Novel Alzheimer's drug set for clinical trials
adhesion molecule NCAM is due to take place in the UK in the third
quarter of this year, bringing a potential new treatment for
Alzheimer's disease a step closer, reports Phil Taylor.
Danish company Enkam Pharmaceuticals filed for approval to start trials of the peptide, called FGLL, last month, said chief executive Dr Morten Albrechtsen.
FGLL acts as a mimic of NCAM, which is the subject of intense research at present, both in Alzheimer's because it seems to play a pivotal role in the pathology of the disease.
Dr Albrechtsen told DrugResearcher.com that unlike current drugs for the condition - which only try to prop up the impaired cognitive and memory systems in Alzheimer's sufferers - FGLL appears to tackle the underlying mechanisms behind the disorder.
"The optimal Alzheimer's disease drug has to fulfil three criteria," Dr Albrechtsen explained. "First, it has to be able to remove the 'bad protein', beta amyloid, which deposits as plaques in the brains of Alzheimer's sufferers. Secondly, the drug has to be able to re-establish the functions of, and mutual communication between, neuronal cells. Thirdly, it has to improve memory and learning abilities. Our molecule satisfies all three criteria when tested in a model of Alzheimer's disease in rats."
NCAM interacts with a receptor in the fibroblast growth factor (FGF) class and activates two intracellular kinases - protein kinase C and P13K - which are both critically involved in the regulation of another kinase called GSK-3beta. The latter is implicated in the degeneration of the neuronal network in Alzheimer's, according to Dr Albrechtsen.
The uncontrolled activity of GSK-3â leads to hyperphosphorylation of a protein called tau that is an important component of the microtubules that make up the cytoskeleton of the neuron. This destabilises the cytoskeleton, which in turn results in collapse and degeneration of neuronal processes.
NCAM has also been implemented in brain plasticity associated with learning and memory. For example, 'knockout' mice that have been designed to lack NCAM expression display serious cognitive deficits.
So by stimulating the FGF receptor for NCAM, the company hopes that to prop up the signalling pathways controlling stability of neuronal connections, which should prevent the progression of the neurodegenerative process in Alzheimer's, and also to enhance cognition in patients with the disease.
The initial clinical study will be a Phase I/II trial and will involve 48 patients with early-stage Alzheimer's disease. They will be treated with the FGLL peptide - given intranasally - over the course of one month, said Dr Albrechtsen.
Meanwhile, Enkam is among a group of companies and academic research groups that have just been awarded a €9.7 million grant from the European Commission to explore the biology surrounding NCAM and its role in CNS diseases.
There are an estimated 18 million people in the world with dementia, accordng to the charity Alzheimer's Disease International, which estimates that by 2025 this figure could increase to 34 million. And finding a treatment that could delay onset by just five years could reduce the number of individuals with Alzheimer's disease by nearly 50 per cent after 50 years.