Preclinical Characterization

Memogain® (Gln-1062) has been shown to be effective in the T-maze alternation rat model of cognition in which intranasal administration achieved dose-related and complete reversal of the impairment of cognition produced by scopolamine with a potency approximately 5-fold greater than that of oral galantamine. When the nicotinic antagonist methyllycaconitine (MLA) was used instead of the muscarinic antagonist scopolamine, reversal of impaired cognition was achieved by much lower doses of nasal Gln-1062 compared with oral galantamine, these results attesting to significantly greater effectiveness (potency) of the pro-drug as a cognition enhancer.

At present, the only drug therapies available for AD are cognition-enhancing and though much effort is going into finding a mechanism by which to modify the relentless progression of the disease, none has yet been successful. It is known that cholinergic activity can reduce the characteristic pathological changes in the brain of AD, namely ß-amyloid plaques and tau protein tangles, using transgenic mouse models. Experiments have shown substantial reductions in this pathological markers of the disease when Gln-1062 was applied in such a model. Intranasal administration of Gln-1062 has also been shown to stimulate cell proliferation in the rat hippocampus. Thus, the pro-drug does offer the possibility of disease modification through further enhancement of localized cholinergic stimulation in the brain.

Pharmacokinetic (PK) studies in mouse, rat and dog show that, after intranasal administration of the pro-drug, it has high bioavailability and rapid absorption with peak concentrations in the brain occurring within a few minutes. Galantamine is then formed by cleavage of the pro-drug in the brain. Gln-1062 is not a substrate of acetylcholinesterase but is cleaved by carboxyesterases. The relative bioavailability of galantamine in the brain and the blood approached 90 % after dosing rats with 5 mg Gln-1062 base/kg. More than 10-fold higher Gln-1062 levels were recorded in rat brain compared to blood in contrast to the brain-to-blood concentration ratio for galantamine of only 1.3, attributable to its much higher hydrophilicity. Exposure to Gln-1062 and galantamine was proportional to dose.

In Beagle dogs absorption after intranasal dosing of Gln-1062 proceeded rapidly with peak concentrations of Gln-1062 reached mostly within a few minutes and those of galantamine within 1-2 h. The half-life of galantamine varied for the different animal species from 3 to 7 h.

The metabolite profile of Gln-1062 from human hepatocytes is very similar to that of galantamine, with galantamine and two minor metabolites formed initially and then followed by the usual metabolic breakdown profile of galantamine. The two additional metabolites were also observed in the species used for toxicology.

Systemic adverse effects of intranasal administration of Gln-1062 in rats and dogs and ferrets in high doses are confined to behavioral changes due to excessive cholinergic stimulation and high concentrations of galantamine. These effects, seen in an Irwin study and a number of other studies include salivation, muscle twitching, vomiting, shivering and diarrhoea and, at very high doses, ataxia, disturbed respiration, convulsions and death. Studies of cardiovascular function indicate that effects on heart rate, blood pressure or the ECG, including QT interval, are unlikely. Similarly, effects on respiratory function were not seen except in extremis. As the only significant toxic effect, a number of studies provided evidence that intranasal administration of high doses of Memogain may be associated with local irritancy in the nasal cavity.

Toxicity studies in rat and dog showed a marked absence of systemic toxicity. Gln-1062 showed no evidence of mutagenicity or clastogenicity.

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