P4‐265: Memogain, a pleasant, highly potent and neuroprotective novel drug treatment in Alzheimer's disease

Abstract

Present symptomatic AD medications suffer from limited potency as cognition enhancers and from unpleasant side effects. All attempts to develop therapies that inhibit formation of amyloid plaques and neurofibrillary tangles so far failed to show any clinical benefit in the domain of cognition. Memogain, a pro-drug of galantamine, providing supra-bioavailability in the brain, overcomes these limitations by means of much higher cognitive effectiveness, absence of gastro-intestinal side effects, and inhibition of amyloid plaques built-up. Memogain is formulated as an aqueous spray and is administered intranasally. Toxicity and tolerability were probed by a complete GLP toxicity program and by additional studies in animal models. Cognitive effectiveness, in comparison to orally administered galantamine and donepezil, was probed by a cognition paradigm in scopolamine-treated mice. Reduction in number and size of amyloid plaques and enhanced cognitive performance, produced by several months of chronic treatment with Memogain, was studied in an animal model of early onset AD (5xFAD transgenic mice). Bioavailability of Memogain after intranasal administration was > 70%, with a brain-to-blood concentration ratio > 10. Pharmacologically inactive Memogain is cleaved by a brain-endogenous enzyme to galantamine, dramatically increasing the brain levels and corresponding activity of this drug in the target organ. Due to much lower drug levels in the periphery, and rapid metabolism and excretion, Memogain treatment is accompanied by very little toxicity. In particular, there was no indication in all four animal species tested, of significant emetic responses or other gastrointestinal side effects. In the T-maze alternation task, Memogain was up to 5-times more potent than galantamine in compensating scopolamine-induced amnesia. Chronic treatment with Memogain of 5xFAD transgenic mice reduced the plaque loads in hippocampus and cortex by more than one third, concomitantly with improved cognitive performance. Based on a comprehensive body of preclinical data, we expect Memogain® to show in AD patients (i) significantly improved potency on the ADAS-cog and MMSE scales, (ii) no gastrointestinal side effects, even at higher doses than presently applied for galantamine, (iii) immediate onset of medical benefit because of immediate dosing at the most effective level, and (iv) much longer medical benefit due to slowing of disease progression.