Safety, Pharmacokinetics And Pharmacodynamics Of Memogain® In Healthy Male Volunteers

EP Hart1, AC Baakman1, A Maelicke2, GJ Groeneveld1. 1Centre for Human Drug Research, Leiden, The Netherlands, 2Neurodyn Life Science Inc., Charlottetown, Canada

Introduction: Cholinergic neuronal dysfunction plays an important role in Alzheimer’s Disease (AD), the most common cause of senile dementia. Symptomatic treatment is available and involves administration of cholinesterase inhibitors such as galantamine. Their cognitive effects are, however, limited by off-target peripheral effects, increasing patient burden and reducing patient compliance. Memogain is a pharmacologically inactive prodrug of galantamine that is hypothesized to have higher CNS penetration than orally administered galantamine, thereby increasing the effectiveness of the galantamine that is enzymatically released from Memogain in the CNS. This should lead to stronger cognitive effects compared to galantamine that is administered through the usual oral route., Because of its lower peripheral exposure, Memogain is also expected to lead to fewer gastrointestinal side effects which may allow higher dosages.

Methods: This was a first-in-human single ascending dose study of intranasally administered Memogain in healthy young (N=16, 18-65 yrs, 5.5 and 11 mg) and elderly (N=42, >65 yrs, 22, 33 and 44 mg) men, compared to oral administration of galantamine 16 mg, donepezil 10 mg (elderly subjects only) and matching placebos. Safety, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed at high frequency. Safety assessments included incidence and severity of adverse events (AEs) and abnormalities or changes in laboratory measurements, vital signs and ECG. Standard PK parameters were derived from non-compartmental analysis (NCA). For PD the NeuroCart, a computerized test-battery of CNS tests designed for repeated measurements, was used. CNS domains tested included attention, episodic and working memory, executive functioning as well as pharmaco-EEG, eye movements, pupillometry, body stability and visual analogue scales (VAS) for mood and drug effects.

Results: Administration of Memogain was well tolerated and safe. All AEs were either mild or moderate and self-limiting. There were no serious adverse events. The most prevalent AE was nausea. VAS nausea values were only elevated after administration of oral galantamine 16 mg and Memogain 44 mg. Nausea was reported sooner after galantamine administration (peaking +/- 2 h post-dose) than after administration of Memogain 44 mg (peaking +/- 4-6 h post-dose). Based on the NCA of the plasma Memogain concentrations, a dose dependent increase in exposure was observed up to 33 mg. Memogain 44 mg led to a mean exposure that was comparable to 33 mg. Memogain was rapidly absorbed into the systemic circulation with a Cmax after approximately 15 min after Memogain 5.5 mg, up to approximately 45 min after Memogain 44 mg administration. PD effects of Memogain were seen on attention and memory. The adaptive tracking test, a psychomotor test that has proven very sensitive to disturbances and enhancement of vigilance/arousal, showed an improved performance of +3.47% in young men after administration of 11 mg Memogain compared to placebo (95%CI 0.52-6.42). In elderly men beneficial effects of Memogain were observed after 33 mg (+1.79%, 95%CI 0.07-3.52). Improved short term memory was evident from the direct word recall variable yielded by the Visual Verbal Learning test, which was enhanced in older men after administration of 22 mg (2.67 more words, 95%CI [0.17-5.16) and of 44 mg (2.57, 95%CI -0.05-5.18) compared to placebo.

Conclusion: Memogain nasal spray was well tolerated and found to be safe in young and elderly men in the dose range investigated. A dose dependent increase in plasma exposure was observed up to a dose of 33 mg. The PD effects of Memogain, an improvement of (short term) memory and an improvement in vigilance/arousal, were generally larger and more consistent than those of galantamine.