, EAPC and EAS.
Rose
Approval was 25 months ago and typically coverage happens 18-24 months after approval. When will V get approval? No idea. People I talked to at both HLS and Pfizer were hoping for the end of March but a conversation I had earlier this week indicated no sign of imminent approval.
Another relevant question is how broad. The guy I talked to seemed to think CVD was a sure thing but primary prevention in DM2 was unlikely. Primary prevention had a lower RRR, higher NNT. Also, DM2 Pts are already on a ton of meds so adding 4 large capsules daily is a tuff sell - I know because I’ve had that conversation with several DM2 Pts. They are usually on 3-4 DM drugs, 2-4 BP meds, 1-2 cholesterol meds not to mention the pills for gastritis, insomnia, depression etc. Telling these Pts to add 4 large capsules to reduce the chance of a heart attack typically gets a response of “let me think about it, I already take enough pills as it is.” Diabetics die of heart disease but all their care givers focus solely on getting their sugars down on a day to day basis and that is a big enough challenge as it is.
I promise to post the news as soon as I hear anything.
Gusman, Sluicebox, louieblouie etc
I believe the purpose of NICE is similar to the CADTH organization in Canada - to decide on reimbursement for the government plans. CADTH claims to be an independent third party giving the government an objective review of the data and costs. The reality is they are there to provide the government with leverage in price negotiations. The CADTH review in Canada concluded that V’s price had to be reduced by 48% (IIRC) to be cost effective. Their report was similarly slanted against V. Normally drug approval takes 18-24 months. We are 2 weeks away from being 2 years since V’s launch and it’s been 25 months since V’s approval. The cost implications to the drug budgets are substantial and the government will use any means available to delay reimbursement and pressure the manufacturer to reduce costs.
The results of this meeting are not surprising and they will not refuse to cover a drug already listed in the Standards of Care and treatment guidelines.
Marjac
As I previously posted, estrogen is known to reduce ApoB and therefore the cropped ApoB table shows an expected reduction in ApoB levels in both the placebo (estrogen only) and the estrogen/EPA groups. Since it would be necessary to show that POSA at that time would know that, I have linked a study showing these results from 1997 just in case the generics argue that it wasn’t known at the time of the patent being issued.
Effect of Estrogen on Very Low Density Lipoprotein and Low Density Lipoprotein Subclass Metabolism in Postmenopausal Women
https://academic.oup.com/jcem/article/82/12/3955/2865931
“These metabolic changes reduced light LDL cholesterol and apoB concentrations by 26% (P = 0.005) and 19% (P = 0.03), respectively.”
Kiwi/dogn
Don’t forget that Novartis owns Sandoz, the 3rd largest generic drug manufacturer in the world. Their strength is in generic injectables, like IV antibiotics, and ophthalmic products but it still leaves them well set up to maximize gV revenue from the US market (in the event marjac ends up with another appeals court of judges who don’t bother to read the briefs and can’t be bothered to ask questions that may go against their personal/political agenda).
Capt
Great post but keep in mind that V reduces deaths in Pts with existing ASCVD and/or high risk DM2 Pts with elevated TG’s on a statin. It doesn’t work across all CVD causes of death (eg: sudden cardiac death is primarily in an electrical problem for which V is unlikely to help, nor would it help pts dying from heart failure, etc).
Iryokabu
I only see that it will be “considered for” publication. At the time of submission they likely don’t have any idea of the success/failure of the trials.
“Each accepted submission will be considered for JACC Rapid Review and publication in JACC, JAMA and NEJM”
At the moment it looks like PP1 and PP2 - both having been accepted as a late breaker but so far we are 0 for 2 in successes.
Let’s hope “third time’s a charm” as they say
I remain doubtful of any stat sig data
(I only said that to piss Kiwi off)
Iryokabu
Where do you see that the MITIGATE trial results are going to be published in JAMA?
dogn
This does explain a lot IMO. I agree completely with your assumptions of this coincidence.
Lizzy
IMO the new board member (from Merck) is more likely a “friend” or supporter of KM brought onto the board before Denner to support the existing board and stack the board as they saw Denner moving in. There was no other reason to add another board member at this time other than a defensive move against an incoming activist who is known to be disruptive to existing boards.
Kiwi
What you are asking is for a statistical analysis of the data. I have never studied statistics, whereas you have (1 course IIMC) so you would be more qualified than me but better yet would be to have Iryokabu give his opinion.
sstyles
I tagged my Vascepa handout to that Thomas Barton tweet. Thanks for posting
Regardless of your view as an investment, if you know someone with cardiovascular disease make sure they ask their doctor about Vascepa. Summary of the data here: https://t.co/VADbiGzxWR
— Mark Brady (@MarkBrady2014) January 26, 2022
Ziploc
I believe we already know that V was a fail in the NASH trial or at least it failed to prevent a rise in TG levels. Keeping in mind that the MOA of V is not lowering of TG’s, it’s more likely a secondary effect, these negative findings aren’t that surprising.
Results: All treatments were well tolerated; most treatment-emergent adverse events (AEs) were Grade 1-2 severity and there were no discontinuations due to AEs. At baseline (BL), median (Q1, Q3) triglycerides were similar in the Vascepa and fenofibrate groups (177 [154, 205] vs 190 [144, 258] mg/dL, respectively). Median changes from baseline in triglycerides for Vascepa vs fenofibrate after two weeks of pretreatment were -12 mg/dL (-33, 7; P=0.09) vs -32 mg/dL (-76, 6; P=0.010) and at 6 weeks were +41 mg/dL (16, 103; P <0.001) vs -2 mg/dL (-42, 54; P=0.92). In patients with baseline triglycerides <250 mg/dL, fenofibrate was more effective vs Vascepa in mitigating triglyceride increases after 6 weeks of combination treatment (+6 vs +39 mg/dL); similar trends were observed in patients with baseline triglycerides ≥250 mg/d (-61 vs +99 mg/dL).
Conclusion: In NASH patients with hypertriglyceridemia treated with CILO and FIR, fenofibrate was safe and effectively mitigated increases in triglycerides associated with ACC inhibition. ClinicalTrials.gov NCT02781584.
https://pubmed.ncbi.nlm.nih.gov/34999207/?dopt=Abstract
Study
In Canada there are 2 significant barriers holding back V sales. 1) not covered by government insurance and 2) COVID restrictions are preventing any medical education.
For #1: like everywhere, docs don’t like filling out forms and most private plans require a PA (although HLS has a a system where the doctor fills out a single page, ticks a few boxes and sends the form to a company hired by HLS who then contacts the Pt and insurance company and they do all the work getting the insurance approved). If you meet the label criteria you get approved. Once V has government coverage the potential Pt pool gets much bigger and no forms required. So, yes there will be a significant growth in scripts.
For #2: reps can’t get in to see docs because of COVID restrictions so docs aren’t hearing about V. I estimate 80% of doctor visits are still virtual so at the end of the day docs are not interested in logging back in for a virtual drug presentation. There has been close to zero continuing education here in the past year. Early COVID there was some presentations but now everyone is sick of being online and turnout died. Restaurants are closed so reps can’t put on dinner presentations which is the only way to get a doc to show up - free dinner in a nice restaurant with colleges for a social night out. There hasn’t been any of these in 2 years. We have had minimal COVID cases in our area but omicron has hit hard. We have lots of positive cases but hardly any hospitalizations. I think omicron will change the future of the pandemic as more people get it and are mildly ill there will be less fear of the originally deadly variant. I predict restaurants reopen within a few weeks and things approach normal.
Locally the reps desperately want to put on a big event, the speakers are all lined up, docs will want to get out and socialize again and when that happens HLS and Pfizer will put marketing into high gear.
Kiwi
Until I read Iryokabu’s interpretation of the stats I didn’t follow MITIGATE because I didn’t believe it was powered to succeed. Now that they have doubled the size, probably because of PI2 results and their similar fear of reaching stat sig, I feel they have a much better chance of providing positive COVID data but doubt the therapy is long enough for the CVD benefits to show. With the new increase in trial size and resulting extension in time I don’t get excited about MITIGATE because we won’t see data for a very long time.
Only things I am looking at now are: improved insurance coverage (hoping the HealthNet case moving forward motivates some companies to acknowledge the patents), generic supply (expecting H and DR to stay as is for the next year, Apotex API supply is the unknown), and any sign that total V scripts start to grow (evidence that KM’s new platform for promoting has an effect).
The biggest influence on SP will be a sector wide reversal of the biotech slide for the past 11 months. XBI keeps dropping in spite of biotechs be significantly undervalued. Each attempt at reversal has been killed by a news event precipitating panic selling (bad COVID news, record inflation, interest rate hikes being moved up etc). When XBI manages a sustained reversal Amarin’s SP will rebound quicker than most IMO.
These are the things I feel are more relevant than MITIGATE.
Kiwi
Although her statement is correct (additional supporting trials are always a bonus) how many people have to die early awaiting an impractical second CVOT when we already have 4 trials - all of which were positive?
https://docs.google.com/file/d/1TcjxoXuOT_2srcLqJ9KQERCvWxs96Dy2/edit?usp=docslist_api&filetype=msexcel
Yes, yes, I know what you are going to say “but MITIGATE will solve this problem”.
The most obvious answer is that that E series Resolvins provide CVD protection above a certain blood level while D series Resolvins have no benefits for CVD and possibly have detrimental effects on CVD.
The evidence is already available:
https://drive.google.com/file/d/1CXsKuxNuvNM-xv9Z_UE7YVSWRF5stCGh/view?usp=drivesdk
EPA serum levels determine CVD benefits
Capt
Although this is true in the macro picture insurance companies, like many businesses, are focused on “this quarter” - being on budget, reducing expenses and achieving budget goals that earn the decision-makers their bonuses for that quarter.
The second obstacle is that Pts often switch insurance providers and therefore the Pt May no longer be a client at the time the benefits of the preventative therapy are realized.
A third obstacle can be that the budget for hospitalization costs do not transfer funds over to the prescription drug budget because the drug therapy saved money in another department’s budget. Even within the same company individual budgets are managed for that department’s best interest and not always for the company’s best interest.
Capt:
Here is a ROUGH GUESS of how I think the finances of Amarin vs generics plays out. I don't fully understand the US system so I may be totally off. Also, I have used rounded estimates and generalizations (eg: insurance = insurance companies, pharmacy benefit managers, anyone else looking for a kickback) and ignored wholesale markups:
Amarin cost/bottle: $30
Net revenue: $145 (I did this before seeing your data saying $135)
Profit: $115/bottle (78% margin from previous quarterly reports)
They sell it to the wholesaler for $300 and pharmacy sells it for $330 (10% profit)
Insurance pays the pharmacy $330 - copay(if copay is $10 then insurance pays pharmacy $320)
Amarin rebates insurance $175 and the insurance company ends up paying $145/month ($320 - $175)
Generics cost/bottle: $50
net revenue: $125/bottle
Profit: $75/bottle (60% Margin IIRC from a quarterly report)
sells to wholesaler for $270 (customer pays $300)- pharmacy makes 10% ($30)
generics give rebate to insurance of $165/bottle
cost to insurance company $125/month
Insurance pays pharmacy $300 minus copay (if $10 then $290)
generics rebate insurance $165
net cost to insurance company is $125
Bottom line: V costs insurance companies $145 and gV costs $125 - so they force their clients to gV to save $20/month/pt
Negotiations with insurance companies for coverage and Tier level is all about how much Amarin is willing to pay in rebates. Insurance company "X" may say they will only cover in Tier 2 if Amarin rebates them $215 to bring their cost to $100. Amarin says no so the company either doesn't cover or puts it on Tier 4 where the higher copay keeps the insurance companies costs under $100/month. The Amarin coupon is Amarin's way of reducing the copay but limits their ability to offer bigger rebates to insurance unless V is Tier 2. If the copay for V is $150/month (ie: the pt is paying the entire net cost of V) it is probably because the insurance company wont pay for the drug and Amarin has agreed to rebate the insurance whatever the insurance has to pay the pharmacy. In this scenario the drug is listed as covered in Tier 4 but the insurance company never pays a dime toward the cost.
If Amarin (JT) had agreed to raise the rebates to insurance in the past then when it came time to negotiate prices in EU they would have been forced to take a lower net EU price for the next 9 years. US insurance companies played hardball, refused to cover a CVD preventative medication and sales have sucked. The payoff is that MK was able to get $200 euro's in EU. Now that EU pricing is starting to get finalized they may be able to increase rebates to US insurance companies to get better coverage.
Ironic part: V has been available in the US for 9 years but CVD pts in Canada and EU will end up getting V before US CVD pts. US insurance companies have TOO MUCH POWER and control over what pts get.
I will repeat what I have said several times before: US insurance lobby paid MRC, Pyr, AF and Steve. Creating doubts about the efficacy of V allowed/justified the insurance companies to refuse to cover V for 3 years now - saved them a FORTUNE!!!!!
Canes
Lovaza was never marketed in Canada. No Omega3’s available by prescription. Pts with elevated TG’s don’t get anything unless their TG’s are very high at which time they get a fibrate.
The obstacle in Canada has been that doctors have been told for so long that TG’s under 500 are unimportant and can be ignored.
Kiwi
Both double vaccinated (I got my booster yesterday). My wife and I on V but he is not. We were all in the house together for a significant time before he isolated. My 7 and 9 year olds don’t appear to have caught it either.
Zip
My healthy, athletic 17 year old son had fever, cough and fatigue. Quick test positive and PCR positive. I wanted to get COVID (omicron is mild, I work with vulnerable seniors etc) so I spent 2 hours with him in a closed room, no masks, he was coughing, helping him do his biology homework. I never developed COVID, nor did my wife - both of us on V. Just to be sure I had an antibody test. Results came in yesterday- positive (very high) for vaccine induced antibodies, negative for COVID antibodies.
The virus must have entered my respiratory track with my son coughing in my face but my immune system cleared the virus before my adaptive immune response needed to kick in.
Kiwi
What’s the status of V and gV with KP for 2022? At one point I thought you mentioned it wasn’t going to be covered.
Iryokabu
With PI2 Pts starting V only after getting infected (possibly 3-5 days into the infection/inflammatory response) I would expect that V would be less effective at reducing the inflammatory (over)reaction than if the Pt had already been taking V for weeks or months like in MITIGATE. PI2 had a 22% (p=.18) reduction in actual hospitalizations (53 vs 70) so given your stats analysis of MITIGATE I think there may be a reasonable chance of success.
Rose
I don’t know the State laws for auto substitution well enough to have an opinion on how Amarin overcomes that obstacle.
Golf stud
“if healthnet continues to sell and infringe aren’t they looking at a huge lawsuit if they keep infringing???? “
Yes they are, which is why they will have to seriously reevaluate their current reimbursement plan.
Insurance companies have long felt they were untouchable because prior rulings have stated that merely offering a drug at a lower price is not enough to be found guilty of inducing infringement. For the first time a judge has now stated that they may be inducing infringement by encouraging generics over brand when they know the intended use is patented.
Insurance companies will either have to stop asking why the Pt needs Vascepa (stop requiring a PA) or they will have to cover Vascepa for Pts they know are being treated for CVD prevention.
Amarin should start adding new insurance companies to the lawsuit to serve notice to the industry they will be going after anyone who openly supports generics for CVD.
BBI
“Regarding Hikma, I would have preferred that the generic-making vulture stay in the lawsuit too (of course), but given the choice of only one proceeding to trial, I think I'd pick keeping Health Net in the picture.”
Totally agree!!
Patients will always pick what their insurance will pay for. If insurance companies are forced to respect the patent and only pay for brand-name Vascepa for Cardiovascular patients it would be the equivalent of complete restoration of our patents IMO.
NS
“I lost my ability to send private messages again. Don't know why I had it. Don't know why I lost it”
You do realize there is free private messages for everyone on Friday afternoons from 4:00 until at least 5:00?
Kiwi
You know my opinion on MITIGATE - there will not be enough Pts who become infected during the 6 month period they are on V, of which only a small percentage will become sick enough to be hospitalized (yes they are older, sicker Pts than PI2) to be stat sig. Disclaimer: I am NOT a stats expert, far from it, having never taken a stats course or even made an effort to learn/understand it
Quote: “A total enrollment of 16,500 patients pre-randomized in a 1 (IPE):10 (usual care) allocation ratio with an overall event rate of 15 per 100 person-years, would result in 80% power to detect a RR?=?0.82 (ie, 18% relative rate reduction, 2.7% absolute rate reduction) given a 2-sided a?=?0.05.”
15 per 100 person years- so if they are only taking V for 6 months then you need 30/100 people on it for 6 months. No way do 30% of Pts get COVID during the limited 6 month period they are on V. Add to that, of those that do develop COVID during that 6 month period how many will be sick enough to be hospitalized? PI2 only had 6.7% hospitalized (IIRC) so even if MITIGATE is much higher, like 20%, that still isn’t enough people to produce strong data. The 1:10 ratio part is something I know nothing about for p values but I just don’t see enough Pts on V getting hospitalized to make the trial significant.
And since you brought up Dr Bhatt I will repeat what he said to me “KP does not believe in preventative cardiology”. When I asked him if the majority of the 15,000 control group should be on V anyway he replied “yeah, probably”.
I will be happier than most and very willing to admit I was wrong if MITIGATE is stat sig, I just don’t expect it to be. Hope I’m wrong.
NS
Could Apotex be the authorized generic V?
Amarin may want to have Apotex “market” their gV so that Apotex could negotiate supply contracts with pharmacies. Eg: Apotex signs a deal with pharmacy chain “X” where X agrees to exclusively supply the apotex generic as their “generic of choice” for their top 50 drugs. The pharmacy gets preferred pricing and payment plans in exchange for using Apotex for any generic script for the listed 50 (for example) drugs. Amarin wouldn’t be able to compete with H or DR as a single supplier whereas they could if aligned with Apotex.
Just a theory
Interesting article about the biotech sector in general and why it has been such a brutal year.
https://www.nasdaq.com/articles/heres-what-happened-to-biotech-this-year
NS
Thanks! Best wishes to you and your loved ones as well.
We are not having the ideal start to the holidays, my very healthy and athletic 17 year old son tested positive for COVID with cough, fever etc. Symptoms only lasted 36 hours and he is fine now (started Vascepa 4gm twice daily immediately at first symptom). No sign of anyone else being infected. My wife and I are on Vascepa and feeling fine (PCR negative as of yesterday). We also have 7 and 9 year old boys who also seem fine.
All Christmas plans are cancelled and we are quarantined for now. We still have it much better than most so we are grateful and will have a great holiday not matter what. Last year we spent Christmas at a hospital where the same son had emergency surgery for a pneumothorax (hole in his lung, for no reason) eating turkey on the end of his bed.
Best wishes for everyone!
I’m optimistic for 2022
Mark
NS
My contact in a US pharmacy (VascepaBID) on ST says no sign of Apotex gV in their system not at their wholesale Amerisource.
NS
Their website says they launched on the 20th. A guy that works in a pharmacy is going to check his wholesalers tomorrow and let me know if they have any stock.
My guess is that they do a silent launch- no PR, no marketing, nothing that could be used against them in court. They will just make the product available and have their reps verbally tell their pharmacies that it’s available. Word will spread fast and if the price is even a dollar less/bottle insurance companies will jump on it and insist their clients be given the Apotex gV.
https://www1.apotex.com/products/us/detail.asp?m=69232
ambiente
“ I would love if mgmt would shed some light on their targets/forecasts, plans and activities.”
Just as Amarin makes no comments on how HLS will operate in Canada, nor do they speculate on marketing or guidance, I expect Amarin to be silent on China and leave it to Edding to run their own launch. I suspect they will release a PR congratulating Edding for their achievement but that’s about it.
NS
There may also be a significant cost to entering the market to get government coverage which appears unlikely before 2023. Once approved then can begin negotiations to be included in the following year’s list of covered drugs. In 2022 they will have to rely on private insurance coverage which, like in Canada, will be slow to roll out.
“Most innovative drugs would strive to be included in the NRDL for the 70-80 percent coverage it affords. This has long been considered the primary driver for pursuing the listing. At the same time, NRDL inclusions typically come with significant price cuts, which, on average, stood at 61 percent in 2019, and 51 percent in 2020.”
https://www.pharmexec.com/view/china-2021-national-reimbursement-drug-list-outlook
Marjac
Another point to keep in mind is that when a drug study involves two active drugs at the same time you cannot tell whether the effects of the second drug are direct or indirect.
Patients were getting estrogen or estrogen and EPA. Estrogen is known to effect lipids and therefore a POSA would see the Apo B levels dropping in both groups as believably an estrogen effect. The EPA group had a bigger effect BUT there is no way of knowing if that was because EPA directly lowered Apo B (independently from of the estrogen effects) OR it potentiated the estrogen’s effects on Apo B and that EPA on its own may have zero effect.
A person could argue that the study shows: if you give EPA with estrogen the estrogen has a much stronger effect at lowering Apo B. EPA alone may have no effect on Apo B. EPA could work like an enzyme, speeding up the estrogen driven reaction.
P less than 0.05 or NS, you still couldn’t KNOW the effects were independent of estrogen.
https://www.verywellhealth.com/how-does-estrogen-protect-against-heart-disease-1763978
“The majority of estrogen’s protective effects are likely to come from its influence on regulating cholesterol levels. Estrogen acts on the liver to cause an overall reduction in the total amount of cholesterol in the body, increases the amount of good cholesterol (HDL) and decreases the amount of bad cholesterol (LDL).”
I like this photo to help people understand what Apo B is and it’s relation to LDL-Cholesterol.
https://drive.google.com/file/d/1xU-jM8h_-F0uDKMeFfyTKYHYbS2-j-nd/view?usp=drivesdk
LTTRO
Both groups, control group and EPA group, we’re receiving estrogen. Blood levels of Apo B were taken at four different times. When you look at the table you see the control group Apo B level went from 123.4 to 121.5 and to the right you see NS - not a stat sig change from first (baseline) to last measurement WITHIN the group. For the EPA group you see an initial level of 124.8 and a final level of 116.2 which represented a stat sig reduction in the level from baseline WITHIN THE GROUP. Both groups had a reduction in the level from baseline to endpoint which could be the result of the effects of the estrogen on Apo B. The key here is that you have to compare the levels BETWEEN THE GROUPS to see the effects of EPA. The cropped table does not show that the P with the cross is indicating the “intergroup difference” which is the value showing the effect caused by the EPA and ALL 4 measurements showed the differences to be NS (not stat sig difference between the 2 groups). Judge Du stated there was a state sig difference BETWEEN THE GROUPS and therefore the change in Apo B was obvious. It wasn’t.
Marjac
“This is affirmation of my career choice to represent individuals and small businesses against corporations and governments. Individuals are vibrant and real, institutions and their senior leadership not so much”
If I heard that from any other lawyer I would view it with scepticism. Your incredible pro bono efforts clearly prove the sincerity of your statement. You have my utmost respect as both a lawyer and as a human being. Your dedication and commitment to seeing justice restored is inspiring. Thanks!
Proof that actions give sincerity to words, which is why I joined the GFM efforts and encourage others to do so as well.
Zip
Although I agree with you as a scientist I fear Du would fall back on the excuse that although not stat sig there was a significant difference between the 2 groups which would satisfy the legal definition of obvious (obvious to try with a reasonable expectation of success - IIRC from a post by North). BUT, at the same time, she needed “clear and convincing evidence” which IMO would be a study with a p value of 0.05.
I just don’t trust the “justice” system. Judges seem to find a way to interpret the law to satisfy the outcome they want to make happen.