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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

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February 24, 2002

Toxicolottery

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Posted by Derek

I'll continue to talk now and then about some topics that won't necessarily be news to those inside the pharma industry. I see from my traffic stats that most of the hits are from outside it, although there are increasing numbers from both my own company and the competition.

Thoughts of work prompt me to quiz non-specialists: at what point do you figure most drug projects fail? Ever thought about that one? You can be sure that everyone inside the industry has, oh yeah. There are plenty of data points to study - the sound of failing projects is this constant clanging in the background.

Failure in clinical trials get the most press attention. They're certainly bad enough to deserve it. You lose lots of candidates in Phase I, because they turned out to be toxic in normal volunteers. (Well, at least toxic in the sort of person that signs up for Phase I studies, but that's another story.) Then you lose some of those non-toxic candidates in Phase II, because they didn't work well enough, or at all. Failure at those stages is particularly expensive and frustrating; it's late in the game. And it means that your animal models turned sour on you somehow, by telling you the compound would be safe and that it would be efficacious.

Your disease models are what tell you the latter, and they vary from target to target. As I mentioned the other day, the ones for CNS ailments are particularly hairy; other fields have it easier (but not easy!) The animal toxicity tests for general safety, though, don't vary much between therapeutic areas. They're a notorious hurdle.

Tox is a long and expensive study, by preclinical standards. It usually calls for the largest batch of your drug candidate that you've made until then, and it's the usually the longest animal study you've run, too. And it makes everyone involved hold their breath, because it's a complete black box.

It really is. That's actually where more projects wipe out than any other, in my experience. We really have no idea what's going to happen. Well, you may have some clue about toxicity based on your drug's mechanism, and you're already braced for that (and hoping it cuts in at much higher levels than you need to show the beneficial effects.) But it's that non-mechanistic tox that's out there waiting for all of our projects, and when it hits all you can do is run for cover. Kidney? This protein isn't even expressed in the kidney, what the. . .liver? But the tests on hepatocytes all came back OK. . .spleen? Who ever heard of a drug showing tox in the spleen? Heck, who needs a spleen anyway? And so on.

As I've alluded to in the past, you can sell just about anything to a big drug company if you promise to do something about the failure rate. If anyone has a bright idea for how to predict toxicity before we go into animals (or, God help us, humans,) then here's your chance to cash in. The management would be thrilled at all the time and money that doesn't go down the pipe. The scale-up chemists would be thrilled not to have to make buckets of loser compounds. Even the animal-rights people would be happy.

Note that the obvious ideas have probably already been tried. But don't be afraid to ask.

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