Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
HD I always believed that plaque stability is more
important than size.
AMIRINV: I believe you have it right. Kudos !
There are many ways to look at data, it's a
Risk/Adjusted Probability Model. Plain and
simple. Your % is a highly Variable. You create
a Market both ways.
marzon : FDA has never accepted Jelli's , for numerous reasons,
most of them very valid That's why it's so difficult to accept Jellis as a metric , because if FDA doesn't, who can ? It never
satisfied the guidelines that FDA sets as Gold Standard.
marzon : FDA has never accepted Jelli's , for numerous reasons,
most of them very valid That's why it's so difficult to accept Jellis as a metric , because if FDA doesn't, who can ? It never
satisfied the guidelines that FDA sets as Gold Standard.
sts66: I am not particularly concerned about Biotech
pricing be pressured by the Democrats. The Industry Org's
have a STRONG defense, that is logical, valid, transparent
and makes a lot of sense. Remember that Drugs account for
only a little over 10% of the Health Care Dollar. The highly
marked up costs are related to Hospital charges for starting
an IV , dispensing Meds, inserting a Catheter etc, etc. This
accounts for the largest portion of the health care dollar.
I seriously doubt AMRN's Vascepa will come under scrutiny.
From what I hear the major changes will be in tying the price
increases on Generics to Inflation. The Industry is not worried
regardless of what Hillary, and her Commie opponent have to say.
It's mostly for public consumption. Also recall that the ACA has
strong language stating that the Gov. will not engage in Drug
Price negotiations, The Bio Pharm Industry has pledged about
$120B in rebates to help fund Obama Care. I doubt they will try
to change the language, unless they are financially prepared to
have our industry stop paying quarterly Kickback's ( Rebates)
It's no more than the usual Political rhetoric. ie, GILD pays
about $300M + QUARTERLY. So do all the Bio Pharm revenue and earnings positive Co's. pay varying amounts based on their earnings.
zum: The reason they don't want the trial stopped
is simple and something I've posted on many occasions
in the past The Hazard Ratio and Power of the trial
is very important. I have always been puzzled by
the fact that AMRN never fully enrolled the trial,
and my only assumption was they never wanted to spend
the money. I chastised the Co for that, to no avail.
Now they've opened their eyes and realize how vital
it is to have the Cohort size fit in with the above
cited metrics. I doubt we'll have results prior to
2018 , as I've also previously stated.
BB : The delay is standard for FDA. They keep taking
advantage of
Investorfreak: To set the record straight, Dr's today are
on average earning half the income they became accustomed
to, seeing more patients for a fraction of a regular fee,
and in all probability, being hassled by their wives to
keep their kids in private schools. Managed Care, the Alphabet
Soup, HMO's PPO's and the ACA have created a situation where
for the first time in 5776 years, Jewish women don't want
their daughters to marry Doctors. Your post was another piece
of inaccurate information about todays health care environment.
Today's NEJM
Brendan M. Everett, M.D., M.P.H., Robert J. Smith, M.D., and William R. Hiatt, M.D.
October 7, 2015DOI: 10.1056/NEJMp1508120
Share:
Article
References
In early June, the Endocrinologic and Metabolic Drugs Advisory Committee of the Food and Drug Administration (FDA), on which we serve, met to consider marketing applications for the new molecular entities alirocumab and evolocumab on the basis of their ability to lower low-density lipoprotein (LDL) cholesterol levels and their effects on other lipid fractions in patients at risk for cardiovascular disease. These first-in-class medications are fully humanized monoclonal antibodies that inactivate proprotein convertase subtilisin–kexin type 9 (PCSK9). That inactivation results in decreased LDL-receptor degradation, increased recirculation of the receptor to the surface of hepatocytes, and consequent lowering of LDL cholesterol levels in the bloodstream. Statins, by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, similarly act by increasing LDL-receptor expression. This shared LDL cholesterol–lowering mechanism, combined with data on cardiovascular events from genetic studies of persons with PCSK9 gain- or loss-of-function mutations, has led to optimism regarding the potential — but as yet unproven — cardiovascular benefits of these agents.
Both alirocumab and evolocumab, which are given by injection, cause large reductions in LDL cholesterol levels, as compared with placebo (39 to 62% reduction for alirocumab and 47 to 56% for evolocumab). In the drugs' development programs, LDL cholesterol levels in approximately 37% of patients receiving evolocumab and 24% of patients receiving alirocumab dropped below 25 mg per deciliter on two consecutive measurements. Because such low plasma cholesterol levels can be attained with these medications, particularly when they're given in conjunction with a statin, the FDA raised concerns about possible gastrointestinal, metabolic, and neurocognitive adverse effects. The target populations considered for long-term use of either drug include adults with primary hypercholesterolemia (nonfamilial or heterozygous familial), patients with mixed dyslipidemia (including those with type 2 diabetes mellitus), and patients unable to take statins. The evolocumab studies also included patients with homozygous familial hypercholesterolemia.
Both drugs were submitted through the traditional FDA approval pathway, with LDL cholesterol reduction as the surrogate measure of clinical benefit. No efficacy data on cardiovascular outcomes were provided to the advisory committee, except for encouraging but preliminary analyses of cardiovascular adverse events with evolocumab. During the meeting, the FDA noted that if a medication is approved through this traditional pathway on the basis of a surrogate end point, the FDA can subsequently mandate postmarketing safety studies but cannot require postmarketing studies of benefits, such as cardiovascular event reduction. Thus, the principal issue before the advisory committee was whether the observed LDL cholesterol reduction provided sufficient evidence to substitute for demonstration of clinical cardiovascular benefit.
LDL cholesterol reduction was the basis for FDA approval in 1987 of the first statin (lovastatin), 7 years before the publication of the Scandinavian Simvastatin Survival Trial, the first trial to provide definitive evidence of a statin's clinical benefit. Subsequent statin approvals were also based on the LDL cholesterol surrogate, as was approval of the first-in-class drug ezetimibe in 2002. However, one subsequent randomized trial raised concerns about an increased risk of cancer or an increase in cancer-related deaths with ezetimibe, prompting additional review and communication by the FDA. These safety concerns appear to have been favorably resolved by the recently published results of the IMPROVE-IT study, which showed a modest reduction in rates of major cardiovascular events in comparison with the control group and no increase in cancer risk.1
These results could be interpreted as evidence that LDL cholesterol reduction will reduce cardiovascular risk regardless of a drug's mechanism of action. However, aside from IMPROVE-IT, several trials with other nonstatin medications that lower LDL cholesterol do not fully support this hypothesis (see tableSelected Clinical Trials of Medications for Lowering LDL Cholesterol Levels Other Than Statins Alone and Their Effects on Cardiovascular Events.). The ILLUMINATE study and the HPS2-THRIVE study are of particular interest, given the relatively large percent differences in LDL cholesterol levels they revealed between the study drug and comparison groups. They also showed other salutary effects on lipid levels, including decreased triglycerides and increased high-density lipoprotein (HDL) cholesterol levels, but neither trial demonstrated a benefit in terms of cardiovascular outcomes. In fact, ILLUMINATE was stopped early because of a significantly increased rate of major cardiovascular events in the torcetrapib group. These trials and others call into question whether LDL cholesterol reduction is a reliable surrogate end point for the approval of new nonstatin drugs.
There are benefits and risks in using LDL cholesterol reduction as a surrogate end point for drug approval before the completion of definitive outcome trials. One potential advantage is the ability to demonstrate a statistically significant beneficial effect of a novel medication on the surrogate while exposing relatively few patients to the drug for a short period. The desired outcome would be lower-cost drug development and accelerated availability of new therapies. However, the limited number of patient-years of randomized, controlled drug exposure makes it difficult to assess the safety of new agents, particularly in terms of uncommon but clinically important adverse events, and leaves unevaluated the safety of agents intended for long-term use. Adverse effects may not be anticipated and may be recognized only when a large number of patients are exposed to a drug over a long period. For example, an increased risk of death with torcetrapib was evident in a large trial (>15,000 patients) of cardiovascular event outcomes.4 Had torcetrapib been approved on the basis of LDL cholesterol reduction alone, its association with an increased risk of death might not have been detected until it was in widespread use.
A second advantage of using LDL cholesterol as a surrogate is that it can facilitate evaluation of new medications in patients with uncommon disorders for which trials with a clinical end point would not be feasible. For example, cardiovascular outcomes trials are not possible in homozygous familial hypercholesterolemia, which is quite rare. Evolocumab was shown to significantly reduce LDL cholesterol levels in patients with this condition and, on the basis of the high prevalence of premature death associated with the disorder, was unanimously recommended for approval by the advisory committee.
Patients with existing cardiovascular disease and persistently high LDL cholesterol levels despite high-intensity statin therapy also have important unmet medical needs. For this much larger population, the FDA must weigh the benefits of early approval against the possibility that the drugs will be substituted for maximally tolerated statins, even though there's much better evidence of statins' clinical benefit. The proposed labeling for the PCSK9 inhibitors would support their use in patients unable to take statins — a matter of concern, since statin intolerance appears to be overdiagnosed (e.g., 70% of patients who were considered unable to take statins in blinded alirocumab studies tolerated 20 mg of atorvastatin daily for 24 weeks). Although unlikely, an additional theoretical concern is that widespread availability of PCSK9 inhibitors might prompt patients enrolled in ongoing end-point trials to receive the medications outside the protocol, thereby compromising the trials' integrity.
Despite the limitations in the benefit and risk data raised in the discussion of both PCSK9 drugs, the advisory committee voted 13 to 3 to approve alirocumab and 11 to 4 to approve evolocumab. The committee members voting for approval were motivated by the goal of providing a potentially beneficial option to patients with very high risk of disease before large cardiovascular outcome trials are completed. Many committee members, including those who supported approval, emphatically stated that LDL cholesterol levels were not a reliable surrogate for cardiovascular benefit and acknowledged that approval could lead to widespread use before definitive efficacy and adequate safety data are available. This concern may be somewhat mitigated by the high cost and requirement for parenteral administration of PCSK9 inhibitors.
Establishing evidence of improved cardiovascular outcomes is key to evaluating medications from any new drug class intended to reduce such risk. As substantially as alirocumab and evolocumab reduce LDL cholesterol, definitive evidence of reduced cardiovascular event rates is essential. Ongoing trials designed to provide such evidence should elucidate the medications' true clinical benefits and possible risks.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on October 7, 2015, at NEJM.org.
Source Information
From Harvard Medical School and Divisions of Cardiovascular and Preventive Medicine, Department of Medicine, Brigham and Women's Hospital — both in Boston (B.M.E.); the Department of Medicine, Alpert Medical School, and the Department of Health Services, Policy, and Practice, School of Public Health, Brown University; and Ocean State Research Institute, Providence VA Medical Center — all in Providence, RI (R.J.S.); and the Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, and CPC Clinical Research — both in Aurora (W.R.H.). All three authors participated as voting members of the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting on alirocumab, and Drs. Smith and Hiatt participated as voting members of the Advisory Committee meeting on evolocumab.
Tools
PDF
Print
Download Citation
Supplementary Material
E-Mail
Save
Article Alert
Reprints
Permissions
Share/Bookmark
Topics
Lipids
Prevention
Drugs, Devices, and the FDA
Diabetes
More In
Perspective
click here
Trends
Most Viewed (Last Week)
Images in Clinical Medicine
An Acute Dystonic Reaction after Treatment with Metoclopramide [53,200 views]
October 1, 2015 | M. Leus and A.V.D. Ven
Review Article
Maintenance Intravenous Fluids in Acutely Ill Patients [31,034 views]
October 1, 2015 | M.L. Moritz and J.C. Ayus
Original Article
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes [21,754 views]
September 17, 2015 | B. Zinman and Others
More Trends
CareerCenter
PHYSICIAN JOBS
October 7, 2015
Internal Medicine
FT Day and Night Physicians: Hagerstown, Maryland
Maryland
Chiefs/Directors/Dept. Heads
Chief, Gastroenterology – NYC
New York
Hematology/Oncology
ONCOLOGIC ENDOCRINOLOGIST - Banner MD Anderson Cancer Center - Phoenix Metro
Arizona
Hospitalist
Hospitalist Jobs in Oregon City, OR
Oregon
Pediatrics, General
Pediatric Physician Jobs in Spokane, WA
Washington
Hospitalist
Hospitalist
Colorado
nejmcareercenter.org
sts66: I don't believe that a Cardiologist would
let the LDL get much below 90. if you recall the
Viox recall, the take away was that their trials
included about 10,000 patients. The incidence of
AE didn't manifest until over 125,000 patients were
on Viox. That said. the greater the numbers, the
greater likelihood of AE's showing up. With Statins
no one was vociferous about Musculo-Skeletal symptoms
until well after launch. Any thing is possible, but
I would not be hesitant to suggest that PCSK9 + V
would be the best of all therapeutics to treat CAD.
BioC ; The ideal would be PCSK9 + Vascepa. The PCSK9
will replace Statins following CVOT . Why do you think
Express Script's will pay for it. Statins have not shown
reduction in MACE, with the exception of AZN's cherry
picked Crestor trial. FDA has never accepted it. They
did not follow FDA guidelines. Statin's are 30+ years
old and PCSK9's are cutting edge with better PK and
greater % of reduction of LDL
zum>: They will replace Statins in @3years
zum> They may have some experience, though on the job experience is not what I'm talking about. However, they are not the Dedicated Cardiology Sales Force that we really need. Those
reps have pre existing relationships with Doc's and front office
people that get through the front door. Huge Advantage !
In comparison, they are not the seasoned Reps that hawk Crestor, or the sales force that sold Lovaza for for GSK. Admittedly AMRN is constrained, but you need to do whatever it takes to sell V a superior drug to Lovaza (raised LDL)
HD: The problem with the Reps and scripts is a specious
argument. When GSK was doing $1.3B a year in Lovaza sales,
AZN selling Crestor, and PFE selling Lipitor when sales
were $17.1B a year, they had between 1100 and 1300 dedicated
Cardiology reps with considerable experience and pre existing
relationships with the Cardiology community . Unfortunately AMRN doesn't have a decent sales force. I believe it is in part budget,
trying to do it on the cheap, and FDA
BB: Great question ! Short answer is I honestly don't
know. I could speculate, but too much of that already on
this site. I would assume one of two things. 1- If they
present, they can't comment on FDA ongoing negotiations.
NCE, or Anchor. They may be sniffing around about a financing. They will certainly require more boots on the ground. (Reps)
I guess we'll find out soon enough. We could use an upside
surprise.
Someone mentioned "not being fully enrolled" It could be
an issue as both the "Power" and Hazard Ratio are calculated
on full enrollment.(8000Pts) It just sets up a higher bogey for an interim look. I also have concerns about the enrollment criteria not being smartly fulfilled on the first 2000 patients. Maybe HD or one of the other smart guys on here could run the math ?
1bill: Yes but they are a NASDAQ listed company and
therefore SEC trumps Ireland
GGWPG: You are correct ! However he sold $M's when he
pumped the stock to $19
TORTLAW: You are one ignorant and lazy, or lazy and
ignorant poster. All my statements are accurate. Ask
ZUM, as to whether or not I had two conversations
with Thero. They were about a potential partnership
between Davita and AMRN on treating patient's with
Diabetic ESRD. The COO of Davita sat on the same Board
I was on and we became friends. Ask Thero ? Check my
earlier posts. Ask Zum how much Waxman did to help AMRN
following my 2 meetings with both he and his staff. I'm
putting you on Ignore as this business is tough enough
without wasting my time with a crumb bum like you. I'd
wager you are not even a lawyer.
Invest: What you neglected to mention was that
JZ sold stock at $19/ sh. Called pump and dump.
This is what initially pissed off FDA. Btw, he is
still on the Board as a Director. What you also
neglected was that he sold $M's worth of stock into
the Marine approval, with some VC's and the BOD. This
is unprecedented and speaks volumes. Check the 8K's
filed. If there were in fact an offer, the SEC requires
the Term Sheet to be presented to the BOD. It further
requires filing an 8K revealing the decision of the BOD.
Invest: Ask John Thero ! I am not even justifying
your moronic response. Check for yourself, before
you continue to make incorrect statements.
Invest: JL is correct. The chip on your shoulder
is not in keeping with the civility that this Board
has achieved in recent months. You are incorrect with
your statement regarding an offer of $20/ sh. I asked
JT on a personal call whether AMRN had ever received
an offer, and he unequivocally said NO.
JL: The problem is the Biotech ETF's are dumping stock.
I believe the IBB will retest 284, its low during the flash
crash, and bounce. Hopefully not a dead cat bounce. The
S&P will retest 1870 and hopefully bounce. If both break
support, then there is something out there that will be
like a Lehman Bros, only of greater magnitude. I am of
the belief that one of the large European Banks may
impload, and be catastrophic. Watch Deutsche Bank, the
stock is at an all time low, and they are as highly
leveraged, if not more so , than Lehman. Lehman was
considered a smaller Bank. Deutsche Bank is the 4th
largest Bank in the world. JMO
JL: If you took the time to read H-W-A you'd realize
that you are flat out wrong. The intent of H-W was to
level the playing field so that small Biotech wasn't
screwed over by Large Pharma or misinterpretation and/or
bias by FDA. Would you expect to get an NCE that
disappears in less than 20 months ? I don't think
so. All I stated was that I believe it is on the table.
Let the FDA's and Congress's mother worry about how
they word it and justify it. Let the Generics scream !
I couldn't care less. They will be doing what I believe
was the intent of the Federal Judge. JMO !!!
JL: I've seen the FDA do some weird stuff over the last
20 some odd years. FDA has to give something big to AMRN
if for nothing else than having been on the wrong side of
two Federal Court decisions. FDA would rather have Generics
"scream" than BP. What Generics pay toward FDA budget is chump
change compared to BioPharm
HD: Just maybe the reason it has not been listed in the OB,
is that the NCE may be on the negotiating table for a going forward 5 yrs, instead of from July 2012. At the end of the
day it may be easier for FDA to give that to AMRN, as the
ambiguity related to not receiving it, may be remediated.
FDA can cite the Federal Court Decision, and the Street would
not bat an eyelash.
James: HDL is no longer considered as prognostic a
Bio Marker as it was in the 80's and early 2000's. I
honestly have no recall of the specific publications,
but I'm sure there is data out there. Mine scared the
life out of me in the late 80's, that is until I researched
it. Mine is 12 . Yep, actual number.
zip: The take away from the ACC/AHA was LDL and
unfortunately the Orgs didn't include Trigs. Plain
English. AMRN got screwed on the SPA, but the new
Science in the guidelines was just LDL, which had
been shown to lower CVE. Not so for Trigs.
zip: You don't have the facts correct. When the PCSK9
trials were being run early on, ACC/AHA came out with
new guidelines for treating Hypercholesterolemia. They
were plain and simple. The only Lipid metric that would be acceptable for FDA approval was LDL. They told REGN,.AMGN,
and PFE if their trials were efficacious in lowering LDL,
then their drugs would be approved. They also stated that
CVOT would be required, but results would follow approval.
IMO, the FDA had these guidelines about 3 weeks prior to
AMRN's ADCOM. I believe this was the cause of ADCOM being
high jacked, and a mockery, because the ACC/AHA did not
include Trigs as a non Statin Lipid lowering agent. Thus
their reasoning for R-IT results prior to label expansion.
Trigs,being a bit controversial and never proven to reduce
CVE, were set aside till the results of R-IT.
HD: Reminds me of the old story of the MC at the Paladium
in London announcing the singing of God save the Queen by
a popular London entertainer. A voice from the upper balcony
yells out "She's a Bloody Whore". The MC unfazed, announces
"Never the Less", Mr so and so will sing God Save The Queen.
Kiwi: Agree completely. Amarin has a unique opportunity
to play nice and show the ability to compromise with the
FDA. Remember there is far more at stake, involving the
Agency coming up. A compromise could hopefully change the
FDA's mind set re Amarin. We have R-IT results, and I hope
the DSMB doesn't (at the sponsors request) break the blind.
That could trash the trials credibility. I doubt that FDA
would grant an approval until the whole trial is Data Mined.
Completing the trial would negate FDA from citing an insufficient number of patients to establish safety. I've actually seen them do that. That said, it is obviously more important for a compromise so as to clear the air and eliminate stalling (aka delaying tactic), and other odious acts FDA has in it's quiver. Hopefully a compromise may allow the FDA to give the
NCE a go forward date 5 years out. JMO
BB: Sorry, sNDA ! If you recall, I spoke with JT and
set up a call with an old buddy who was COO of Davita.
( Largest Dialysis Co.) in the US. Unfortunately Davita
isn't set up to do Clinical Trials, and AMRN didn't have
the funding to do the trial. I've got to give JT credit
for getting involved; however, it was like throwing a
drowning person a rope.
BB: Thanks for your post and kind words. Yes, as I mentioned
I do have skin in the game and purchased shares on 8-25-15.
I believe HD has an interesting idea about withdrawing the
aNDA, and refilling for another indication. Personally Diabetes
would be my first,2nd and 3rd choice. If they can then negotiate
an expedited review, as the FDA already has the data in house
and has already reviewed it, we may all have a Merry Xmas.
HD: If I'm interpreting the FDA rule book correctly,
it does state that a new aNDA must be filed for a
new indication. I wish we could get Diabetes, but
changing the rules flirts dangerously with precedent
setting. I would guess the FDA may not be amenable to
that. What needs to happen is for a creative solution
that gives both parties what they want. I personally
can't think of anything that works. I hope AMRN is
compromising and respectful this time.
TortLaw: I've read and for the most part enjoyed your posts.
I really understand what happened and what the current reality
is. I am not suggesting a change now, and with a first rate
legal team, this is the first time since 2010 that management
has e3ver had "Add in" to use a tennis metaphor. I am aware
and present as far as AMRN management is concerned. At the time
I argued for a change, I believed it to be in everyone's interest.
You are correct, that time has passed.
MRMAIN: If you take a look at other Biotech Co's with
a commercialized product, and check out their MGMT team
as far as credentials, Industry experience, track record,
and any other metrics you choose to compare, I suspect
the differences should be quite apparent. The time I was
lobbying for change was the lengthy period when management
did nothing, and the stock drifted lower. What I refer to
as a real management team, is one that proactively manages
crisis, and makes overt efforts to reassure shareholders.
Unfortunately, our leadership was negligently absent. The
only thing they did was award themselves stock and cash bonuses.
Nothing was done for the shareholders in any way to assuage
their angst, loss of money etc. A simple buying of shares on
the open market, say $20K per each Director and Senior level
management would have shown faith in the Co. and sent a message
to the Investment Community. They chose to do absolutely nothing. IMO there is no substitute for a well credentialed management team that has been there and done that. We simply missed the opportunity to give some seasoned Pros the opportunity to do CPR on a company that had at that time done everything wrong. I am a big believer in Vascepa, take it personally, and currently have skin in the game. These are my own opinions and reflect 23+ years experience, intimately involved in in our sector.
MRMAIN: If you take a look at other
HD: They have been collecting salaries and stock
bonuses at the drop of a hat. They have sold stock
options every time they can. Take a look at the Balance
Sheet. Not a pretty site. Rather than taking a mild
haircut with their salaries, and even putting more
Reps boots on the ground, like many other Biotech's
I have been involved with. Their Mission Statement
like all Publicly traded companies, should be to
build shareholder value, not destroy it. I don't
think they are concerned about shareholders, that
is until the Baker Bros got involved. Forget Mother
Theresa, another Martini for Mother Cabrini. JMO
LOts: JMO He's history and I have no interest in him.
William Faulkner : "The past is never passed". Now
we have to dance with the girl who brung us. I was
lamenting the myriad mistakes that cost every one
a lot of money. A real MGMT team from the start
would have led to a different story with a happy
ending. I couldn't give a F..k about JZ or their
current management.
MRMAIN: I don't believe that would be prudent at
this time. My comment only addressed what I believe
to have been a pathetic management team from the get
go. Their only interest was to sell the Co immediately
if not sooner. They still are not shareholder friendly.
Look at their compensation packages and it should be
obvious.