Corante

About this Author
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

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Blogroll Update | Main | Stem Cell Politics »

March 15, 2010

Tricor's Troubles

Email This Entry

Posted by Derek

It's easy to lose sight of what a drug is supposed to do. Many conditions come on so slowly that we have to use blood chemistry or other markers to see the progress of therapy in a realistic time. And over time, that blood marker can get confused with the disease itself.

To pick one famous example, try cholesterol. Everyone you stop on the street will know that "high cholesterol is bad for you". But the first thing you have to do is distinguish between LDL and HDL cholesterol - if the latter is a large enough fraction of the total, the aggregate number doesn't matter as much. And fundamentally, there's not a disease called "high cholesterol" - that's a symptom of some other cluster of metabolic processes that have gone subtly off. And the endpoint of any therapy in that field isn't really to lower the number in a blood test: it's to prevent heart attacks and to extend healthy lifetimes, mortality and morbidity. As we're seeing with Vytorin, it may be possible to drop the numbers in a blood test but not see the benefit that's supposed to be there.

Another example of this came up over the weekend. The fibrates are a class of drugs that change lipid levels, although the way they work is still rather obscure. They're supposed to be ligands for the PPAR-alpha nuclear receptor, but they're not very potent against it when you study that closely. At any rate, they do lower triglycerides and have some other effects, which should be beneficial in patients whose lipids are off and are at risk for cardiac problems.

But are they? Type II diabetics tend to be people who fit that last category well, and that's where a lot of fenofibrate is prescribed (as Abbott's Tricor in the US, and under a number of other names around the world). A five-year study in over five thousand diabetic patients, though, has just shown no difference versus placebo. Again, there's no doubt that the drug lowers triglycerides and changes the HDL/LDL/VLDL ratios. It's just that, for reasons unknown, doing so with fenofibrate doesn't seem to actually help diabetic patients avoid cardiac trouble.

Mortality and morbidity: lowering them is a very tough test for any drug, but if you can't, then what's the point of taking something in the first place? This is something to keep in mind as the push for biomarkers delivers more surrogate endpoints. Some of them will, inevitably, turn out not to mean as much as they're supposed to mean.

Comments (15) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Drug Assays


COMMENTS

1. Dr Jimbo on March 15, 2010 8:17 AM writes...

Well, statins are pretty good at lowering LDL and preventing heart attacks, which has no doubt caused a lot of companies to pursue other strategies for altering lipid profiles.
But statins' pleiotropic effects may have a lot to do with their benefits in cardiovascular disease. For instance, improvements in mortality are seen before any real change in lipid profile, but this area still isn't as well-studied as it might be (putting 'statins pleiotropic effects' into Pubmed pulls out almost as many reviews as original papers).
As you say Derek, it's important to keep your eye on the ball of the disease being treated.

Permalink to Comment

2. PharmaHeretic on March 15, 2010 11:11 AM writes...

Why am I not surprised? Smoke and ash are indications of combustion, not the process of combustion!

Permalink to Comment

3. barry on March 15, 2010 1:59 PM writes...

So should all FDA approvals for drugs that passed on surrogate endpoints be provisional, requiring a showing of reduced mortality ("delta death") after launch on the market? Is it possible to run such a study (in which has the participants would get a placebo, rather than the approved drug)?

Permalink to Comment

4. retread on March 15, 2010 4:41 PM writes...

Ah surrogate endpoints. I would have thought that approach would have died after the AZT fiasco for AIDS years ago. AIDS patients have a decline in the number of lymphocytes carrying a particular surface marker (CD4), and when this number gets below a certain point, the patient is almost certainly likely to get into very serious trouble with infection. AZT definitely raised the number of cells carrying CD4 but had little or no effect on survival.

People who own yachts survive longer than those who don't. Giving everyone a yacht is not a solution to the health problems of the populace. This is why surrogate endpoints are dangerous when applied simplistically.

The NYTimes today has the results of 3 studies in type II diabetics, where manipulating a surrogate had zero or negative effects on survival.

Surrogates are certainly reasonable things to look at and manipulate, but there is just no substitute for the data that comes after they've been manipulated in large numbers of people

Permalink to Comment

5. MIMD on March 15, 2010 6:30 PM writes...

It's clear there are many things going on in diabetes and other metabolic disorders that we simply do not understand.

It's also very likely that there are new drugs, yet undiscovered, that could be developed and that *will* improve mortality and morbidity.

It's too bad the entire pharma industry is now run by dyscompetents, incompetents, and other management fools who - by the very sight of comments on this blog on layoff threads - have so demoralized the very soul of drug discovery (chemists) that these new drugs are unlikely to be developed at all.

The industry in its current anti-intellectual, "lay them off and watch the stock price rise", short term idiocy death spiral is basically good for nothing except money games.

Pity.

Permalink to Comment

6. MIMD on March 15, 2010 7:00 PM writes...

Amplifying the comment in #5 above: see here.

Permalink to Comment

7. GladToMoveToProcess on March 15, 2010 7:32 PM writes...

Vaguely related: we had a compound just about ready for IND, when a long-term study on a marketed drug acting by the same mechanism came out. The marketed stuff shortened survival slightly (but significantly, per the statistics), but the patients' "quality of life" improved, according to the (surviving!) patients' comments. What to do? Our management decided to stop development immediately - "doctors have long memories" or words to that effect....

Permalink to Comment

8. MIMD on March 15, 2010 8:13 PM writes...

#7 but the patients' "quality of life" improved

How did their quality of live improve?

Permalink to Comment

9. scott on March 15, 2010 10:05 PM writes...

In addition to hyperlipidemic disorders and diabetes PPARs are also being studied for the treatment of polycystic ovary syndrome, psoriasis, autism, and even drug addiction. The full reach of this family of compounds is just being explored.

Permalink to Comment

10. Evorich on March 16, 2010 7:55 AM writes...

Well better results on the cholesterol test might lower your life insurance premium costs! Is that a useful endpoint for a drug?

Permalink to Comment

11. Matt Herper on March 16, 2010 7:41 PM writes...

Retread: The TriCor studies is actually one of the studies mentioned in the NYT.

Permalink to Comment

12. GladToMoveToProcess on March 17, 2010 7:55 PM writes...

#8: I should have been more specific. This was for congestive heart failure, basically just symptomatic treatment. The patients said they felt better, were more active, and so on. Could be they were a little TOO active...

Permalink to Comment

13. Stevedoc on March 17, 2010 9:02 PM writes...

The Tricor result is not surprisng to anyone who has actually read the label, which notes multiple studies that showed no benefit in cardiovascular outcomes for fibrates in general. In fact, mortality trends repeatedly favored placebo. On the other hand fibrates were good at giving you gall stones. It's all in the official FDA-approved label. Incredibly, these facts have been consistently ignored for years (go figure). I guess free pens and mugs work.

Permalink to Comment

14. Philip on March 22, 2010 5:08 AM writes...

The Framingham study evidence underlying the “lipid hypothesis” was never strong to start with. Since then a massive lipid lowering campaign has shown no effect on heart disease rates. While an elegant and seemingly intuitive hypothesis, more and more openly people are rightly questioning the wisdom of the cholesterol lowering campaign.

Cholesterol is an essential component of every cell membrane and important for myriad physiologic functions. When Dr. Uffe Ravnskov, MD PhD looked at the medical literature he found something quite surprising had been documented there. On average people with higher cholesterol live longer.
http://healthjournalclub.blogspot.com/2009/10/do-people-with-high-cholesterol-live.html

The side effects of statins are myriad, rhabdomyolysis, (muscle injury), liver damage, in Crestor's case kidney damage. Dr Duane Graveline an MD and former NASA astronaut has also compiled extensive data on a more rare statin side effect, global transient amnesia, which afflicted him and many others, he has written a book on it, "Lipitor thief of memory". http://healthjournalclub.blogspot.com/2009/11/statins-and-global-transient-amnesia.html

Don't forget co-enzyme Q depletion. All this while the "lipid hypothesis" is falling like a house of cards as decades of intensive lipid lowering efforts have done nothing to improve heart disease rates.

Permalink to Comment

15. Scott on August 2, 2010 8:18 AM writes...

I believe the reference to morbidity improvements are associated with the benefits on eye disease, and amputations that have been observed with TriCor. It might appear that you don't live any longer but may in fact live a better quality life.

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
A Last Summer Day Off
The Early FDA
Drug Repurposing
The Smallest Drugs
Life Is Too Short For Some Journal Feeds
A New Look at Phenotypic Screening
Small Molecules - Really, Really Small
InterMune Bought