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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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November 29, 2012

Roche Repurposes

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Posted by Derek

Another drug repurposing initiative is underway, this one between Roche and the Broad Institute. The company is providing 300 failed clinical candidates to be run through new assays, in the hopes of finding a use for them.

I hope something falls out of this, because any such compounds will naturally have a substantial edge in further development. They should all have been through toxicity testing, they've had some formulations work done on them, a decent scale-up route has been identified, and so on. And many of these candidates fell out in Phase II, so they've even been in human pharmacokinetics.

On the other hand (there's always another hand), you could also say that this is just another set of 300 plausible-looking compounds, and what does a 300-compound screening set get you? The counterargument to this is that these structures have not only been shown to have good absorption and distribution properties (no small thing!), they've also been shown to bind well to at least one target, which means that they may well be capable of binding well to other similar motifs in other active sites. But the counterargument to that is that now you've removed some of those advantages in the paragraph above, because any hits will now come with selectivity worries, since they come with guaranteed activity against something else.

This means that the best case for any repurposed compound is for its original target to be good for something unanticipated. So that Roche collection of compounds might also be thought of as a collection of failed targets, although I doubt if there are a full 300 of those in there. Short of that, every repurposing attempt is going to come with its own issues. It's not that I think these shouldn't be tried - why not, as long as it doesn't cost too much - but things could quickly get more complicated than they might have seemed. And that's a feeling that any drug discovery researcher will recognize like an old, er, friend.

For more on the trickiness of drug repurposing, see John LaMattina here and here. And the points he raises get to the "as long as it doesn't cost too much" line in the last paragraph. There's opportunity cost involved here, too, of course. When the Broad Institute (or Stanford, or the NIH) screens old pharma candidates for new uses, they're doing what a drug company might do itself, and therefore possibly taking away from work that only they could be doing instead. Now, I think that the Broad (for example) already has a large panel of interesting screens set up, so running the Roche compounds through them couldn't hurt, and might not take that much more time or effort. So why not? But trying to push repurposing too far could end up giving us the worst of both worlds. . .

Comments (14) + TrackBacks (0) | Category: Drug Assays | Drug Development | Drug Industry History


COMMENTS

1. John Wayne on November 29, 2012 9:22 AM writes...

I am both a fan and detractor of the drug repurposing fad that is starting up.

On one hand, it is a great way to take either drugs or molecules with known properties in Phase 1 to 3 trials and come up with new indications. I think this is a great fit for neglected diseases.

On the other hand, the only steps these efforts cannot skip is generating positive phase 3 data; you know, the expensive, risky part.

If you know how to select for patients, this sort of effort could also be useful in cancer. Should we start thinking of all the different types of cancer as neglected diseases? It may make sense. We have a vague but improving understanding of the biology, but we know enough to know that we are probably dealing with hundreds (to thousands) of different diseases that will each have to be treated with different strategies depending on when they are noticed. That is a lot of work, unless we cheat.

Permalink to Comment

2. The Aqueous Layer on November 29, 2012 9:25 AM writes...

It's a low-risk venture for Roche, and a somewhat higher profile project for Broad. If they get even one thing out of this everyone is a winner. If they don't, no-one really loses either. I'm pretty sure that the expectations from Roche's end aren't very high.

I'm wondering how many of these compounds fell out due to lack of efficacy versus tox issues. You'd think that anything that had potential tox problems wouldn't been included in this screening deck for obvious reasons.

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3. anon the II on November 29, 2012 9:54 AM writes...

Repurposing is, at best, a weak idea, except for its ability to generate a press release.

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4. Morten G on November 29, 2012 10:07 AM writes...

I'm a big fan of drug repurposing but it seems like they want to put them in "biological" assays so probably target-based, possibly cell-based assays... These compounds should go into what I would call phenotypic screens (I don't agree with Derek's definition), that is actual, live creatures. With a biology compatible with the actual disease under study. This means:
No mice for TB.
No rodents for obesity.
Etc.

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5. HTSguy on November 29, 2012 11:53 AM writes...

@1 "...phase 3 data; you know, the expensive, risky part." Actually, if you look at risk-adjusted cost, LO is the expensive, risky part. Changes by Pharma Co in the last few years make a lot more sense when you take this into account.

@2 You are probably right that some of them "lacked efficacy" because they were dose-limited by tox. Will be interesting to see if they can change this equation in another indication. Maybe the best bet is one where the risk/benefit ratio is more favorable - e.g. a currently untreatable fatal disease.

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6. John Wayne on November 29, 2012 12:17 PM writes...

@5 - I have to admit that I do not really understand the concept of 'risk adjusted cost.' If a lead op program costs 20 million dollars, and a clinical trial costs 180 million dollars ... even if you somehow get rid of the lead op program you only saved 10% of your premarketing investment.

I am honestly interested in what I'm missing (no sarcasm intended; please educate me)

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7. Andy on November 29, 2012 12:45 PM writes...

The Broad Institute's business model is indirect costs reimbursement from federal research grants. So long as the compounds let them pull a bazillion dollars in grant funding by having a plausible enough claim on doing groundbreaking translational science to fool the NIH review panel (made of other academics so easy to fool about these things) it's total victory for Broad.

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8. Andrew on November 29, 2012 1:01 PM writes...

Good ol' repositioning. Brings back memories of Gene Logic $GLGC, my first big biotech trading mistake!

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9. MoMo on November 29, 2012 1:07 PM writes...

Sounds like Roche figured out how to get work done for free on the Taxpayer's dime. But that's what the NIH is for, is'nt it? To provide welfare for scientists?

Where's all those DOS compounds and their success? I asked this a while back and of course no one answrs these difficult questions.

Get back to work Roche and the Taxpayer is on to you! Get your hands dirty instead of using us!

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10. HTSguy on November 29, 2012 1:40 PM writes...

@6 John Wayne - "risk adjusted cost" - for simplification, let's assume we are talking about success as getting Registration (i.e. leave out the commercial risk). Using your numbers, LO and PhIII would have equal "risk adjusted cost" if a new PhIII trial was 9X more likely to result in Registration than a new LO program. Given all of the ways to fail between the start of LO and the start of PhIII, this is not unreasonable.

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11. RM on November 29, 2012 2:49 PM writes...

But the counterargument to that is ... any hits will now come with selectivity worries, since they come with guaranteed activity against something else.

But the counter-counterargument is that they're unlikely to be too much of a selectivity worry, because you just spent millions of dollars showing that they don't actually have all that much in vivo activity against that something else. (Because, you know, they're failed clinical candidates.)

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12. Anonymous on November 29, 2012 7:42 PM writes...

@9
They are very hard at work at Roche....on their CV's. Another slap in the face of the nutley scientists. Regarding potentially toxic compounds, well I'd bet the vast majority of them originated in Basel or Palo alto....

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13. JB on November 30, 2012 12:20 AM writes...

@9 Momo- ML187. ML238. More to come...

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14. z on November 30, 2012 7:06 AM writes...

Rather than trying to find actual drugs out of these, would they be valuable as tools or as starting points for further optimization for a new indication? Since they have good PK and an otherwise pretty clean profile, it seems like they might be useful for in vivo phenotypic studies, then you could optimize away from the original target while trying to maintain the new activity?

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