UPDATED: Eli Lilly racks up another Alzheimer's failure after BACE drug sparks safety fears

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In yet another indication of the yawning gap between what drug developers know about Alzheimer's and how it could be treated, Eli Lilly ($LLY) today decided to scrap its Phase II study for a BACE inhibitor after gathering abnormal liver tests from patients.

Lilly says that the monitoring team had gathered the liver tests on Alzheimer's patients taking LY2886721, one of several beta-secretase inhibitors in Big Pharma's pipeline. Merck ($MRK) recently launched a Phase II/III program for its BACE inhibitor, MK-8931, despite deep fears in the research community that BACE inhibition could possibly trigger a sequence of harmful events for patients. And AstraZeneca ($AZN) has a program of its own in place.

The investigators for Lilly say they don't know what caused the liver abnormalities but don't think it had anything to do with BACE inhibition. And they want to continue to pursue this line of inquiry. 

For Lilly the clinical failure marks the latest in a string of setbacks for Alzheimer's and another black eye for its R&D division, which has been plagued by trial fiascos. Last year Eli Lilly famously--though reluctantly--conceded that its Phase III study for solanezumab was a failure, forcing it to go back to the drawing board to redesign a new approach tailored to early-stage patients. And that flop followed the failure of Lilly's semagacestat, a gamma-secretase therapy that harmed patients who took it. 

Lilly, of course, isn't alone. There hasn't been an effective new Alzheimer's therapy in years, and none actually slow the disease. More than 100 clinical trial failures have been recorded in the Alzheimer's field.

BACE inhibitors raise the prospect of threatening patients, much like gamma-secretase inhibitors, because beta secretase is also responsible for multiple physiological functions, raising the prospect of unintended consequences. But for researchers, it's proven a compelling target, as they've often seen distinct signs that this approach also eliminates beta amyloid, a toxic protein associated with the memory-wasting disease that now afflicts more than 20 million people. By inhibiting beta secretase, a drug can prevent the production of beta amyloid.

"LLY and another company, Merck, have been racing to take their respective BACE inhibitors through development and have been neck-and-neck in terms of timelines," notes Bernstein's Tim Anderson today. "Both compounds have been working their way through brief phase 2 studies, with large and long phase 3 studies likely starting in the late 2013/early 2014 timeframe. LLY's is now out of the race, leaving MRK's compound as the survivor and investors will naturally wonder whether this new news heralds a problem with all BACE inhibitors or whether it was specific just to LLY's lead candidate. There had been some rumbling in the drug industry about LLY's compound potentially having a safety issue, which led to them choosing a lower dose of drug that could have explained the slightly weaker level of beta-amyloid lowering compared to Merck's compound.  We asked LLY directly about this at one point, and they denied knowing of any safety issues."

"While stopping this Phase II study for our BACE inhibitor is disappointing, patient safety is of utmost importance to Lilly," said Jan M. Lundberg, executive vice president, science and technology, and president, Lilly Research Laboratories.

Lilly says it has yet to calculate the charge that it will take for this latest failure.

- here's the press release

Special Reports: The Top Phase III Disasters of 2012 | The Alzheimer's pipeline: What's next?

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