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June 14, 2013
A Beta-Secretase Inhibitor Hits the Skids in Alzheimer's
The brutal drumbeat of Alzheimer's clinical failure continues at Eli Lilly. After the Phase III failure of their gamma-secretase inhibitor semagacestat, and a delusional attempt to pretend that the anti-amyloid antibody solanezumab succeeded, now comes word that the company has halted studies of a beta-secretase inhibitor.
This one wasn't for efficacy, but for tox. The company says that LY2886721 led to abnormalities in liver function, which is the sort of thing that can happen to anyone in Phase II. There is that thioamidine thing in it, but overall, it's not a bad-looking compound, particularly by the standards of beta-secretase inhibitors. But what does that avail one? We'll never find out what this one would have done in a real Phase III trial, although (unfortunately) I know how I'd lay the odds, considering what we know about Alzheimer's drug in the clinic. Beta-secretase inhibitors are an even higher-stakes bet than usual in this field, because mechanistically they have pretty strong support when it comes to inhibiting the buildup of amyloid protein, but they also have clear mechanistic liabilities: the enzyme seems to be important in the formation of myelin sheaths, which is not the sort of thing you'd want to touch in a patient population that's already neurologically impaired. Which effect wins out in humans? Does a BACE inhibitor really lower amyloid in the clinic? And does lowering amyloid in this way really affect the progression of Alzheimer's disease? Extremely good questions, all of those, and the only way to answer them is to round up a plausible drug candidate (not so easy for this target), half a billion dollars (for starters) and try it out.
This failure makes Lilly perhaps the first company to achieve a dread milestone, the Amyloid Trifecta. They have now wiped out on beta-secretase, on gamma-secretase, and on antibody therapy. And you know, I have to salute them for it. They've been making a determined effort against a terrible disease, trying all the most well-founded means of attack, and they're getting hammered into the ground like a tent peg for it. Alzheimer's. At the rate things are going, Lilly is going to end up in a terrible position, and a lot of it has to do with battering themselves against Alzheimer's. Remember this next time someone tells you about how drug companies are just interested in ripping off each other's baldness cures or something.
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