Corante

About this Author
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

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
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

« Unknown - But You Can Buy It | Main | The Gates Foundation: Dissatisfied With Results? »

June 30, 2008

Another Alzheimer's Compound Goes Down

Email This Entry

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


COMMENTS

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.

Permalink to Comment

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.)

Permalink to Comment

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".

Permalink to Comment

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.

http://tinyurl.com/3k2bbd

Permalink to Comment

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

Permalink to Comment

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.

Permalink to Comment

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

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

Permalink to Comment

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"

Permalink to Comment

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.

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
One and Done
The Latest Protein-Protein Compounds
Professor Fukuyama's Solvent Peaks
Novartis Gets Out of RNAi
Total Synthesis in Flow
Sweet Reason Lands On Its Face
More on the Science Chemogenomic Signatures Paper
Biology Maybe Right, Chemistry Ridiculously Wrong