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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

« Writing It Down | Main | Vytorin Numbers »

April 1, 2008

Vytorin: It's A Pity

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Posted by Derek

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 or Schering-Plough stock already knows, both companies took a pounding yesterday 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 not 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. Yesterday 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 taken 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 (19) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage | The Dark Side | Why Everyone Loves Us


COMMENTS

1. Uni Bayreuth on April 1, 2008 8:47 AM writes...

I just read an article on the ACC's Vytorin verdict in todays Wall Street Journal Europe.
Concerning the prior use of statins it said: "But other doctors said that the 19% of patients who hadn't had prior statin treatment also saw no benefits." Any thoughts?

Permalink to Comment

3. sroy on April 1, 2008 9:23 AM writes...

The data from recent large clinical trials (last 5 -6 years) that study the correlation between statins and LDL reduction versus it's effects on CRP has tended to show that CRP reduction to below 1 mg/l is a much better predictor of reduction in risk of MI.

Unfortunately many mainstream physicians/ researchers still try to dispute/obfuscate this for reasons that have nothing to do with science. Imagine your reaction if someone came out with more evidence for a heliocentric model of the solar system when your livelihood/ prestige depended on a geocentric model.

The metabolic syndrome seems to cause both dyslipidaemia and increase in chronic inflammation through alterations in liver physiology that are not well understood. It certainly helps that statins reduce both CRP and LDL. So does continuous consumption of moderate amounts of alcohol and it is also associated with a decreased risk of MI. Coincidence?

Fibrates, niacin, CETP inhibitors and inhibitors of intestinal cholesterol transport do not reduce CRP to any worthwhile extent. Large clinical trials on the therapeutic effects of these drugs also tend to show that they are rather ineffective for reducing the risk of MI, as might have been especially evident in the last 3 years.

And yes, I have said this before. It is just that when I first said this a few years ago, it was dismissed by everyone who heard it. It seemed that people then believed that the well payed doctors + researchers working on new wonderful new cholesterol lowering drugs knew more than me. Turns out that objective assessments do win in the end.

Permalink to Comment

4. CynthG on April 1, 2008 9:40 AM writes...

Now, apparently, the best drug for allowing people to live longer with less disease is also the least expensive, and therefore, the least advertised.

Thus far, based on empirical study, the only cholesterol-lowering drug to actually prolong life is niacin. The interesting report is at www.cholesterolscore.com

Permalink to Comment

5. Zeke on April 1, 2008 10:14 AM writes...

And please always remember that when the press releases and MDs extoll the virtues of statins by claiming a "20%" reduction in cardiac events, they are referring to the RELATIVE risk reduction (5% with cardiac events untreated vs. 4% with statins), never the ABSOLUTE risk. Repeating the "20% Reduction!!!!" statistic sells drugs better, doesn't it? I bet telling patients that the number of patients to treat to save a single life would be met with skepticism to be sure. Especially when Statins have a significant, but always downplayed, rate of advese effects. Everyone I know on statins have muscle pain, a very well known side effect. But it's always discounted as "old age" or being "out of shape".


Drug companies are not in the business to save people's lives. They are in the business to make maximum profit any way possible, even if it results in patient deaths and unecessary drugs. And accomplished with the help of a massive sales force to sell drugs to MDs and the public.

The LDL-C mantra will eventually go by the wayside, just like the previous state of the art treatments like X-rays for acne, bleeding/purging and ill-humours.

Permalink to Comment

6. Analytical Scientist on April 1, 2008 11:59 AM writes...

A further concern from the ENHANCE trial is that many in the public have drawn the wrong conclusion that it also means that statins don't work. My own father falls into this category, and I have been hard-pressed to fix the PR damage that this has done to statin therapy in his mind.

Permalink to Comment

7. Petros on April 1, 2008 1:11 PM writes...

The companies' behaviour has certainly done the industry and its reputation no favours. However, Having been around a while I can recollect how long it took to demonstrate any significant benefit with statins, and the reluactance to prescribe them until such data were available.

Permalink to Comment

8. sroy on April 1, 2008 1:41 PM writes...

In related news

http://www.theheart.org/article/852735.do

JUPITER halted: Rosuvastatin significantly reduces cardiovascular morbidity and mortality

March 31, 2008

Chicago, IL - Rosuvastatin gained clinical traction today with the announcement that a large event-driven study was stopped early because the lipid-lowering agent was shown to be more beneficial than placebo in reducing cardiovascular morbidity and mortality [1].

The study is known as the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), a large, multinational, long-term, double-blind, placebo-controlled, randomized clinical trial designed to assess directly whether statin therapy (rosuvastatin 20 mg/day) should be given to apparently healthy individuals with low LDL-cholesterol levels but elevated C-reactive-protein (CRP) levels.

The halting of JUPITER was announced in the wake of the presentation of the disappointing results of the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) study and an American College of Cardiology consensus panel that urged physicians to prescribe statin medications with proven clinical effectiveness. AstraZeneca issued a press release saying the independent data monitoring board observed "unequivocal evidence of a reduction in cardiovascular morbidity and mortality" among those treated with rosuvastatin compared with placebo.

Permalink to Comment

9. Derek Lowe on April 1, 2008 1:54 PM writes...

By the way, I should note that according to the NEJM article, Vytorin lowered C-reactive protein significantly over simvastatin alone. Depending on what's going on here, that could be good news in the long run. If Jack F.'s interesting link above is the story, though, then all bets are off. . .

Permalink to Comment

10. sroy on April 1, 2008 2:26 PM writes...

Hi Derek,

The important number for CRP is 1mg/ L. If you can reduce it to around this level the risk of excess MI events is almost gone (at least in people without familial hypercholesterolemia). Reducing the median from 1.2 to 0.9 will not translate into any further therapeutic effect. This is based on the epidemiological studies.

The next important level for CRP is below 0.5 mg/ L. At this level the risk of MI is considerably below normal. If the person does not have any other MI risk factors like type II DM or untreated hypertension the chances of ever dying from a MI are slim.

Cancers, alzheimer's, stroke, hip fractures and other problems of old age will still prevent immortality.

Permalink to Comment

11. Bruno on April 1, 2008 8:30 PM writes...

Analytical Scientist,
Stains do work well for lowering LDL-C, if that's all one is after. Otherwise, the HOPE, PROVE-IT and public-relations-named, Pharma-funded and vetted, clinical trials really never have shown significant mortality prevention of primary cardiac events. How can there be such fanacticism regarding the notion that Statins provide total protection and saves lives?
Even in secondary event prevention, the NNT is 75. Compare that to antibiotics for Heliobacter-induced stomach ulcers, with an NNT of 1.1. I remember how the Med community, under the guidance of pharma sales reps, fought to the bitter end regarding Heliobacter. It finally turned out not to be such a great idea to treat patients forever with proton pump and H2 inhibitors, never achieving a cure, if a single course of cheap antibiotics was the best course.

Permalink to Comment

12. milkshake on April 1, 2008 8:39 PM writes...

It is always sad when medicinal chemists and biologists achieve exactly what they were asked to do, putting hundreds of men-year worth of work into it and it all goes to naught. At least in this case it looks like it happened for a scientific reason and it falsified the dogma that high LDL=bad therefore low LDL=good

Permalink to Comment

13. BCP on April 1, 2008 10:30 PM writes...

Oh boy -- what kills me here is that we're trading one surrogate endpoint off against another. Are we really about to throw the LDL baby out with the ENHANCE bathwater? I can't believe that for a minute. The caveats around the population and trial are too many. If SP and MRK have the stomach, they should continue with IMPROVE IT which is a study done in the non-familial hypercholesterolemic population. Two years seems a long ways a way, but what are the odd on that looking possibly different....?

Permalink to Comment

14. Lila on April 1, 2008 11:06 PM writes...

I hate to bust everyone's bubbles...LDL-C and CRP have NOTHING to do with Cardiovascular disease.

Everyone knows it's caused by ill humors and can be cured with a little bloodletting.....

Permalink to Comment

15. sroy on April 1, 2008 11:12 PM writes...

There is only one chemical whose consistent consumption has been associated with a 50% or more reduction of MI mortality/ morbidity (ethanol at 30-50 g/ day).

Less than 30g= effects not consistent
above 50g = blood pressure/ stroke risk starts increasing

Ethanol simultaneously reduces formation of unstable plaques, decreases CRP and other measures of chronic inflammation and increases insulin sensitivity. If these effects were due to inhibition/ modulation of one single paththway and could be mimicked by an otherwise reasonably safe drug it would become a mega blockbuster. Such a drug could reduce the risk of MI + type II DM (and its vascular complications) to a level that is not currently possible with any drug for either condition.

Permalink to Comment

16. Anonymous BMS Researcher on April 2, 2008 6:53 AM writes...

I feel for thousands of rank-and-file employees at these two companies; as a long-time BMS employee I know exactly what it's like to watch one's employers get lambasted in the media for questionable decisions by top management.

If the Feds really want to improve transparency of decision making in Big Pharma -- and quite possibly even benefit Big Pharma as well as the public in the long run -- they should have some of their brightest minds ponder ways to strengthen the hand of the scientific side within companies. I have never, thank God, been involved in any situation where I felt pressured to downplay important scientific data, but I'm familiar enough with the dynamics of decision making in Big Pharma to see how such things can happen. I've certainly seen enough cases where I felt some business decision was harming the long-term future of the company due to short-term financial pressures. Just about any reasonable policy intervention that would stiffen the spines of the scientific side in such internal debates would benefit everybody in the long term.

Permalink to Comment

17. anon on April 2, 2008 10:32 PM writes...

Derek wrote:

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?

Ah! Climate! The social climate of disillusionment with the industry. Such social issues are critical to the industry. Incompetence in them is just as deadly as scientific incompetence.

In this climate, perhaps it should have been asked "what is the SOCIAL risk of an unexpected Enhance outcome, such as it showing no plaque thickness difference difference, considering past drug flaps and what we are charging for the drug?"

Perhaps pharma should go back to studying drugs primarily in their major intended audience, with truly meaningful endpoints - i.e., actual patient outcomes - and use surrogate endpoints more cautiously.

Permalink to Comment

18. BEW on April 3, 2008 3:18 PM writes...

sroy,
You have made several comments on several threads that alcohol reduces mortality.

I don't know of any clinical trials showing this effect. Do you have any references/links you can provide?


Permalink to Comment

19. milkshake on April 3, 2008 5:41 PM writes...

I hope this link helps you, BEW, for it has plenty references:

http://www.moderndrunkardmagazine.com/

Permalink to Comment

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