Developing a NAMPT activator for Alzheimer’s disease

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Currently there are no therapies that can slow or reverse the cognitive decline seen in late-onset Alzheimer's disease (LOAD). The single greatest risk factor for this condition is chronological age and as the global population ages, the number of AD cases is expected to continue to rapidly increase. This age-dependent association has led many to suggest that strategies that slow or reverse aspects of brain aging might be of particular use in patients with LOAD. In normal human subjects, there is an age-dependent decline in brain NAD+ levels and in animal models, a decline in brain NAD+ is strongly associated with aging and cognitive decline, while restoring NAD+ can improve cognitive function. Moreover, evidence suggests that in pre-clinical AD models, there is an accelerated loss of NAD+ and that neurons are particularly vulnerable to a reduction in intracellular NAD+ levels. It is well established that the rate limiting enzyme in the NAD salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT) and that the enzymatic activity of NAMPT largely determines the level of NAD+ within cells. Here, we describe an early stage drug development proposal to advance a brain penetrant, small molecule that augments NAMPT activity, thus increasing neuronal NAD+ levels and combating brain aging. We describe the development plan of this molecule up to the IND filing stage. The ultimate clinical indication for such a molecule would be in patients with LOAD and mild cognitive impairment. We have assembled a team with extensive drug development and AD experience, both in the pre-clinical and clinical arena. This proposal describes a series of milestones and go/no go decision points to advance our current set of three distinct chemical series, all of which directly bind to NAMPT and increase enzymatic activity, to a single final clinical candidate that would be ready to advance to Phase I testing in human subjects. This compound would be a first- in-class small molecule that seeks to reverse the age-dependent decline in NAD+ levels as a means to treat mild cognitive impairment in LOAD patients.