Myriad Genetics' Alzheimer's drug candidate improves learning

MPC-7869 (R-flurbiprofen), the Alzheimer's disease drug candidate in Phase II human clinical trials being conducted by Salt lake City-based Myriad Genetics, shows improved memory and spatial learning in a model of Alzheimer's disease, the Company claims.

The new data from a study entitled, 'Chronic treatment of transgenic APP mice with R-flurbiprofen', led by Dr Todd Golde and associates at Mayo Clinic Jacksonville, and Dr Edward Koo and associates at the University of California, San Diego, was presented at Neuroscience 2003.

The study was designed to determine whether a reduction in the toxic Abeta42 peptide leads to improvement in memory and spatial learning in a mouse model of human Alzheimer's disease. To answer this question, the authors allowed transgenic mice to age until they began to show signs of the onset of neuronal plaques and learning disabilities. This stage of impairment may be compared with mild Alzheimer's disease in humans. The mice were then treated on a long-term chronic basis with either R-flurbiprofen (significantly lowers Abeta42) or very high doses of ibuprofen (less potent Abeta42 lowering activity). Treated mice were tested for memory using the well-established Morris water maze test, a highly sensitive assessment of cognition in animals.

The mice used in this experiment were transgenic Tg2576 mice that produce the human amyloid precursor protein and demonstrate a progressive, age-related deposition of beta-amyloid plaques, modeling human Alzheimer's disease. In the Morris water maze, mice learn the position of a partially submerged platform within a circular water tank using spatial cues around the tank. In several trials per day, they are released from different starting points close to the wall of the tank and must swim until they find their way to the platform. After a few days of training, the time to reach the platform will decrease because the mouse learns the location of the platform relative to the spatial cues. The platform is then removed from the tank and the animal's spatial learning is evaluated by the length of time it spends searching the appropriate quadrant of the tank, where the platform was located. A mouse with difficulty learning or poor memory would swim randomly around the tank, and on average, would spend 25% of its time in each quadrant.

Untreated control animals in this experiment spent approximately 30% of their time in the correct quadrant, indicating little ability to learn and remember spatial cues. Ibuprofen had no significant effect on learning, even at very high doses, compared with untreated control mice in this study. However, R-flurbiprofen treated mice spent approximately 60% of their total time, more than twice as much as the controls, in the correct quadrant, indicating that they still recalled its location.

'This is a truly remarkable result for the R-flurbiprofen treated mice in this study,' said Todd Golde, Ph.D., Chairman of Neuroscience at Mayo Clinic. 'Our experience is that the water maze is a difficult task for mice generally, and well-trained normal healthy mice rarely spend more than 50% of their time in the correct quadrant. This group of treated mice performed exceptionally well, at 60%, with no apparent loss of cognition as measured in this study.'

In addition to improving spatial learning, mouse pathology was examined to determine whether a difference could be detected in the accumulation of amyloid plaques in the brain, between the drug-treated groups and controls. Initial analysis indicated that there was a robust reduction in the amount of insoluble amyloid levels in the brains of the R-flurbiprofen treated mice.

Myriad is developing R-flurbiprofen (MPC-7869) for the treatment of Alzheimer's disease, and has a Phase II human clinical trial ongoing in the United Kingdom and Canada.