Public Release: 

Early study reveals new drug could improve executive function in Alzheimer's patients

Lancet

An early study has shown that the new drug PBT2 improves two indicators of executive function in patients with Alzheimer's disease (AD), and reduces the levels of the Alzheimer's-associated protein amyloid β in the spinal fluid in these patients. These are the conclusions of authors of an Article published early Online and in the September edition of The Lancet Neurology, timed to coincide with the announcement of the findings at the International Conference on Alzheimer's Disease (ICAD), Chicago.

Amyloid β can build up into plaques in the brain, and is thought to be toxic to brain cells and prevent them functioning correctly. To accumulate in the brain, amyloid β needs the metals zinc and copper, and levels of these two metals are elevated in the brains of people with AD. PBT2 works by interrupting the interaction between amyloid β and these metal ions. PBT2 restores normal function to amyloid β impaired synpases and improves congnitive performance in mouse models of Alzheimer's.

Dr Lars Lannfelt, Uppsala University Hospital, Uppsala, Sweden and Dr Craig Ritchie, Imperial College London, UK, and colleagues did a randomised trial to test the safety and efficacy of PBT2, and its effect on the biomarkers of AD. The trial included 78 patients aged 55 or over, randomised to receive 50mg PBT2 (20 patients) 250mg PBT2 (29) or placebo (29). All patients had early AD.

Cognition testing included several standard tests for Alzheimer's patients, and among these two executive function tests showed improvement in 250mg PTB2 patients compared with placebo. In the first, patients on a 250mg dose of PBT2 were able to complete the task in a test known as 'Trail Making Part B' by an average of 48 seconds faster than they had at the beginning of the trial. The placebo group was an average of 5 seconds slower. In the 'Category Fluency Test', which looks at a person's ability to come up with as many relevant words as possible in relation to a specified category, those in the 250mg group were able to produce an average of 2.8 more words than at the beginning of the trial. This compared with a decrease of 0.3 words in the placebo group. Levels of amyloid β in the spinal fluid of the PBT2 250mg group were reduced by 13% compared to placebo at the end of the 12-week trial.

While memory loss is the problem often most associated with AD, there were no significant differences in tests assessing memory between PBT2 and placebo patients. However, the researchers say that this could be because memory functions deteriorate more slowly than executive ones during early stage AD, making changes harder to detect in such a short study. In terms of safety, no serious adverse events were reported by patients on PBT2, and proportions of patients reporting other adverse events were similar in the three groups.

The authors conclude: "The safety profile is favorable for ongoing development of PBT2....future trials that are larger and longer will establish if the effects of PBT2 on biomarkers and cognition that are reported here translate into clinical effectiveness."

In an accompanying Reflection and Reaction Comment, Professor Norman R. Relkin, Director, Memory Disorders Program, Weill Cornell Medical College, New York, USA, says: "To go forward as an AD treatment, PBT-2 must still surmount the high hurdle of additional safety and efficacy testing in large scale clinical trials...Assuming that the amyloid hypothesis holds water, future clinical studies with PBT-2 will not only test the mettle of metal-protein attenuating compounds, but also provide the first real world test of the importance of metal ion homeostasis in the pathogenesis of AD."

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Prof Lars Lannfelt, Uppsala University Hospital, Uppsala, Sweden T) +46 186 117 189 E) Lars.Lannfelt@pubcare.uu.se

Dr Craig Ritchie, Imperial College London, London, UK T)+44 (0)207 386 1216 E) c.ritchie@imperial.ac.uk Professor Norman R. Relkin, Director, Memory Disorders Program, Weill Cornell Medical College, New York, USA T) 1-212-746-2441 E) nrelkin@med.cornell.edu

for full paper please contact tony.kirby@lancet.com

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