Merck and Schering-Plough Make the Bad News About Vytorin Even Worse

Ezetimibe, known as Zetia and as the key component of Vytorin, was invented by friends and colleagues of mine. It was the first drug I ever saw discovered after I joined the drug industry. The initial discovery of the whole compound class happened around the corner from my lab, and the compound that became ezetimibe itself was synthesized down the hall.

So, no, I’m not taking the current news about it very well. The situation is still quite confused, but there looks to have been enough stupidity, greed, and plain bad luck involved to make anyone despair. Read on – but I should warn you, I’m probably just going to get madder and madder as the post continues.

As anyone unfortunate enough to be holding Merck (MRK) or Schering-Plough (SGP) stock already knows, both companies took a pounding Monday after the American College of Cardiology issued its recommendation on the use of Vytorin (ezetimibe/simvastatin). This call was based on the now-infamous ENHANCE trial, which was just published in the New England Journal of Medicine. The main points of the study had already come out in January, of course, but a closer look at the data has done nothing to help explain its results: no improvement over existing therapy.

Addition of the cholesterol absorption inhibitor to the statin appears to have done nothing to help clear arteries (based on measurement of intima-media thickness) over what could be done with the statin alone. Ezetimibe seems to have had no bad effects, fortunately, but no good ones, either.

The ACC’s verdict is that Vytorin should only be used as a last resort, and that patients currently taking it should strongly consider going back to plain statin therapy. Based on these study results, that seems like a reasonable recommendation. There’s a large outcome trial (IMPROVE-IT) underway comparing the two treatments, but we’re not going to see results from that one for another three years at the earliest. Until then, there doesn’t seem to be any reason to recommend Vytorin. (There may not be any reason to recommend it afterwards, either, but we’ll have to wait to see about that).

Fortunately for everyone involved, no one seems to have been harmed, outside of the insurance companies who have paid out for Vytorin for the last few years – they no doubt have their own views on the subject.

It’s important to remember that this result is indeed a surprise, since the combination definitely does do a better job at lowering LDL (As an editorial in the NEJM puts it, this "dramatically contradicts our expectations"). You’d think that extra LDL reduction would be associated with a better outcome, but one of the panelists at the ACC, Dr. Harlan Krumholz, points out (PDF) that hormone therapy lowers LDL as a side effect, but isn’t associated in that case with better atherosclerosis outcomes, either. Does that mean that there’s more to the effect of statins than just lowering LDL, too? That possibility has to be taken seriously. The non-lipid effects of inhibiting HMGCoA reductase, the statin target, may be part of the answer, although the authors of the NEJM paper are reluctant to make that their whole explanation.

What they suggest instead is disturbing. The study may have been doomed from the start. The ENHANCE subjects were not taken from the general population, but rather were patients with a genetic abnormality in LDL handling, familial hypercholesterolemia. The idea was that these patients would be even more likely to show a benefit from Vytorin. But as the NEJM authors make clear, this may at one time have been a good patient population to show benefits in, but now the great majority of people with this condition are treated with statins starting at an early age. This, naturally, has an effect on their arterial walls. So the subjects of this trial may have already had a head start on reducing their arterial thickness, which means there may well have been a limit on what any particular therapy could have accomplished. Instead of being a better group to demonstrate your LDL-lowering powers in, they could well be worse.

If that’s true, there is, in fact, a chance that the IMPROVE-IT trial could show a clear benefit for Vytorin, since it’s being run in a broader population (Just watch the confusion if that happens). But what will that mean? The results will be far too late to help Merck and Schering-Plough, and will be a clear disservice to the patients that could have benefited from the drug before then. ENHANCE would then turn out to have been a huge mistake.

But not content with that, the companies have managed to make it into a complete disaster. The controversy has been whether Merck and Schering-Plough sat on the results of the trial or spent extra time trying to find a way to make them look more appealing. This has drawn the attention of Sen. Charles Grassley and an investigative committee, which is the sort of thing that no company can wish for. Monday Grassley released some of the text of his letters to the management of both companies, and these include quotes from e-mails sent by John Kastelein, the lead investigator on ENHANCE. They do not look good, not by any stretch of the imagination:

Is it correct that SP has decided not to present at AHA, but to await the two other, completely unvalidated, endpoints, which analysis is going to take us straight into 2008??!!??

If this is true, SP must have take this decision without even the semblance of decency to consult me as PI of the study. I can tell you that if this is the case, our collaboration is over…This starts smelling like extending the publication for no other [than] political reasons and I cannot live with that.

In another e-mail, Kastelein expresses more frustration that the results would not be presented at that AHA meeting (as indeed they weren’t, in the end), and says that ”... you will be seen as a company that tries to hide something and I will be perceived as being in bed with you!”

Schering-Plough, for its part, says that these statements are taken out of context, but good grief, what other context could that possibly be? Kastelein has also backed off, saying that he wasn’t accusing the company of “deliberately withholding data for political reasons”, but again, it’s hard to read those excerpts in any other way. These days, no one should make statements in e-mail that they’re not comfortable seeing printed in the Wall Street Journal, which is where I got these.

And does it need to be said that this is exactly, I mean exactly the kind of thing that the drug industry does not need? Vytorin as a drug is easy to forgive – the combination makes perfect sense, and the fact that it didn’t show a good result in ENHANCE took everyone by surprise (and, as mentioned above, it may in the end turn out to be a good therapy in the end). But the marketing of Vytorin is perhaps another thing – the companies really made a huge aggressive push to get as much of the cholesterol-lowering market as they could. That’s no sin by itself, unless business is a sin, but if you’re going to push that hard, you’d better make sure that you’re standing on something firm.

This trial definitely wasn't that sort of foundation, and the fallout from it has been made much, much worse by its handling. It's distressing to me that the management at Merck and Schering-Plough would even take the chance, in this climate, of being seen as data-massaging study-burying slime. What words do I find if that's what they turn out to be?

Ezetimibe was (and is) a wonderful scientific story in the drug discovery labs, and its development is a testament to some very dedicated and persistent people. What a pity that it's all come to this.

Comments

[Steve Hochhauser]

It's good to hear about this from someone who not only understands the science, but the drug discovery and development process as well. This is the first I'd read about the patient inclusion criteria for the ENHANCE study, and that is a key piece of information that has been missed in other reports. I agree - whether or not the drug turns out to be useful, the management of these companies has done a great disservice to their patients, their employees, and even to their shareholders. Keep up the good work!

[crysball]

As a Zetia patient for years, have ABSOLUTELY NO SYMPATHY for SGP or MRK,...... they made their bed, and now must lay in it ........with the full consequences of bad management decisions impacting shareholders & employees. This well written article only hints at what went on behind the closed doors at both MRK & SGP to OBFUSCATE, STONEWALL, AND DELAY THE DAY OF RECKONING.

[generic internist]

19% of the ENHANCE group who were statin naive showed no benefit either, nor did a subgroup with greater plaque burden, at study entry. This bodes poorly for the Improve -it outcome study and the fate of zetia.

[mvp3]

While it may be implied in the shock that the medical community has expressed in the results of the ENHANCE trial I am somewhat surprised that there is not more open discussion regarding the connection of free cholesterol in the blood and arterial plaque build-up. It seems that this trial was the first to truly measure the plaque build-up and despite significantly lower LDL numbers the thickness was unaffected. Perhaps this is due to the fact that the patients were "too well medicated" but what if the entire relationship between measured cholesterol levels and arterial plaque is not correct? I have heard from at least one Cardiologist that irregularities in the autonomic nervous system may have as much to do with hypercholestimia as does the amount of free LDL in the blood. Improper movement of the arterial walls allows the LDL to stick whereas proper movement "pushes" the LDL away. Perhaps those physicians who do true science should investigate this further and view the ENHANCE trial as a valuable piece of data rather than Pharma's big blunder.

[jack reacher]

As a Pharmacist, I see so much wrong with 1) the study, and 2) with how the drug company management handled it on Monday. The article in the Wall Street Journal has the management saying, "...oh well, back to the drawing board..." when it seems real clear to me that the drug does what they said it does. The companies should have defended the drug. The WSJ article mentioned that only one "panelist" gave the presentation, and it was not what was expected. The whole thing sounds fishy to me. Zetia works. It FURTHER lowers cholesterol in the blood. The study smells from here. But, hey...if people want to stop taking it and INCREASE blood levels of cholesterol---that's up to them. Something is not right here.

[Coyote]

Throwing the baby out with the bathwater would be an understatement of the unadulterated stupidity of this article's commentary and the subsequent lynch mob formed for Mrk. I'm wondering if this assualt has anything to do with MRK's aquisition of Sirna Theraputics and the class action efforts on behalf of the companies that saw the future of modern medicine evade their grasp. These antics seem to attempt to establish a "precedent of mood" towards Mrk which will be helpful in prying Rnai inhibition from its future at Mrk.

[clitosil]

How do we know this isn't just some cynical market manipulation ploy, to allow big money to get into these companies at a bargain price?

[TonyC-SA]

As a statistician, I would take this result, along with the results of Dr. Krumholz on hormone therapy, as clear and convincing evidence that the correlation between higher LDL and atherosclerosis does NOT imply causation!

To go further than the author, I would suspect the lowering of LDL by statins is a result of effect on some underlying and unidentified factor in atherosclerosis while the higher LDL itself is just an indicator of this underlying factor. If true, reducing LDL means nothing and the standard wisdom that high LDL causes atherosclerosis is simply false. Mask the indicator all you want, it doesn't address the root cause. And to whatever extent statins DO address the root cause, they incidentally cause a reduction in the LDL that indicates the severity of that root cause. Stop chasing the shadow of the problem and figure out what is casting the shadow.

[User 148301]

I have taken MANY stains for years, and NONE HAVE WORKED (including Zocor). Vytorin immediately lowered my bad and raised my good levels.

I have a basic question I have not seen addressed -- did the existing statins on the market today have to prove that they got rid of the plaque? If not, then this is a screw job to Vytorin patients, SGP and MRK investors!

Please, someone direct me to work that shows the drugs these Dr's are suggesting I switch to show statistical evidence thath THEY get rid of that plaque.

Color me confused!!!