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.