Quote of the week

"I believe that [Zetia] is clinically beneficial, but I cannot prove that."

Dr. Roger Blumenthal, Director, The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease.

Source

Dissecting ezetemibe and ENHANCE

The manufacturer "has invested far more in marketing than in science".


At present, ezetimibe’s mechanism of
action is not fully understood, and its benefit—
for now, only mild LDL-C reduction—is too
uncertain for us to be spending $5.2 billion a
year for it. Its manufacturer is fortunate that
the drug is even licensed, given the current
and seemingly appropriate regulatory changes
under which drugs introducing new therapeutic
classes are scrutinized more closely for benefit.

Wondering what to buy Fred Hassan and Carrie Cox as leaving presents?

How about a cartoon?

Hat tip: PM

Vytorin - The Truth

....according to Condor.

The Vytorin Saga contd. - over to you Melissa

Probe

Dissection

Dick Clark - on the other hand

Quote 1 Quote 2

Vytorin sales - just for Jami Rubin

Fred's body language can sometimes help decipher what he means!

Vytorin contd. - that tricky Merck / Schering Plough relationship

The Cordaptive angle.

Business partners - what to do?

You can't live with 'em , and you can't kill 'em!

To the Dechert lawyer

Is this what you were looking for?

Merck - the price of ENHANCE

Around $300 million in lost sales in the first quarter of 2008.
Tell 'em Mike.

The Vytorin Saga contd. - The Condor speaks

What a blog!

Here we get some insights into its author as they answer questions:

Smile -- I've NEVER worked for Schering-Plough; I am NO journalist. Did you ever see "Three Days of the Condor"?

I am a. . . . reader, I guess. I've spent some time really "reading up" on SGP, over the past three months.

Now, your questions do deserve answers, and I do have my opinions(!), but I want to be careful not to libel/defame any private person. I do think Dr. Bots was right. I think the data were "fine." I think it likely that Schering and Merck just didn't "like" what the data pretty-plainly implied. Note that I've echoed, and amplified, Sen. Grassley's publicly-aired concerns that the very-likely outcomes from even the "blinded" data, were discernible to a medically-trained eye, long-before the data were actually, formally, unblinded.

So, I think -- emphasis on "think", here -- Schering and Merck asked to have the data "refined" -- to try and tease some statistically-significant outcome, from it. But even the expert panelists then later agreed, on November 16, 2007, that it was likely that any variance in the "blinded data" could be the result of pure chance, not treatment/control arm outcomes.

The Condor finshes with:

Now, I will say that -- as a matter of law -- even innocently delaying such data, and then selling stock to the public at $27.50 (near the high-price for the year!), is generally-frowned upon, over at the SEC.

Note that Schering sold $3.8 billion of equity, and another ~$4 billion of debt -- right in the middle of this "entirely innocent delay" on a project that impacted (or should I say sustained) 60-plus percent of Schering's 2007 profitability. That much is entirely undisputed -- and fascinating, no?. . . .

The Vytorin Saga - The MedPage Debate

Evan A. Stein, M.D., Ph.D., of the Metabolic and Atherosclerosis Research Center in Cincinnati and the only U.S. ENHANCE investigator, defended the use of ezetimibe.

Taking the opposing view is Allen J. Taylor, M.D., of the Uniformed Services University of the Health Sciences Walter Reed Army Medical Center in Washington and co-author of a New England Journal of Medicine editorial on the ENHANCE trial.

Drs. Taylor and Stein were interviewed separately at the MedPage Today offices in Little Falls, N.J., on April 9 and 10 by Peggy Peck, Executive Editor, MedPage Today.

The physicians received no honoraria from MedPage Today. They were reimbursed for travel expenses.

Source

Schering Plough - Vytorin: quote(s) of the week

"I'm an honest guy, and my first obligation is to tell the truth. Even if it means I'll probably never get to do a scientific investigation with Schering-Plough again."

And:

"For anyone to say the data in the study are bad, they either need to say that John Kastelein is a liar, which I'm certain he is not, or they need to talk to the [Schering-Plough] statisticians for the study and ask them if there are any problems with the data,"

Professor James Stein - speaking to Matt Herper

James H. Stein, MD is a Professor in the Division of Cardiovascular Medicine at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin. He is Director of the Preventive Cardiology Program and Director of the Vascular Health Screening Program at the University of Wisconsin Hospital and Clinics. Dr. Stein also is the Director of the University of Wisconsin Atherosclerosis Imaging Research Program.

Dr. Stein received his baccalaureate degree with honors from the University of Wisconsin. He received his Doctor of Medicine (cum laude) degree from the Yale University School of Medicine in New Haven, Connecticut. His Internship and Residency in Internal Medicine were at the University of Chicago Medical Center in Illinois. He completed a Cardiology Fellowship at Rush-Presbyterian-St. Luke's Medical Center in Chicago, Illinois.

Dr. Stein has been named one of Madison's “Top Docs” in Cardiology by Madison Magazine since 2000 and in 2007 was named one of the 20 best cardiologists in America by Men’s Health Magazine.

Interested in Vytorin? Then this is a MUST READ blog.

http://shearlingsplowed.blogspot.com/

Mike Huckman has the answer

Merck and SGP's Vytorin/Zetia: Are Doctors Writing Fewer Scripts?

Schering Plough - ENHANCE: a rhetorical question?

Maybe Carrie can help you Fred - or this.
Ed at Pharmalot has the latest twist in the sorry tale.

Vytorin - Schering Plough share price

Click for larger.

Pathophilia has some "fancy graphs" with a time line on them.

However, the y axes change between graphs, so this should help you with the overall picture.

This might help as well.

And here's another hard reality, Fred

Sometimes negative studies can provide very important insights. You have just seen a negative trial that should change practice, especially given the way that we, in this country, have been prescribing ezetimibe.

There are several things to notice about this study and Dr. Kastelein’s presentation. It seems to be a strong study for one focusing on a surrogate outcome of artery thickness. In the ASAP study, his earlier study of a similar population, such an approach showed that more intensive lipid lowering with atorvastatin was associated with less progression of atherosclerosis. In a pediatric population, another Kastelein study, this approach showed that pravastatin compared with placebo was associated with less progression of atherosclerosis. In this study, the addition of ezetimibe to a statin did not slow the progression of atherosclerosis. And this was true for various subgroups, including those who were statin naïve and those with stratified by baseline artery wall thickness.

Critics may opine about reasons for the findings including the possibility the measures were not precise enough or the population was not typical – but the most likely explanation is that the compound did not work. It lowered LDL, but did not retard the progression of atherosclerosis as we saw in prior studies where the use of statin therapy or intensive statin therapy had this effect. Now this is still just one study of ezetimibe and one that employed measurements of arteries and not clinical endpoints, but this study provides no new evidence to support the use of the drug. And it moves us to more uncertainty about the benefit of the drug.

What about the presumption that knowing that a drug lowers LDL is enough to know its effect on our patients. Dr. Kastelein’s presentation also has a message that is important in this respect. In his 5th slide Dr. Kastelein said that ezetimibe was known to reduce LDL-c when added to a statin but that the effect on the progression of atherosclerosis was not known. This is a very important slide.

This study was developed by experts.

Whether the incremental lowering of LDL by this drug had an effect on the progression of atherosclerosis was an open question – worthy of study. As is the question of what effect the drug has on our patients – it is an open question – worthy of study. We do not know.

Remember that this is a new drug – with a novel mechanism – first in class – we do not have outcomes studies.

But you might say, but the drug lowers LDL, isn’t that a good thing?

Shouldn’t that be associated with benefit?

Wasn’t that enough for the FDA?

Well, although LDL is an important risk factor for cardiovascular disease, we have already refuted the assumption that just because a drug reduces LDL it must improve patient outcomes. Hormone replacement therapy reduces LDL and is not associated with cardiovascular benefit. Torceptrapib, the Pfizer drug, lowered LDL and raised HDL, but did not improve outcomes and never made it to FDA approval.

Drugs are complex compounds with an array of biological effects – knowing how they affect lipids does not tell us how they affect people. This observation does not unravel the lipid hypothesis, but says it may matter how we lower cholesterol. The drugs that we use make a difference in the net effect on people.With knowledge of its effect on LDL but no information about its effect on the progression of atherosclerosis or patient outcomes, how have we used this drug? We, in the US, have embraced this medication. Amid an aggressive marketing campaign this drug has been rapidly adopted into practice and become one of our favorite options for patients with hypercholesterolemia. Within 6 years of its introduction, prescriptions for Zetia and Vytorin in this country skyrocketed. In a paper published online today by the NEJM, Jackevicius and colleagues show that by 2006, four years after its introduction, 15% of US prescriptions for LLAs included ezetimibe.

In Canada, the rate was only 3%.

In the US ezetimibe supplanted statins to some extent and led to use of lower doses of statins.And the cost was great. In 2006 we in the US spent billions of dollars on this drug. Perhaps $1.5-2.0 billion more was spent than would have been had our pattern been more like the Canadians.So what do we know now about the effects of this drug on people’s health?

There are three possibilities with this drug.

Eventually – one day – when outcomes studies are finally done — we may recognize that it is an effective medication for reducing cardiovascular risk – the ENHANCE study makes that less likely – but it is not impossible.

Or it could be that ezetimibe is just an expensive placebo and its principal harm is that it drains precious resources from our health care system – and maybe leads people to use less of the drugs that have been shown to be beneficial. The ENHANCE study suggests that this may be true.

Third, it could be harmful. Honestly, we do not know enough about the clinical risks of this drug. It is well tolerated and there are no obvious safety problems, but we cannot say if there is an increased risk of AMI or death or another important health problem.Important clinical risks like this can be imperceptible in clinical practice; we need large clinical studies to tell us about them. We learned that with encainide and flecanide – and hormone replacement therapy – and many others.

For this novel medication for which there are some plausible biological mechanisms that could link it with harm – and see the NEJM editorial by Taylor and Brown for some possibilities – it is important to know more about safety. No one can tell you with certainty that they know about the clinical risks of this drug. We just do not know. And ENHANCE does help us in this regard.

So where does this leave us?

ENHANCE is an important negative study that provides no new support for a widely prescribed drug and whose surprising findings remind us how little we know about the overall risks and benefits of this drug – whether there is really a net clinical benefit to its lipid lowering effect.For clinicians who may have employed this medication before exhausting options with statins, the strongest recommendation here is to turn back to statins, especially those with favorable outcomes data. Go back to what we know works. Let us stay with the evidence. Patients who need medication to treat cholesterol should be maximized on statin therapy – and different statins may need to be tried before a patient is considered to have failed statin therapy.

Then, the next options should be medications that have been shown to be associated with better clinical outcomes – niacin, fibrates and resins. We know that they are not tolerated as well, but they have evidence and are worth trying.

And then for those who have failed these therapies, and this should be a relative small group, the question of whether we should use ezetimibe will likely be unresolved until the outcomes studies are available. Until then we will not know the net effect of this drug on patients – and whether the reduction of LDL with this drug produces a clinical meaningful effect. And we will not really know the strategy that is in the best interests of our patients. It is an unfortunate predicament.

This study heralds the need for clinical research to guide us in decisions for our patients – and ideally this work needs to be done early in the drug’s development. It is not right that we are this far down the line with this drug and we have so much uncertainty about its balance of risks and benefits. We need to understand the effect of new drugs on people. And that relying on a drug’s effect on a set of lab tests may not tell the whole story.

We have learned this lesson before – it appears that we need to learn it again.

Professor Krumholz's credentials.

Schering Plough - Hassan's hard new realities

The pressures that Schering-Plough has been suffering amid the criticism of its cholesteriol drugs Vytorin and Zetia, sold through a joint venture with Merck & Co, has led the firm to announce major job cuts and plant closures.

S-P has unveiled what it calls a “productivity transformation programme”, which targets $1.5 billion in annual savings and includes previously-announced synergy targets of $500 million from the November 2007 acquisition of Organon BioSciences from Akzo Nobel.

The company said the move is a response to “dramatically intensifying pressures on the pharmaceutical industry, especially new pressures in the USA, and also to the confusion in the US market around cholesterol management”. It is expected that around 10% of its 55,000 workforce will be laid off.

This specifically refers to the results of the controversial ENHANCE study confirmed at the American College of Cardiology meeting in Chicago which demonstrated that Vytorin, a combination of Zetia (ezetimibe) and Zocor (simvastatin), may not be any more effective than cheaper statins, notably generic Zocor, in preventing heart disease. As a result, panellists at the ACC recommended that widespread use of Vytorin and Zetia should be curtailed.

Specific details of the programme have not yet been finalised but S-P said that more than 80%, of the planned savings are targeted to be accomplished by the end of 2010. As well as the reduction of the number of facilities across the world, it will create “more focused and high-efficiency plants by 2012”.

Chief executive Fred Hassan said “savings and productivity improvements will be realised across the company and around the world. No area will be exempt”. He added that the first step will be to reduce “higher management levels in the company's headquarters and elsewhere”, noting that “a major focus will be the USA, where the most intense new pressures on our industry and our company are centred."

Mr Hassan, claiming that S-P will “not engage in across-the-board cost-cutting” and “will avoid unwise short term actions”, said the firm is progressing well, citing the Organon purchase. He insisted that “we now have perhaps the most impressive late-stage pipeline in our peer group -- including cutting edge projects as TRA for deadly blood clots, and sugammadex in anaesthesiology".

However the firm has seen its stock plummet in the past few months and "hard new realities are requiring the hard new actions" he added, claiming that “the reality is that we face today a new political and overall environment in the USA that is increasingly discouraging pharmaceutical innovation." An example of this, Mr Hassan said, "has been the confusion in the cholesterol market largely caused by the overreaction to conflicting results of the relatively small ENHANCE clinical trial, involving Vytorin”.

He continued: “This confusion, in the absence of an open and balanced scientific discussion of this clinical trial, have caused an unwarranted concern among millions of patients who need to get to their cholesterol goals". The Vytorin tale “has been a case study of the impact of the hard new realities," he added.

Source: PharmaTimes

Vytorin - a drug that dodged scrutiny

The Ledger writes:

The study that sent Merck and Schering-Plough stock plung ing and put doctors in a tizzy this week did not find any harm from taking the drug Vytorin -- except to pocketbooks.

The problem was that while there was no harm, there was not much benefit either. Vytorin, which combines Merck's drug Zocor and Schering-Plough's Zetia, does not seem to clear arteries any better than taking Zocor alone -- and generic Zocor sells for a mere one-fifth of Vytorin's price.

The other problem for the pharmaceutical giants is that some members of Congress are investigating whether the companies delayed the release of the study's not-so-good news to protect profits for as long as possible.

If so, they did it at the expense of stockholders as well as consumers and insurance programs, including Medicaid and Medicare, which paid for Vytorin when cheaper Zocor would have done. Was the combined drug about science or a market device to up the price of one old drug by dressing it up as something new?

There are still unanswered scientific questions. Merck and Schering-Plough chose to study Vytorin in patients with an elevated genetic predisposition for very high cholesterol. Vytorin reduced the so-called bad cholesterol levels although not as low as target levels set by experts.

Reducing the buildup of plaque on artery walls is the business end of cholesterol control, and Vytorin did not perform any better than plain old, cheap Zocor. Why not? Might the results be different in a more typical population? In a larger study?

Those are important questions. So is this one, for Congress and the Food and Drug Administration: Why is it that Vytorin has been on the market for years, has saturated consumer and medical minds with $140 million a year in advertising and raked in more than $5 billion in sales -- yet we're just getting around to finding out if it works?

Insider's view: Hear hear!

The FDA should, and will, be more cautious when approving NCE's like ezetemibe based only on weak surrogate endpoints.

Pargluva was stopped with a request for harder data.

I wonder which drugs in development will now have the bar raised for them!?