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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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June 30, 2008

Another Alzheimer's Compound Goes Down

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Posted by Derek

I was mentioning the gamma secretase enzyme around here just the other day as a longstanding target for Alzheimer's therapy. I remember the periodduring the 1990s when the enzyme hadn't been identified yet, and frankly, it was a lot easier to get excited about it then. That's because when it was finally worked out, the protease turned out to be a big multifunctional multiprotein complex, and among its many functions was affecting Notch signaling.

That's worrisome, because a lot of important cellular development pathways go through the Notch receptor, and these are things that you'd really rather not mess with. (Just run the word "notch" through PubMed to see what I mean). Indeed, some of the toxic effects of the earlier gamma secretase inhibitors seem to have been mediated through just those side effects. So for some years now in the gamma secretase field, the hunt has been on for compounds that will shut down beta-amyloid production without messing with the other functions of the enzyme complex.

Myriad Genetics took such a compound of theirs, Flurizan, into the clinic, after licensing it out to the Danish CNS drug company Lundbeck. They claim that these aren't straight inhibitors, but rather change the activity of the protease in some way that relatively less amyloid is produced. The drug showed some effects in Phase II studies - nothing to jump up and down about, but enough for Lundbeck to pony up for Phase III.

They wish now that they hadn't. As of this morning, the drug appears to have missed all its clinical endpoints in the Phase III trial: no improvement in cognition, no improvement in quality of life. There's no way to spin this kind of result, and the company announced at the same time that they're discontinuing any further work on the compound. (Interestingly, this news seems to have actually made some of its investors happier). It's Lundbeck, though, that seems to be left holding the bag, and their stock is getting hammered to multiyear lows. They have a monstrous patent expiration coming up in 2012 (Lexapro, by far their biggest drug ever), which might explain why they took a flier on the Myriad compound in the first place. The whole effort looks like something of a Hail Mary throw on their part - and most of those go down as incomplete. . .

Comments (9) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


1. UK Chemist on June 30, 2008 8:27 AM writes...

One of the main reasons for big pharma being in such a mess is because we are throwing too many Hail Mary throws.It must be because our collective, various incentive programes encourage this.The only upside of the sector's future decline in profits will be a decline in this approach,or perhaps that's wishful thinking.

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2. qetzal on June 30, 2008 8:45 AM writes...

UK Chemist:

Interesting comment, given how many others criticize pharma for not taking enough risks! (E.g., for focusing too much on me-toos, line extensions, life-style drugs, etc.)

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3. weirdo on June 30, 2008 11:10 AM writes...

If a Big Pharma does it, it's called "desperation".

If a biotech does it, it's called "innovation".

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4. Robert Guerrero on June 30, 2008 1:15 PM writes...

I'm really looking forward to this year's ICAD conference. I think that the oxidative stress concept plays a crucial role in the development of Alzheimer's disease. Some of this year's abstracts exhibit much-needed neuroprotective effects in some cases.

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5. Petros on June 30, 2008 2:01 PM writes...

I must admit to having been somewhat sceptical about the reported protease activity of Flurizan becuase of its identify as R-flurbiprofen

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6. vasili on June 30, 2008 3:21 PM writes...

All in all research is that way.
Let's put all the way round, imagine the profits they could obtan with such a drug in the market. This business is that way.

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7. milkshake on June 30, 2008 7:54 PM writes...

The most frequently reported side-effect of Flurizan is suicidal ideation in investors

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8. burt on July 1, 2008 12:26 PM writes...

"If a Big Pharma does it, it's called "desperation".

If a biotech does it, it's called "innovation"."

Edison (paraphrased): "Genius is 1% inspiration and 99% desparation"

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9. Anonymous on July 1, 2008 12:30 PM writes...

Modulation of gamma secretase is a mechanism with huge potential. Modulators change the cleavage position on the amyloid precursor protein C-terminal fragment so that rather than producing the long, lipophilic A-beta 42 peptide, they produce the shorter A-beta 38 peptide, which is less prone to aggregation and therefore has less propensity to form toxic oligomers that go on to form amyloid plaques.

However, Flurbiprofen, with an IC50 of around 200 micromolar, coupled with a Brain:Plasma ratio of 0.05 was not the right compound to test the hypothesis.

A more potent compound, with better brain penetration, would be very interesting as a potentially disease altering drug.

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