Ashley Bush and PBT2

For years, clinicians and physicians have had little to offer Alzheimer’s disease (AD) patients in the way of effective therapies. Current drug treatments can help manage symptoms and can even delay progression of symptoms for approximately six months, but these drugs have had no observable effect on the underlying pathology of AD. That could change if a new drug, known as PBT2, shows as much promise in humans that it has shown in mice.

PBT2 is a second-generation chemical designed by a team of scientists led by Ashley Bush, MD, PhD. A Beeson scholar, Bush focused on PBT2 after studies revealed that PBT1 could reduce beta-amyloid plaques in mouse models of AD. PBT1, a topical antibiotic that goes by the trade name Clioquinol, also showed great promise in a randomized, double-blind, placebo-controlled clinical trial involving 32 AD patients. In this trial, PBT1 was shown to halt cognitive decline in the most severely affected individuals.

Studies with PBT2 indicate that it might be even more effective than PBT1. In seven-month old transgenic amyloid mice treated with PBT2, the brain concentration of PBT2 was about 50-fold greater than PBT1 for an equivalent dose, leading to a rapid and potent onset of benefits. One of those benefits was significantly improved spatial memory, which Bush and his colleagues measured using the Morris Water Maze Test. The Morris Water Maze Test involves remembering the location of a submerged platform, requiring the mouse to employ higher-level learning and spatial memory skills in order to successfully navigate the maze. Mice treated with PBT2 showed improved memory performance within just five days of oral dosing.

Other benefits of PBT2 are directly related to AD pathology. In additional studies Bush conducted with 15-month old transgenic Alzheimer’s mice, PBT2 reduced soluble Aß40 (pronounced “a-beta-40”) and Aß42 (“a-beta-42”) levels by 60 percent within 24 hours of oral PBT2 administration. Aß42, one of many protein fragments that are produced when amyloid precursor protein is cut into pieces, is believed to be the molecular trigger that initiates AD. It and other Aß species can interfere with the synapses, or gaps, that exist between brain cells. By reducing soluble Aß40 and Aß42 levels, PBT2 restores normal function to the synapses that underlie memory foundation.

“This data is compelling and very exciting because it shows that PBT2 not only may facilitate the clearance of Aß from the brain or prevent its production, but more importantly may improve cognition,” said Bush.

As with any novel small molecule, however, much more testing is required to test the safety and efficacy of PBT2. On the basis of the multiple encouraging results achieved to date, demonstrating that PBT2 has a rapid and potent mechanism of action, a Phase II, double-blind, placebo-controlled trial of PBT2 in Alzheimer's patients will begin soon. The study, to be conducted in several sites in Sweden, will evaluate the safety and tolerability of PBT2, as well as measures of the drug’s mechanism of action and indicators of potential efficacy in Alzheimer’s disease. The study is expected to commence enrollment in the fourth quarter of 2006, subject to final regulatory approval, with results expected by the end of 2007.