Memogain® is an investigational pro-drug of galantamine, a natural compound licensed for the treatment of Alzheimer’s Disease (AD). The pro-drug greatly enhances delivery of galantamine to the brain and is expected to offer decisive advantages over drugs currently available for AD that are limited by very modest improvements in cognition, adverse effects which limit adherence, and no significant disease modification. The expected medical benefits of Memogain® include significantly greater effectiveness as a cognition enhancer and absence of dose-limiting gastro-intestinal side effects. The latter offers the possibility that induction of tolerance by gradual up-titration of the dose, a factor which limits acceptability and effectiveness of galantamine, may not be required. More effective cholinergic stimulation locally in the brain also raises prospects for disease-modifying activity as suggested by preliminary evidence of reduced pathological changes in a transgenic mouse model of AD and stimulation of new cell growth in the hippocampus of the rat.
Galantamine, the active principle in Memogain®, has been available in Europe and the USA for more than a decade as a licensed drug for symptomatic treatment of mild to moderate dementia of the Alzheimer’s type. It is one of a class of agents for this indication, whose actions are partly or solely attributable to inhibition of cholinesterases responsible for the rapid cleavage of acetylcholine (ACh), an essential transmitter in the central and peripheral nervous systems, and in muscle and other tissues.
Galantamine differs substantially from other members of this class because, in addition to cholinesterase inhibition, an important contribution to its ability to enhance cholinergic activity derives from binding to nicotinic acetylcholine receptors (nAChR). Binding of galantamine to the nAChR is non-competitive and results in an enhancement of ACh binding and ion channel activation. The resultant enhancement of cholinergic transmission in the brain is associated with a clinically significant improvement in cognition in patients with mild and moderate Alzheimer’s Dementia (AD).
The efficacy of galantamine and other members of this class is modest, mainly because of adverse cholinergic autonomic effects, such as nausea, vomiting, abdominal cramps and diarrhoea, which limit the dose that can be tolerated. To mitigate these unwanted effects, dosing is usually started at a subtherapeutic level and escalated over a period of weeks or months, thereby keeping acceptable levels of tolerance. However, this complicates treatment for patients and carers and often results in discontinuation of the treatment before effective levels are attained. More efficient delivery of galantamine into the central nervous system with reduced systemic exposure offers the possibility of a higher therapeutic index with increased efficacy and reduced peripheral adverse effects.
Memogain®, also called Gln-1062, is a pro-drug of galantamine, exhibiting no pharmacological activity until it is cleaved by a carboxyesterase, which results in release of galantamine. There is substantial evidence from animal studies that intravenous or intranasal administration of Gln-1062 rapidly achieves higher brain concentrations of Gln-1062 and galantamine than intravenous or oral administration of galantamine, and with a proportionally higher brain-to-blood concentration ratio. Hence, this pro-drug offers the prospect of greater efficacy (potency) and fewer systemic adverse effects of galantamine by attainment of higher brain concentrations of galantamine relative to the periphery.