Why isn't ENHANCE at AHA???

ENHANCE is not on the schedule for presentation at AHA, so another major cardiology meeting passes with no word on this study. Investors and the medical community know that this trial is completed and the results have been delayed by almost a year now. The only logical conclusion is that the study is negative and that it is being supressed. If simva+Zetia is no better than simva alone as suspected, this will be a huge hit to the franchise.

You've figured it out. When data is not being released as planned (ENHANCE intended for AHA 2006), then something is awry! I believe that they're trying to weave a silk purse out of a sow's ear, but can't. Therefore, they sweep it under the rug, hide it in the closet or worse. Since the completion was over 12 months ago, the FDA will be on their case soon (12 months rule).

Since earnings fell short due to cholesterol-lowering slow down, they could very well tank if the negative results got out anytime soon. So they've got their biostatisticians analyzing, re-analyzing, re-re-analyzing until they get it right.

And the walls come a tumblin' down, and the walls come a tumblin' down and the walls come a tumblin', tumblin', tumblin' DOOOWWWWNNNN........

Because it's negative! and management is trying to decide what to do with it!!!! Word is ezetimibe didn't do a darn thing for atherosclerosis when added to a statin. It's been put under the carpet and won't be presented until it has to be, though the FDA may get on their SP's back before then. Look out for Dr. Nissen as he's on the prowl!

This was a Phase IV trial done under an IND and was registered. They can't hide the data too long!!! Maybe a smart financial analyst will read this and start asking some pointed questions.

It was done to obtain a new indication. You're absolutely correct that it was under the IND with full regulatory implications for reporting. It's one of those trials that should be reported if it's positive or negative. If the investigators won't stand up, the feds will soon. Not reporting is going to cause SP a big problem down the road. Especially since they're implying that ezetimibe reduces atherosclerosis and events Another off-label promotion that will rise up and bite us in the butt! On the heels of the other $2 billion in fines!!

WTF??? Where is it????

this doesn't make me confident about Improve-it !!!!!!! Seriously, how could just a little zetia make that much of a difference. We're fucked until the generic atorva / zetia combo is ready.

yeah...where is it??? Analysts and reporters are going to be asking some very hard questions very soon.

It's either under the carpet or in the closet until they try to figure out how to explain the negative results. It's 15 months and counting.

Yeah, let's hope Steve Nissen doesn't get pissed with SP, MSD or MSP! That dorky twerp is out to shaft pharma.

Originally Posted by Anonymous

It's either under the carpet or in the closet until they try to figure out how to explain the negative results. It's 15 months and counting.

still trying to figure out how to spin a negative trial....

HAHAHA. Look who is worried now. First AZ - now you assholes!!! HAHAHAHAHAHAHAHAHA!!

Strange concept, but what if it is to the cotrary. The trial showed better than expected results and AHA was not a big enough stage. The world conference is not till 08. what if they are waiting for that so it can be presented on a bigger stage?

Originally Posted by Anonymous

Strange concept, but what if it is to the cotrary. The trial showed better than expected results and AHA was not a big enough stage. The world conference is not till 08. what if they are waiting for that so it can be presented on a bigger stage?

word of mouth from investigators involved in running the trial is that it is a negative study. We and Merck both talked up this study publicly a bunch before the results were known internally, now both are stone cold silent. The study was first supposed to be presented at AHA 2006, then ACC 2007, and now both ESC and AHA are passed this year with not a peep. You do the math.

Originally Posted by Anonymous

Strange concept, but what if it is to the cotrary. The trial showed better than expected results and AHA was not a big enough stage. The world conference is not till 08. what if they are waiting for that so it can be presented on a bigger stage?

How long have you been in this business - 2 months?

The AHA annual meeting has always been the "stage" to release positive news on cardiovascular agents. In fact, if the news was very positive, the news would have been released before the AHA meeting. Any company that has positive results in a major study will publish an abstract to tout the good news at the AHA meeting. Open your eyes!

I'm with AZ..Crestor rep...As one that sells a drug that underperforms, yet the company still pours huge glasses of kool-aid, I just wonder what you guys hear from the powers that be as far as this study and its lack of reporting publicly.

Why can't we all just take the dang generics and Pfizer down!!!

And do me a favor, as I respected you and told you who I was, none of the childish crap....please...just some real responses.

Thanks, and good luck

The Vytorin Question
Matthew Herper, 11.19.07, 7:21 PM ET


Every day millions of people swallow Zetia and Vytorin in the hopes of reducing their risk of heart attacks and strokes, generating $5 billion a year in sales for Merck and Schering-Plough, which produce them.

Do they work?

Despite millions of prescriptions, no study has ever shown that these $3-a-day pills prevent heart attacks, strokes or deaths any better than just taking older, cheaper drugs like Pfizer's Lipitor or Merck's off-patent Zocor, even though they're proven cholesterol fighters. That's why a two-year delay in a 900-person study aimed at clarifying the issue has cardiologists expressing skepticism and spinning conspiracy theories. If the news were good, the companies would rush it out, the thinking goes. Delay doesn't bode well.

"It starts to raise suspicion," says Allen J. Taylor, head of cardiology at Walter Reed Army Medical Center. "The more time it takes, the more you start to naturally wonder what is wrong."

Roger Blumenthal, a director of the Ciccarone Cardiology Center at Johns Hopkins, says he currently suspects the trial may not show a benefit for Vytorin. "I think anyone would have to think that," he says. He blames the study's design, not problems with the drug itself.

(Update: After this story's publication, Schering-Plough issued a statement saying that it had set up an independent panel to offer advice on analysis of the data from the study.)

The study, called ENHANCE, began in 2002 to answer the question of whether Zetia increases the effectiveness of Zocor at preventing heart attack by keeping plaque from building up in the arteries. Vytorin is a combo pill of Zetia and Zocor.

One thousand patients with a genetic disorder that causes high cholesterol got Zocor or Vytorin. Ultrasound pictures were taken of arteries in their thighs and necks. If adding ezetimibe, the crucial ingredient in the drugs, was good for the arteries, the people who took Vytorin would have less heart attack-causing plaque than those who just got Zocor.

All the patients had been treated, and their arteries measured, by April 2006. Cardiologists expected to see results at a medical meeting in November, then at another in March 2007, then at another this month. But none materialized. Schering-Plough and its researchers say the delay springs from technical difficulties reading more than 30,000 artery pictures. Researchers are "reading thousands and thousands of pictures and trying to validate them and make sure the data is right," says Fred Hassan, Schering's chief executive.

"I certainly want it finished," says John J.P. Kastelein of the University of the Netherlands, who led the study. "There are all sorts of conspiracy theories that are not good for my reputation."

Schering and Merck did not list the trial on the government Web site clinicaltrials.gov, which is supposed to have records of all clinical studies, until asked by Forbes.com about its absence. The companies say that it was an oversight resulting from the fact that ENHANCE began before the industry listed every study online.

Another source of suspicion: Top clinical trial experts often now recommend that the outside researchers conducting a study, not the company, have control over the computerized database created to analyze study results. In this case, that database is held by Schering-Plough.

But Kastelein says nothing nefarious is going on with the trial. Explaining the delays, he narrates a long tale of woe, including switching from roomfuls of VHS tapes to new digital imaging technology, training technicians and insuring the security of Internet connections.

The study was the biggest Kastelein had ever attempted. His last project had looked at the arteries of 350 patients at two medical centers. ENHANCE signed up three times as many patients at 26 different medical centers. But everything went smoothly, he says, in terms of recruiting patients and taking artery measurements.

Still, ENHANCE is being delayed again. Schering Plough and Kastelein decided the data needed a rescrubbing through quality control. Kastelein says he thinks that the fact that patients were randomly assigned one treatment or another would solve some of the differences. He says Schering is within its rights to want every "i" dotted and "t" crossed. The delay won't change the way the data is analyzed. Results are now expected at a medical meeting in March.

Skeptics remain. Walter Reed's Taylor worries that if Schering doesn't think the results are positive, its incentive is to delay as long as possible in the hope that better data might emerge from another study. But Paul D. Thompson, director of cardiology at Hartford Hospital in Connecticut, counters that he's not overly concerned about the delay. Kastelein is "a stand-up guy," he says, and the stakes are high. A bad result would cause Pfizer and AstraZeneca sales reps to turn up at every hospital in the country "within milliseconds."

"We'd all agree that having this long a delay after a study's over is a bad thing," says Robert Califf of Duke University, who is one of the leaders of a giant study comparing Vytorin and Zocor on their ability to prevent heart attacks. "I sure hope Zetia works," he says. "I'm taking it myself."

Other doctors argue that even if the data show no difference, it might not mean all that much. Hopkins' Blumenthal notes that only one study has shown that a cholesterol-lowering pill actually reduced artery plaque. "This isn't going to determine the future of Vytorin," he says. For that, doctors will have to wait for studies like the one Califf is conducting.

Prediman K. Shah, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, says that lowering cholesterol is almost always a good thing, and it would not make “an iota of sense” for Zetia not to work. However, Richard Lange of Johns Hopkins University notes that so far there is no evidence patients get extra benefit from adding Zetia. “They're going to have to explain exactly what the delay was,” Lange says. “At that point we'll have enough information to know it passes the sniff test.”

At the very least, the story of the delayed Vytorin trial shows the immense pressure companies are under to prove their medicines really work as advertised--and to show how easy it would be for them to delay negative results. Right now, there's really no way to know what's going on with ENHANCE--at least, not until the data are made public.

Read it and weep!! MSP is on the ropes!! Zetia and Vytorin are under question!

http://www.forbes.com/2007/11/19/zet...rtner=yahootix

or

Merck & Schering-Plough Battle Skepticism
November 19th, 2007 10:31 pm By Ed Silverman
The drugmakers are facing a growing chorus of doubters that a study of Vytorin, which is a combo of Merck’s Zocor and Schering-Plough’s Zetia, is going well. The study began in 2002 and the results have been delayed two years. So tonight, a statement was issued saying an independent panel of clinical and biostatistical experts was created to help analyze the data. But they insist data will be shown at the American College of Cardiology meeting in March.

The study, called Enhance, was designed to explore whether Zetia increases the effectiveness of Zocor at preventing heart attack by keeping plaque from building up in the arteries. It’s an important question for Merck and Schering-Plough because there’s never been a study showing their combo prevents heart attacks, strokes or deaths any better than Pfizer’s Lipitor or generic Zocor.

If the news were good, the companies would rush it out, but delay doesn’t bode well, Forbes points out this week. “It starts to raise suspicion,” Allen Taylor, head of cardiology at Walter Reed Army Medical Center, tells the mag. “The more time it takes, the more you start to naturally wonder what is wrong.”

Reasons to be suspicious: The trial wasn’t listed clinicaltrials.gov until asked by Forbes about its absence. The drugmakers say that it was an oversight because the study began before the industry listed every study online. Also, clinical trial experts often recommend that outside researchers conducting a study, not a company, control the computerized database created to analyze study results. In this case, that database is held by Schering-Plough.


In explaining the delays, the drugmakers point to difficulties reading some 30,000 artery pictures of 1,000 patients, who received Zocor or Vytorin. Ultrasound pictures were taken of arteries in their thighs and necks. If adding Zetia, the key ingredient in both drugs, was good for arteries, Vytorin patients would have less plaque than those who just got Zocor, Forbes notes. The patients have a genetic disorder that causes high cholesterol.

“This has been time consuming and taken longer than originally anticipated because during the analysis, observations of variability in some of the data were detected as part of the validation/data review procedures” the statement reads. “Such potentially confounding observations are not unusual in studies of this kind.”

“It is critically important for researchers to take the appropriate time and rigor to conduct clinical trials, analyze data and report study results. The Enhance trial is complex and is being conducted with great care,” says John Kastelein, a professor of medicine and chairman, Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands, in the statement. And as he tells Forbes, “I certainly want it finished. There are all sorts of conspiracy theories that are not good for my reputation.”

Hey,

We stand for business integrity, honesty, and truthfullness. How dare anyone question us!

Fred H. and Carrie C.

PS: As part of our newest business venture to broaden our scope, we have some oceanfront land for sale in Arizona. Are you interested?

Oh no! The world is on to us now! What in the world are we going to do! Zetia and Vytorin are our our flagships and they've "flunked" their latest test. Just wait until IMPROVE-IT comes out in 2011. Then we'll be vindicated!

Originally Posted by Anonymous

I'm with AZ..Crestor rep...As one that sells a drug that underperforms, yet the company still pours huge glasses of kool-aid, I just wonder what you guys hear from the powers that be as far as this study and its lack of reporting publicly.

Why can't we all just take the dang generics and Pfizer down!!!

And do me a favor, as I respected you and told you who I was, none of the childish crap....please...just some real responses.

Thanks, and good luck

you little AZ reps... showing your doctors some strange piece you got from CORONA (which is what your company must have been drinking when they thought it would prove anything). Join the ranks of Zocor and Pravachol with your AWESOME ability to reduce atherosclerosis (oh, and not to mention destroying kidney function!). You AND your vulva/vytorin species are doomed.

The FDA and the medical community are on to SP now. The truth hurts! Wave good-bye to the flagship franchise!!

Because it's a FAILED trial and completely NEGATIVE!

Now Congress wants to know!!!! Good Bye to the flagship franchise and the good times! How are Fred and Carrie going to weasel their way out of this one? Run away from their responsibilities - just like at AHP and Pharmacia? They've led us down the primrose path and into the rose bushes!

Pandora's box is about to open and reveal all the filthy maggots inside! An investigation of the interior of the company will reveal so much in the way of wrongdoing that they'll never recover from the fines! maybe Fred will head back to pakistan and take his woman with him! It would be a good thing for America! Two less crooks!!

"To earn trust every day". This is like the sleazeball who says "trust me". What is the natural thing to do when someone has to tell you to trust them.....that's right, run quickly in the other direction!

Originally Posted by Anonymous

The FDA and the medical community are on to SP now. The truth hurts! Wave good-bye to the flagship franchise!!

Let's be honest here, SP and Merck rolled the dice and lost on the study. Greed for increased profits once again foils a product. I think the intentions of the study were good and in the best interests of science, however, Wall Street is not interested in good science and will punish the stock.

This is most likely a stupid study! What are they measuring? Regression? Hard Plaque? Vunerable Plaque? Since most data on heart attacks has already proven that the culprit lesion is less than 50 percent closed. The only way to tell is to find a vunerable plaque and measure the consistency of the lipid core. What type of device is being used to measure? Angiography? CT? Schering's research department probably needed to put their ladder against a different wall. That is my guess until we hear more.

Heard from one of the drs involved in the vytorin study that you might as well take simvastatin b/c there was no benefits with zetia plus zocor for reducing cv risk. Reducing numbers doesn't mean reducing heart attacks.

Originally Posted by Anonymous

Because it's a FAILED trial and completely NEGATIVE!

Now Congress wants to know!!!! Good Bye to the flagship franchise and the good times! How are Fred and Carrie going to weasel their way out of this one? Run away from their responsibilities - just like at AHP and Pharmacia? They've led us down the primrose path and into the rose bushes!

Pandora's box is about to open and reveal all the filthy maggots inside! An investigation of the interior of the company will reveal so much in the way of wrongdoing that they'll never recover from the fines! maybe Fred will head back to pakistan and take his woman with him! It would be a good thing for America! Two less crooks!!

This guy has my vote for most likely to go postal.

Yes Schering and Merck have taken a long time to get the final data out. It seemed like they wanted to change the Primary endpoint to make it look as if Vytorin was able to regress plaque more than possibly thought. Maybe the study will show some plaque regression but could have been a better percentage with only the carotid artery versus the other 2. Vytorin lowers LDL, The lower the LDL the lower the risk of having a cardio vascular event. Vytorin would love to prove reduction in plaque and LDL in order to present a valid case of having Vytorin Preferred as a 2 tier medicine meaning around a $20 co-pay for patients with Insurance, which it already is. The more you can prove the more HMO insurance plans as well as Medicare you can get on and make more MONEY$

Originally Posted by Anonymous

Heard from one of the drs involved in the vytorin study that you might as well take simvastatin b/c there was no benefits with zetia plus zocor for reducing cv risk. Reducing numbers doesn't mean reducing heart attacks.

Lower LDL means less risk of having a cardiovascular event. That has been proven in numerous studies Grundy et al. No one has ever claimed that Zetia or Vytorin is able to reduce plaque? That was the whole endpoint of the study, to see if it would. Maybe it does maybe is doesn't. What we do know is the lower your LDL the lower risk you have of having a cardiovascular event. Reduce the risk of have a heart attack by 20-25% by taking Zetia with your statin or Vytorin I would. Who knows what would be proven in terms of plaque regression and reduction of cardiovascular events. You can only speculate but if it did reduce plaque you would see an increase with the stock price and sales of Vytorin and Zetia in 2008.

WAIT. This is all a ploy to raise interest and make it look better when it comes out.

Speculation will run rampant until there are data presented hopefully in enough detail to be fully and independently judged under peer review- although Congressional interest pre-data is unprecedented.

In the interim, the heightened scrutiny is turning attention to the science of ezetimibe and its mechanism of action. This has absolutely nothing to do with serum LDL-C. The drug IS absorbed, and has multiple, presumably negative off-target effects on membrane proteins felt to be important to LDL and HDL metabolism.

This has all been scientific discovery post-drug approval and the initiation of ENHANCE as the mechanism of action was elucidated.

So, in the 3 months until data are available to discuss, a discourse on potential off target effects (whether important or not in people is unknown- but this is the point of concern over the delay in ENHANCE) vs. mild additional LDL-C reductions will help better understand the results when presented.

The paradoxical outcome of torcetrapib with CIMT progression (some segments) and adverse outcomes despite huge HDL increases and LDL decreases (irrespective of opinions on other off-target effects) is an eye opener for a new world order in lipid levels as "surrogates". Heightened concern on ENHANCE is a second order effect of lessons learned from the torcetrapib experience.

Originally Posted by Anonymous

Lower LDL means less risk of having a cardiovascular event. That has been proven in numerous studies Grundy et al. No one has ever claimed that Zetia or Vytorin is able to reduce plaque? That was the whole endpoint of the study, to see if it would. Maybe it does maybe is doesn't. What we do know is the lower your LDL the lower risk you have of having a cardiovascular event. Reduce the risk of have a heart attack by 20-25% by taking Zetia with your statin or Vytorin I would. Who knows what would be proven in terms of plaque regression and reduction of cardiovascular events. You can only speculate but if it did reduce plaque you would see an increase with the stock price and sales of Vytorin and Zetia in 2008.

___________
Kool Aid Drinker:
The reduction of LDL as the means to reduce CV events could be analogous to "turning the key to your car starts the engine". The act of turning the key maybe what gets process started that ends in the car starting but there are many other reactions occuring after the key is turned that are vitally important to the end result. In other words, it may not be as simple as "lowering the LDL" it may be about how you lower the LDL. I will probably leave something out but here goes:
statin mechanism = proven & short in duration before effect is realized
excercize & diet = proven but longer term before effect is realized
niacin = only proven in a very short underpowered study and could have been HDL mediated effect.
fibrates = 50/50, 1 study positive (Lopid), 1 study not so positive (feno)
illeal byspass = positive but long term before benefit realized
Questran = positive but 9 years before benefit was realized
HRT = negative for benefit eventhough LDL lowered, HDL raised, Trigs reduced
Alpha blocker = negative for benefit, see above for effects on Lipids
CETP inhibitor = negative for benefit despite 100% HDL increase & 25% LDL decrease.
Zetia = UNKNOWN, new mechanism but similar to Illeal bypass & Questran so should expect positive benefit but long term before realized.

Wake up and realize that there maybe alot more going on with statins than just LDL reduction, our science and ability to identify may just not be able to pinpoint the effect. Or Maybe it is just about LDL? Point is we are not certain, but there is evidence to suggest that it is not just about LDL.

ENHANCE wasn't at AHA because SP wants to hide it as long as possible ubtil they can figure out how to spin it. The earnings for 2007 may be very good, but look out for 2008, especially if this failed trial comes out at ACC.

Originally Posted by Anonymous

___________
Kool Aid Drinker:
The reduction of LDL as the means to reduce CV events could be analogous to "turning the key to your car starts the engine". The act of turning the key maybe what gets process started that ends in the car starting but there are many other reactions occuring after the key is turned that are vitally important to the end result. In other words, it may not be as simple as "lowering the LDL" it may be about how you lower the LDL. I will probably leave something out but here goes:
statin mechanism = proven & short in duration before effect is realized
excercize & diet = proven but longer term before effect is realized
niacin = only proven in a very short underpowered study and could have been HDL mediated effect.
fibrates = 50/50, 1 study positive (Lopid), 1 study not so positive (feno)
illeal byspass = positive but long term before benefit realized
Questran = positive but 9 years before benefit was realized
HRT = negative for benefit eventhough LDL lowered, HDL raised, Trigs reduced
Alpha blocker = negative for benefit, see above for effects on Lipids
CETP inhibitor = negative for benefit despite 100% HDL increase & 25% LDL decrease.
Zetia = UNKNOWN, new mechanism but similar to Illeal bypass & Questran so should expect positive benefit but long term before realized.

Wake up and realize that there maybe alot more going on with statins than just LDL reduction, our science and ability to identify may just not be able to pinpoint the effect. Or Maybe it is just about LDL? Point is we are not certain, but there is evidence to suggest that it is not just about LDL.

hey einstein,.. you just started reading the right literature,..
Niacin,.. one study,..
CDP, CLAS-I, CLAS-II, SCOR, FATS, FATS p 15 years, HATS, AFREGS, ARBITER 2 & 3,...
90% of the above with NO Pharm Phunding,..
RIF, reading is fundamental,..
BTW

This guy sure loved to put ENHANCE in bold red caps, now if we could only find that crazy computer that could do that and we would know exactly were to find "Deepthroat." Or could it just be....nah...forget it. Just a little more food for thought!!!!!!!

Which AHA? 2007 or 2006? What about ACC 2007? It's outrageous that 21 months passed between the end of the study and top-line results and that nobody, but nobody, knew anything about the results along the way! Studies in this decade are almost always reported in 12 months because the FDA wants them to be filed by then. I wonder if SP told the FDA anything at all about what was going on. or did they just share the information internally?

There have been studies showing that ezetimibe does not improve endothelial dysfunction. So it is not surprising that the trial was negative.

WHERE'S THE BEEF????? SP FRED AND CARRIE ARE THIEVES

Originally Posted by Anonymous

There have been studies showing that ezetimibe does not improve endothelial dysfunction. So it is not surprising that the trial was negative.

WHERE'S THE BEEF????? SP FRED AND CARRIE ARE THIEVES.....???

Originally Posted by Anonymous

There have been studies showing that ezetimibe does not improve endothelial dysfunction. So it is not surprising that the trial was negative.