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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: Twitter: Dereklowe

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« How Not to Do It: Solvent Stills | Main | The Patent Expiration Fun Continues »

September 2, 2002

A Last-Ditch Effort - Or Is It?

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Posted by Derek

There's a rather weird legal fight going on between Glaxo SmithKline and the rest of the world. Like everyone else, GSK is fighting to hold on to profitable drugs that are losing patent protection. A lot of. . .creative. . .arguments are being deployed in these efforts, and I can't figure out if this is one of them or not.

The drug is Augmentin, which is actually two drugs in one. (For those readers old enough to remember it, you can now cue up the voice-over to the old Certs ad.) The antibiotic ingredient is plain old amoxicillin, a beta-lactam warhorse that's been generic for a long time now. Unfortunately, plenty of bacteria can chew right through amoxicillin and others of that era. I mean that literally: they use an enzyme called beta-lactamase to break open the four-membered ring at the core of all the penicillins.

That's where the second ingredient comes in, clavulinic acid (actually, its potassium salt.) It's a natural product that has a roughly similar structure, similar enough to fit into the active site of the beta-lactamase enzyme and gum up the works. Using the enzyme inhibitor leaves the amoxicillin free to do its work, and the combination is quite effective.

Well, amoxicillin you can order by the drum. But clavulinic acid is another matter. It's not economical to synthesize, not from the ground up (and neither are the beta-lactam antibiotics themselves, for that matter.) All these compounds are made (at least partially) by fermentation, which is just short of being a black art. You have to find strains of organisms (fungi for the 'cillins, bacteria for clavulinate) that produce unusually high amounts of the material, and you have to make them do it reproducibly. That means keeping them happy, but not so happy that they decide to give up the hard biochemical work of synthesizing your compound. And you have to find a good way to purify your stuff from the reeking fermentation broth - ideally in a continuous-feed mode so you don't have to run batch after batch. It's not trivial.

Perhaps you can guess where this is heading. GSK claims that they spent a lot of time and money developing a particular bacterial strain that produced clavulinic acid better than anything else known. And they're now claiming that some of these bacteria walked out of their facilities and are being used by their competitors (specifically Novartis as well as the generic companies Ranbaxy and Teva.) They seem to have a particular employee in mind, and a particular transaction history for the theft.

Problem is, that all happened starting in 1988. You wonder why GSK sat back for this long if they knew all this. . .and there are generic Augmentin formulations in Europe which don't figure into the suit. How'd they make their clavulinic acid? You do have to wonder if this isn't a desperation move.

On the other hand, this sort of theft isn't unknown. About twelve years ago, a New Jersey drug company had a former employee walk out with some of their engineered bacteria, which he later tried to sell to at least one small biotech outfit. They went to the Feds. The employee was caught on tape, thinking that he was selling the material to a Middle Eastern government, when he was really selling it to the FBI on two camera angles.

So GSK could be on to something, too. It'll be fun to watch.

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