Alzheimer's rewind

Gamma secretase woes in Alzheimer's prompt search for alternative targetsNext Phase III data in AD will come from beta amyloid mAbs in 2012

A string of Phase II and III failures in Alzheimer's disease has prompted companies to look for new targets beyond the well-known players in the core mechanism of AD - the production and accumulation of beta amyloid deposits in the brain. The next wave of candidates includes more than 20 clinical stage small molecules for targets that indirectly affect beta amyloid production and/or toxicity, or aim for solutions that might be disease-modifying even as they ameliorate symptoms.

Among the latest casualties are gamma secretase inhibitors, which first entered the clinic more than a decade ago. The two most advanced molecules, one in Phase III and one in Phase II, have shown safety signals that suggest the basic approach to the target will need to be refined. A handful of clinical and preclinical programs aiming to create a second generation of molecules are already underway.

Meanwhile, the AD field is awaiting the results of the remaining Phase III candidates, a trio of immunotherapeutics against beta amyloid. Behind them are at least 11 more clinical stage immunotherapies(see "Awaiting mAb Data," A13).

Gamma ghost town

Gamma secretase, the proteolytic complex that processes amyloid precursor protein (APP) into the neurotoxic beta amyloid form, was first proposed as a target in the 1990s and at least a dozen candidates have reached the clinic in AD.

Data presented at the Alzheimer's Association International Conference (AAIC) in July highlighted the difficulty of finding a therapeutic window for hitting the target.

Eli Lilly and Co. presented the results of a follow-up to the Phase III IDENTITY and IDENTITY-2 trials of its semagacestat (LY450139) gamma secretase inhibitor.

Those trials were suspended last year when a safety monitoring committee uncovered evidence of cognitive worsening in treated patients compared with placebo (see BioCentury, Aug. 23, 2010).

New data from a follow-up of 1,534 patients showed that seven months after dosing was stopped, patients who had received once-daily 100 and 140 mg oral semagacestat, respectively, had ADAS-Cog11 scores that were 7.29 and 7.68 points lower than baseline. Patients who got placebo showed a 6.19 point decline compared with baseline.

These data mean the harmful effect was not reversed after treatment was suspended. The rate of cognitive decline after termination of dosing was the same as placebo.

"Semagacestat produced an effect on cognition," said Eric Siemers, the senior medical director at Lilly who presented the findings. "Unfortunately it wasn't the effect we wanted."

Doubts about the target were compounded by results from a Phase II trial of Bristol-Myers Squibb Co.'s BMS-708163, a gamma secretase inhibitor that was intended to be more selective for APP processing.

The rationale for greater APP selectivity was to not interfere with the processing of other gamma secretase substrates such as Notch 1 (NOTCH1), which is involved in normal

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