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June 30, 2008
Another Alzheimer's Compound Goes Down
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. . .
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