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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Backtracking, Necessary and Unnecessary | Main | Patents Stopping an Alzheimer's Wonder Drug? »

July 22, 2008

Vytorin: Another Round of Nasty Results

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Posted by Derek

Merck took the unusual step of delaying its earnings release yesterday until after the close of the market. A report on another clinical study of Vytorin (ezetimibe), their drug with Schering-Plough, was coming out, so they put the numbers on hold until after the press release yesterday afternoon. Naturally, this led to a lot of speculation about what was going on. A conspiracy-minded website vastly unfriendly to Schering-Plough suspected some sort of elaborate ruse to drum up publicity.

But that sort of thinking doesn't take you very far, unless you count the distance you rack up going around in circles. As it turned out, the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis) was, in fact, very bad publicity indeed for the drug and for both companies. In fact, a real conspiracy would have made sure that these numbers never saw the light of day, or were at least released at 6 PM on a Friday. But no, the spotlight was on them good and proper.

This trial studied patients with chronic aortic stenosis, which is a different condition than classic atherosclerosis. The two have enough similarities, though, that there has been much interest in whether statin treatment could be effective. The primary endpoint, a composite of aortic valve and general cardiovascular events, was missed. Vytorin was no better than placebo. It reached significance against one secondary endpoint, reducing the risk of various ischemic events, but not in any dramatic fashion.

That's not necessarily a surprise, since there's not a well-established therapy for aortic stenosis (thus the trial design versus placebo). As several commenters to the conference call after the press conference pointed out, this shouldn't change clinical practice much at all. But it's not what Merck and Schering-Plough needed to hear, that's for sure, because the sound bite will be "Vytorin Fails Again".

Actually, the sound bite will be even worse than that. There are a lot of headlines this morning about another observation from the SEAS trial: that significantly more patients in the treatment arm of the study were diagnosed with cancer. That's a red warning light, for sure, but in this case we have at least some data to decide how much of one.

For one thing, as far as I know there have been no reports of increased cancer among the patients taking Vytorin out in the marketplace - of course, one could argue that this might have been missed, but if the effect were as large as seen in the SEAS study, I don't think it would have been. Analyses of the earlier Vytorin trials and the ongoing IMPROVE-IT trial versus Zocor have also shown no cancer risk, and the latter trial is continuing. So for now, it would appear that either this was a nasty result by chance, or (a longer shot) that there's something different about the aortic stenosis patients that leads to major trouble with Vytorin.

None of these scientific and statistical arguments, and I mean none of them, will avail Schering-Plough and Merck. Among people who've heard of Vytorin at all, the first thing that will come to mind is "doesn't work", and after today's headlines, the second thing that will come to mind is "cancer". Just what you want, to put out press releases that your compound, even though it failed to work again, isn't actually a cancer risk. You really couldn't do worse; a gang of saboteurs couldn't have done worse. Of course, there's no such gang: the companies themselves authorized these trials, thinking that there were home runs to be hit. But all these sidelines - familial hypercholesteremia, aortic stenosis - have only sown fear, confusion, and doubt. The only thing that I can see rescuing Vytorin as a useful drug is for the IMPROVE-IT results to show really robust efficacy in its real-world patients. And I wonder if even that could be enough.

Comments (19) + TrackBacks (0) | Category: Business and Markets | Cancer | Cardiovascular Disease | Clinical Trials | Toxicology


COMMENTS

1. Still Scared of Dinosaurs on July 22, 2008 9:35 AM writes...

Poke around the web and you find a lot of examples of how not to report clinical trial data. Why say "roughly 1800 patients"? Just tell us how many and HOW MANY IN EACH TREATMENT GROUP! Do I have to infer that 102 vs 67 is meaningful only if the treatment groups are the same size - and only after assuming that the placebo group would not have been larger?

Don't tell us there was a "20% reduction in ischemic events" - tell us how many events in how many patients out of how many patients in each group over what total follow up. Maybe it's a lot of numbers for one sentence, so put it in parens or a footnote. Just don't make readers go to another page.

And most importantly - don't tell us there's a statistically significant difference in deaths without telling us if there was a difference in the follow time in patients once they had cancer. It's not unheard of to unblind some patients once SAEs that require changes in medical treatment occur. It's not always warranted and I'm not sure about this trial, but...If that were to occur I would suspect that the placebo patients would withdraw and the actively treated patients might continue if the patients and their MDs thought (1) there was a chance of benefit and (2) the cancer was unlikely to be related.

To make such an observation meaningful you have to eliminate such possibilities and communicate that you have done so. If you want to report on it you need to gather and present the relevant facts.

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2. Condor on July 22, 2008 10:15 AM writes...

Thanks for the link!

-- Condor

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3. Still Scared of Dinosaurs on July 22, 2008 10:19 AM writes...

BTW the above wasn't intended as a criticism of Derek's post but rather of the way that a major release of clinical results creates a cloud of increasingly derivative news items. The more they proliferate the harder it becomes to locate one that presents the numbers properly - especially at break time.

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4. Petros on July 22, 2008 10:32 AM writes...

The markets aren't too impressed. SGP in particular is taking a hammering

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5. Derek Lowe on July 22, 2008 10:39 AM writes...

SSD, I know what you mean. I hunted around this morning looking for the real numbers, and couldn't find them. That's probably because they haven't been officially published yet, but it does make it frustrating. . .

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6. Young on July 22, 2008 11:03 AM writes...

Still Scared of Dinosaurs: Well said.

So, let's see the response of MRK and SGP on stock.
Big hammer falls down

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7. Still Scared of Dinosaurs on July 22, 2008 11:53 AM writes...

Until you have a journal article in hand the two besst sources of numbers are usually (1) a company press release, and (2) ironically, analyst reports.

The former are often not great but they are usually the source from which all the other reports get their numbers so you might as well start there. In the present case I found the earnings release but not the trial results.

The latter are usually at their best when there is a presentation at a major meeting (e.g. ASCO) and they swipe all the numbers and write them up. (I've gotten internally distributed slide sets of photos of presenters' slides with the name of a well known biotech analyst in the path of each slide.) It's ironic to me because the analysts are so often good at presenting the data and yet so laughable at drawing conclusions from them.

Most brokerage accounts give you access to such reports at little or no cost, at least for the major companies like MRK and SGP. You can also buy reports which probably go into detail about how you should do the opposite of what the free reports suggest.

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8. Retread on July 22, 2008 12:40 PM writes...

SSD -- Bravo

This is the way studies were reported to docs in the past. You really had to dig to find the truly important information (even in the published paper). I've been retired for 8 years and hopefully things are bette presently.

Consider the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) study which was of great interest to me as a neurologist. It contained some 19,185 patients at 400 centers in 16 countries.

It was reported as follows. There was an 8.7% less risk of ischemic stroke, myocardial infarction or death in those on clopidogrel than aspirin. Pretty snazzy all right. Neurologists would much rather prevent strokes than attempt to treat them.

HOWEVER -- the actual event rates (stroke, MI, death) were tiny -- 5.83% in the aspirin group and 5.32% in the clopidogrel group. You'd have to treat 200 people for a year to prevent one event !

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9. Still Scared of Dinosaurs on July 22, 2008 2:57 PM writes...

And it always comes back to the benefit/risk. I know nothing about clopidogrel, but if the numbers Retread gave were for aspirin versus placebo I'd guess treating 200 patients for each stroke/MI/death prevented per year would be worth it - depending on how much aspirin you're giving them. I'd really want to see the breakdown by event as well but it still seems like apsirin would be low enough in cost and risk to be worth it in adults at high risk of isch events.

Of course, being able to make sound judgments about benefit/risk requires (1) the ability to estimate the benefit and risk and (2) the ability to make sound judgments. I can do the former if you give me the data. So, hey, MRK and SGP - give me the data.

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10. retread on July 22, 2008 5:10 PM writes...

SSD

I'm not sure this much detail is appropriate in this setting but here goes. The CAPRIE study was 75 mgm clopidogrel/day vs. 325 mgm aspirin/day Even today clopidoregl costs over $1/pill.

Even worse (for stroke patients) consider the following:

[ Stroke vol. 29 p. 1737 '98 (letter) ] When stroke patients alone in the CAPRIE study were evaluated (6400 patients 12000 patient years) were looked at again, there was no advantage at all in using clopidogrel.

[ Stroke vol. 30 pp. 1716 - 1721 '99 ] Over 75% of the therapeutic advantage of clopidogrel over aspirin in the CAPRIE study occured in the group with peripheral arterial disease (there were 62 fewer events in the clopidogrel treated patients (out of a total difference of 82 events in the combined groups). There was less than an 8% reduction in events in the stroke group (I didn't write down just how much less in my notes, as I recall it was quite a bit.

It's enough that I didn't use the drug. Most of my colleagues did for rather dubious benefit (if any).


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11. The Pharmcoepidemiologist on July 23, 2008 12:30 AM writes...

It seems likely the cancer data are not particularly indicative of a true cancer risk--it's one study, it's not large, there isn't a long follow-up period, etc, etc. However, given the problems SGP has had showing the positive effect of Zetia and/or Vytorin, if I were unsure about Vytorin vs Lipitor, I'd go with the latter. Same for my patients. Absent some major demonstration of Vytorin as besting Lipitor, it's dead meat in the marketplace. It's just that simple. And now you'll see the lawsuits from everyone who ever used Vytorin and subsequently was diagnosed with cancer. As sure as the night following the day...

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12. schinderhannes on July 23, 2008 2:30 AM writes...

@retreat: You wrote:
"HOWEVER -- the actual event rates (stroke, MI, death) were tiny -- 5.83% in the aspirin group and 5.32% in the clopidogrel group. You'd have to treat 200 people for a year to prevent one event ! "

Do you have any data what the event rate on placebo would have been?
I know this will be wild guessing, but as an expert you might have some kind of idea.
Cause if it was lets say 20% the reduction would have been equal.
If it would have been 5.84% you could say Clopridogel has at least some effect whilst Aspirin doesn´t....

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13. schinderhannes on July 23, 2008 2:40 AM writes...

retread not retreat!

LOL, nearly missed that

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14. Retread on July 23, 2008 8:23 AM writes...

Schinderhannes:

We have no data on the placebo rate, because obtaining such a rate now would be unethical. Here's why.

Science vol. 312 pp. 1162 '06 (Harold Varmus -- former head of the NIH) "The age-adjusted mortality rate for cancer is about the same in the 21st century as it was 50 years ago, whereas the death rates for cardiac, cerebrovascular and infectious diseases have declined by about two-thirds." Presumably this is due to our improved management.

We just compare 'best' treatments presently. When I was an intern in the 60s the survival of the commonest form of childhood leukemia was between 1 - 2 years. Now we worry about reproductive failure and cognitive problems in the survivors. These results were obtained by an agonizingly slow process of comparing the best known regimen with a newer (presumably better) one, and playing king of the mountain in study after study.

My point about using aspirin rather than clopidogrel is, that for the patient who already had a stroke (and therefore at much higher risk of a stroke than the general populace), aspirin was as effective and gigantically cheaper.

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15. schinderhannes on July 23, 2008 10:46 AM writes...

Retread:

Yeah, and they even confirmed that finding in the CHARISMA study....
Clopidogrel + ASA was not signif. more effective than ASA alone in reducing the rate of MI, stroke or death in high risk patients (30 months follow-up).
Doesn´t stop them from making big bucks...

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16. retread on July 23, 2008 12:39 PM writes...

Schinderhannes:

Thanks for bringing the CHARISMA study in '06 to my attention. I retired from neurology in 11/08 and stopped reading the medical literature at that point.

Thanks to 2 years of graduate school in Organic Chemistry before entering medicine, I knew how to read a scientific paper and evaluate evidence. I'd like to think my patients got the benefit of that. In the case of Clopidogrel they did. The evidence was already present in the CAPRIE study but it took some digging to get at it, as noted by SSD in #7. But that's what you should be paying your doc to do.

At this poiint, I think enough has been said

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17. Retread on July 23, 2008 7:02 PM writes...

Schinderhannes:

Change " I retired from neurology in 11/08 and stopped reading the medical literature at that point."

to

"I retired from neurology in 11/2000 and stopped reading the medical literature at that point."

Sorry -- maybe I'll try one o' them newfangled Alzheimer drugs I've heard so much about

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18. Dan on August 14, 2008 4:19 PM writes...

Published on www.brainblogger.com:

A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial

While it seems that pharmaceutical company sponsors of clinical trials usually end up with results that clearly favor their meds studied in their trial, there are rare exceptions, and Merck and Schering proved that with their disappointing ENHANCE Trial, which many have heard about through the media not long ago. The drugs studied were Vytorin, which was compared with Zocor
Vytorin is a combination med for high cholesterol and contains Merck’s Zocor, which is now generic, and Schering’s Zetia, which works differently than Zocor, which is one of many statin drugs. Both Vytorin and Zetia are co-promoted by Merck and Schering. So, several years ago, an outcomes study was initiated to prove superiority of Vytorin over Zocor. The trial was named the ENHANCE trial, and possibly this trial was initiated because Zocor is generic now, and not a priority from a profit paradigm of its creator.
After several years passed, a disappointment arrived for the sponsors of this trial, which was first brought to the attention of Schering in March of 2007, yet the results existed since the spring of 2006, I believe upon information and belief.
The disappointment is that Vytorin lacked anticipated benefit or superiority over Zocor. Since about 1 million scripts were written for both Vytorin and Zetia every week in 2007, combined with what I believe was about 5 billion in revenue for these two drugs that year, this was a problem for the drug makers, meaning a fear of shareholder reaction. Perhaps for Schering in particular, it was more of a calamity, since over half of their profits and earnings were from these two drugs with Schering, I understand.
Being the responsible corporations both companies are, of course, alterations occurred after such events were discovered that fractured numerous rules and regulations with clinical trials, possibly in illegal and unethical tactics.
The trial sponsors delayed the release of the trial results for secrecy reasons, it has been speculated. Results from the trial existed, yet were not disclosed at the time of their discovery. After several months of possessing these trial results that were only known to the manufacturers, they created or implemented some atrocious tactics to improve the trial’s unimpressive results following the original results of this ENHANCE study. At the end of 2007, the companies changed the primary endpoint of the trial, which is what the results were measured upon during the entire course of the trial. Sort of like sorting cards to make a good hand not dealt to you. Anyway, since their deliberate concealment of these trial results was clearly wrong, to respond to those who asked where the results were actually as they had been anticipated for quite some time, and while such trial manipulation was occurring and results were being kept secret, Schering stated that continued data analysis from the trial results was the etiology for the delay.
With clinical trials, case report forms are used to record data from the trials, and are created in a manner where further analysis is not normally necessary, as such forms are quite clear and often not subject to interpretation as implied by the trial sponsors, one could conclude. So at the end of 2007, both Merck and Schering got the attention of relevant government officials who contacted both companies regarding this ENHANCE trial due to such suspicions on the facts known and presented, and an investigation began into the activities of both companies regarding this trial at that point.
This became a catalyst for the ENHANCE trial results to be finally released at the beginning of 2008, which caught the attention of major media organizations, as expected. In the spring of 2008, a very large cardiology meeting was held, where the audience was told, I understand, to stick with statins due to this trial’s lack of outcomes for Vytorin, when the ENHANCE trial was discussed at this meeting. Furthermore, it has been said that a cardiologist at this meeting also suggested that a moratorium should occur with the utilization of Vytorin by prescribers, since statins are much less expensive, and are highly regarded, as they have been available for a couple of decades, starting with Mevacor in the 1980s. Of course and as expected, Merck and Schering were not pleased, nor were they surprised at the review of Vytorin at this particular meeting. The following month after this cardiology meeting, Schering’s earnings dropped by 48 percent, as I recall. Also during much of this year, Schering in particular blamed the media for amplifying the situation regarding the ENHANCE trial.
Now, these cholesterol drugs promoted by Merck and Schering, Zetia and Vytorin, were aggressively marketed in a number of ways, including investing I believe about 200million dollars in 2007 for DTC ads for these products. To add to this, and soon after both meds were launched, reps from both companies made inferences to doctors about outcomes regarding plaque accumulation and how Vytorin was superior in that area, which, of course, this ENHANCE trial proved it is in fact not the case whatsoever. It did not matter, apparently, to both Merck and Schering that such claims were is entirely void of proof, which is not unique to any pharma rep, in my opinion. No remorse or regret from the makers of these drug makers, either, which did not shock many. Yet what is known now is that these companies, as stated by other researchers, performed junk science with their deliberate manipulation of this ENHANCE trial using such tactics. Also, last year, Zetia and Vytorin had about 20 percent of the cholesterol lowering market. It does not seem that there will be an increase of this percentage because of this scandal. Possibly if they presented the truth, the future of these meds might be better than what is anticipated presently.
Worst of all regarding this ENHANCE trial scandal is the harm caused to both doctors and patients. The ENHANCE trial concerned and confused both of these participants in the health care system. Furthermore, it’s likely they were devastated by being so clearly misled by the marketing of both Merck and Schering regarding the false benefits of Vytorin they were led to believe by the companies that promoted them- the health care providers in particular.
This whole situation is another example of the progressively frequent discovery of corruption of the scientific method by placing profits over the well-being of patients, which harms the well being of patients. In addition, most were shocked by Merck behaving in such a way in particular because of what use to be their excellent reputation as an ethical pharmaceutical company. And this alone shows the progression and infiltration of such damaging ethical atrophy that desperately needs to be stopped and corrected for the sake of others- for everyone.
Don’t just say something. Have something to say- to the right people, with conviction and with others who share your views.
“Try not to become a man of success, but rather try to become a man of value.” --- Albert Einstein
Dan Abshear

Author’s note: What you have read is based upon information and belief. Thank you

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19. Marilyn on August 14, 2008 6:49 PM writes...

Here is a discussion of a biologically plausible way ezetimibe might promote cancer:

http://www.gooznews.com/archives/001140.html

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