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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

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December 5, 2007

Avandia: Going Under for the Third Time?

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Posted by Derek

How many hits can a drug – or a whole class of drugs – take? Avandia (rosiglitazone) has been the subject of much wrangling about cardiovascular risk in its patient population of Type II diabetics. But there have also been scattered reports of increases in fractures among people taking it or Actos (pioglitazone), the other drug with the same mechanism of action.

Now Ron Evans and his co-workers at Salk, who know about as much PPAR-gamma biology as there is to know, have completed a difficult series of experiments that provides some worrying data about what might be going on. Studying PPAR-gamma’s function in mice is tricky, since you can’t just step in and knock it out (that’s embryonic lethal), and its function varies depending on the tissue where it’s expressed. (That latter effect is seen across many other nuclear receptors, which is just one of the things that make their biology so nightmarishly complex).

So tissue-specific knockouts are the way to go, but the bones are an interesting organ. The body is constantly laying down new bone tissue and reabsorbing the old. Evans and his team managed to knock out the system in osteoclasts (the bone-destroying cells), but not osteoblasts (the bone-forming ones). It’s been known for years that PPAR-gamma has effects on the development of the latter cells, which makes sense, because it also affects adipocytes (fat cells), and those two come from the same lineage. But no one’s been able to get a handle on what it does in osteoclasts, until now.

It turns out that without PPAR-gamma, the bones of the mice turned out larger and much more dense than in wild-type mice. (That’s called osteopetrosis, a word that you don’t hear very much compared to its opposite). Examining the tissue confirmed that there seemed to be normal numbers of osteoblasts, but far fewer osteoclasts to reabsorb the bone that was being produced. Does PPAR stimulation do the opposite? Unfortunately, yes – there had already been concern about possible effects on bone formation because of the known effects on osteoblasts, but it turned out that dosing rosiglitazone in mice actually stimulates their osteoclasts. This double mode of action, which was unexpected, speeds up the destruction of bone and at the same time slow down its formation. Not a good combination.

So there’s a real possibility that long-term PPAR-gamma agonist use might lead to osteoporosis in humans. If this is confirmed by studies of human osteoclast activity, that may be it for the glitazones. They seem to have real benefit in the treatment of diabetes, but not with these consequences. Suspicion of cardiovascular trouble, evidence of osteoporosis – diabetic patients have enough problems already.

As I’ve mentioned here before, I think that PPAR biology is a clear example of something that has turned out to be (thus far) too complex for us to deal with. (Want a taste? Try this on for size, and let me assure that this is a painfully oversimplified diagram). We don’t understand enough of the biology to know what to target, how to target it, and what else might happen when we do. And we've just proven that again. I spent several years working in this field, and I have to say, I feel safer watching it from a distance.

Comments (8) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Toxicology


COMMENTS

1. milkshake on December 6, 2007 8:44 AM writes...

I was listening to a PPAR talk recently - and it looks like PPAR gamma ligand binding can produce a puzzling range of responses from the same receptor, depending on how it is activated.

It has been often the case that even drugs that are successful work on a mechanism that is much more complex than the initial model on basis of which the drug was developed

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2. walt on December 6, 2007 12:13 PM writes...

From a patient's point of view and a treatment point of view, the bone issue has always been a bigger issue than the CV issues pointed out in Dereks earlier blogs. I hope it is not serious enough to 'do in' the target as complex as it might be.

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3. Wavefunction on December 6, 2007 12:52 PM writes...

It would be a pity if these effects lead to the glitazones being withdrawn. So many people I know have benefited from them for the last few years.

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4. Green Koala on December 6, 2007 2:55 PM writes...

This is going to be a tricky one for the FDA and physicians and patients.

To reiterate walt's point, any deliterious bone effects are serious. Minor changes in bone health lead to increased fractures; and, fractures have a greater effect on moribidity and mortality than many people realize. I don't have the numbers in front of me, but the survivability graphs after one or two fractures is horrible. They look like Kaplan-Meier plots for some cancers.

Problem is do they look any better if your diabetes is not controlled?

What to do ...

GK
(with a parent currently on Avandia)

Permalink to Comment

5. Skeptic on December 6, 2007 6:40 PM writes...

This isn't surprising. Dynamics in biology has been a backwater despite its importance to drug development. Its a highly quantitative area thus its understandable that medicinal chemists like Derek can't deal with it. The academics are obsessed with enumeration and thus aren't of much help either. Unfortunately, the drug industry is enslaved to the FDA which is full of ivory tower types who worship the god of mathematical statistics and thus only serve as a frustrating example of ignorance being allowed the role of master arbitrator.

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6. Harry on December 7, 2007 8:49 AM writes...

Crimony, Skeptic- did you generate that comment via a random word generator? WTH is "dynamics in biology"? If it's highly quantitative, then why aren't academicians "obsessed" with "enumeration" jumping on it?

If you have such a wonderful solution to all the problems drug companies face, then why haven't you started a company to capitalize in it? I'm sure you can find some VC outfit to front you a few mil for such a great idea.

Oh, yeah- is there any sort of statistics other than mathematical statistics? Please elucidate for us ignoramuses.

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7. milkshake on December 7, 2007 10:40 AM writes...

Skeptic, go get enema - you are full of yourself. If you have nothing to say, please don't.

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8. 7374e9 on December 7, 2007 7:29 PM writes...

What "Skeptic" is trying to say is that there isn't enough complex modeling in drug development to deal with the complex biology of disease. By complex modeling he most likely means dynamic models of molecular mechanism as opposed to the standard tool of trade: descriptive statistical models with two variables: drug and clinical effect, in the extreme case.

Statistics is just fine to understand results of a clinical trial, but to get an idea what your drug is hitting and predict safety issues you need something more sophisticated.

I guess his point is that more sophisticated math analyses are usually brushed away by drug dev people. Part of the reason is ignorance about what said approaches can do for you but on the other hand, frankly, they haven't so far delivered the goods.

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