Prana Alzheimer's drug confirms therapeutic promise

A Phase II clinical study under way in Melbourne has confirmed the promise of metal-chelating agents for treating -- and perhaps even preventing -- the devastating neurogenerative disorder Alzheimer's disease.

A paper published today in Archives of Neurology reports that the experimental therapy being developed by Melbourne company Prana Biotechnology (ASX:PBT) significantly improved cognitive function in patients with moderate to severe Alzheimer's disease.

The pilot-scale trial, conducted through the Mental Health Research Institute in Melbourne, involved 36 Alzheimer's patients. Eighteen were treated with Prana's now-superseded lead compound, PBT1 -- the antimicrobial drug clioquinol -- and 18 received a placebo.

A large team of Australian, US, British and Norwegian researchers were involved in the trial, and in analysing its results.

Before the trial, all patients were rated on the 70-point Alzheimer's Disease Assessment Scale (ADAS), a composite measure of memory, orientation, language, attention and reasoning. The higher the ADAS score, the more severe the patient's cognitive deficits.

According to a Prana press release, the ADAS score of a typical patient with mild to moderate to severe Alzheimer's disease would be expected to increase by 6 to 12 points over 12 months. A special panel of the US Food and Drug Administration has deemed that any improvement of 4 points would be clinically significant.

The current best-available clinical treatment for Alzheimer's disease, Aricept, which seeks to reduce neuron loss by enhancing activity of the neurotransmitter acetylcoline (ACH), results in a difference of 3 points after 24 weeks.

The Melbourne patients treated with PBT-1 showed an ADAS score increase of only 1.5 points after 24 weeks, where the placebo group score averaged 8.9 -- a difference of 7.4, and a 1.4-point improvement over patients treated with Aricept.

Internationally renowned Alzheimer's disease researcher Prof Colin Masters, of Melbourne University, the senior author on the Archives of Neurology paper, said the significance of the study was that it showed metal-chelating compounds can modify the course of the disease in the human brain, and "gives us hope that we can delay its progression".

Masters said the study also provided proof of concept, for the first time in any human cohort, that a drug targeted specifically to the neurotoxic protein beta-amyloid, long suspected to be the primary cause of Alzheimer's disease, actually reduces levels of beta amyloid in blood.

Beta-amyloid, a soluble protein in the blood, aggregates to form distinctive structures called amyloid plaques that clog the brains of Alzheimer's patients, disrupting nerve transmission and eventually causing cells to die.

In the 1990s, Dr Ashley Bush, Prana's co-founder and CEO, advanced a radical hypothesis that metal ions -- specifically, copper and zinc -- are the 'glue' that binds the beta-amyloid fragments together.

Copper ions, in particular, are thought to catalyse a chemical reaction that produces hydrogen peroxide, which spawns highly reactive hydroxyl radicals that intoxicate, and eventually kill, cholinergic neurons.

Bush then showed that clioquinol, a metal chelating compound could dissolve stubbornly resistant amyloid plaques extracts in vitro, and subsequently showed that clioquinol dramatically improved the cognitive function of transgenic mice expressing a mutant human gene that causes a severe, early-onset form of Alzheimer's disease.

Bush's hypothesis is now regarded as the best explanation of the mechanism of Alzheimer's, and the Melbourne trial has now confirmed the promise of metal-chelating compounds for treating Alzheimer's disease in humans.

The Archives of Neurology paper reported that zinc levels in patients treated with PBT-1 actually increased, while copper levels remained stable.

Masters said the rise in serum zinc was evidence that the drug had displaced zinc ions from the brain -- by implication, that it had actually dissolved amyloid plaques, as predicted by Bush's hypothesis.

Masters said the absence of a corresponding increase in patients' serum copper levels may reflect the fact that copper is under much tighter metabolic control in the body, and was either sequestered or excreted without causing a significant rise in serum levels. Future trials will seek to determine copper turnover patterns after administration of chelating drugs.

"Overall, the results are very encouraging, and give us a lot more confidence to move ahead with the next generation of [metal-chelating] compounds, and to move to much larger trials," he said.

Masters said the trial had also provided reassurance that copper-chelation therapy will not adversely affect normal levels of copper and zinc in the body.

He said Prana's new lead compound, PBT-2 -- a synthetic molecule developed by Prana chemists -- had already been shown to be much more active than clioquinol. "On each of five different laboratory assays, it looks substantially better."

Subject to toxicology tests, PBT-2 is expected to go into Phase II trials in the third quarter of 2004.

Some caution

William Thies, vice-president of medical and scientific affairs at the US Alzheimer's Association, said that while the trial was promising it was too small to draw definitive conclusions. "The sample size is very, very small and the effect is not dramatic," he said.

"The main importance of studies like this is to attempt to prove the principle that amyloid-lowering agents can stabilise or possibly even reverse cognitive decline in Alzheimer's."

Researchers plan to continue to study clioquinol. "I think the general approach is extremely exciting," said Sam Gandy, director of the Farber Institute for Neurosciences of Thomas Jefferson University in Philadelphia. "At this point in the field of Alzheimer's the most important question to answer is whether plaque is causative of the disease or merely a bystander."

Several other companies, including Canadian firm Neurochem, are developing drugs aimed at inhibiting the development of amyloid protein or dissolving it once it is formed. There is some evidence that dissolving plaque reduces symptoms of the disease, which range from memory loss to dementia.

"Any study that establishes that an anti-amyloid drug could stabilise or reverse cognitive decline would be a landmark study," Gandy said.

Additional reporting by Reuters