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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: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« A Farewell to Tin | Main | Godzilla vs. Mothra? Relman vs. Epstein! »

July 23, 2007

Deactivation, After All

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Posted by Derek

Four years ago I wrote about an unusual Roche diabetes compound targeting glucokinase. The odd thing about it was that it made the enzyme more active, which is something you can only rarely hope to do. Enzymes generally run near the top of their specs, unless there's some built-in switch that keeps them damped down until they're needed. That's often phosphorylation, but another trick inside the cell is to keep the concentrations of substrate low (or the concentrations of some inhibitor high). But once they go, they usually go about as fast as they can. This glucokinase example is still about the only one I can think of in drug development, and it's had a fair amount of attention over the years.

Maybe I should switch the tense, though, because reader Daniel H. has informed me that Roche seems to have stopped work on the compound in Phase II. The company had taken their lead compound (R1440) through several different trials, so something seems to have been working, but they don't seem to have given any reasons as to why they abandoned it.

After that much Phase II work, the most likely answer is some sort of toxicity, the kind that comes up too close to the efficacious dose. A company may try several different dosing regimens, combinations with other drugs, or patient populations trying to get around a problem like that, and perhaps what we're seeing is the end of the line. Nothing looked safe enough to spend the really large money on Phase III.

By now, there are several other companies in the same area, and I'm sure they're rather curious about all this, too. Is glucokinase activation dead as a target? As with many questions in this industry, you'll have to have either a lot of money or a lot of patience to find out. And if you want to come down and try drug development yourself, you'll need a lot of both.

Comments (2) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Drug Development


COMMENTS

1. kinasepro on July 23, 2007 11:14 PM writes...

I haven't been following the glucokinase story, but on agonists: Angion Biomedica has a peculiar sort of c-met agonist which they claim is in Ph1 as an 'HGF mimetic'. Other then what's on their homepage I haven't found anything but WO/2004/058721.

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2. Anonymous on July 24, 2007 2:30 PM writes...

Whatever happened to sGC activators?

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