Pulling Iron From Brain Seen Offering Hope in Alzheimer's Fight
Pulling Iron From Brain Seen Offering Hope in Alzheimer's Fight
(Bloomberg) -- To curb the dementia epidemic, focus is shifting to one of the most abundant elements on Earth: iron.
The familiar metal is key to numerous brain functions, but too much of it is toxic. Researchers in Melbourne showed two years ago that iron levels in the brain can predict when people will get Alzheimer’s disease. Now, the team aims to show how removing excessive amounts with a drug called deferiprone can stave off the memory-robbing disorder.
Starting within weeks, the world-first study will investigate the 23-year-old medicine in 171 patients with early Alzheimer’s. The yearlong, mid-stage trial represents a new approach to finding a treatment for the biggest cause of dementia -- a condition estimated to afflict a new person every 3 seconds and predicted to cost the global economy $1 trillion next year.
“The feeling of all of us is that we are on a winner,” said Michael Woodward, a geriatrician and principal investigator of the study at Melbourne’s Austin Health, which pioneered brain-imaging techniques used to diagnose Alzheimer’s. “But, who knows -- we have to prove it.”
Targeting Amyloid
Countless researchers’ hopes have been dashed in the pursuit of a cure, while drugmakers have spent billions on more than 100 failed treatments. The latest disappointment came earlier this year from targeting a protein called beta amyloid that clumps in the brain of patients, a target pursued by companies such as Merck & Co., Eli Lilly & Co. and Biogen Inc.
There hasn’t been a new drug for alleviating symptoms in more than a decade and, even as patient ranks swell across the globe, there are no medicines proven to slow the condition.
“Alzheimer’s is a complex disease of a very complex organ,” said Sam Fazeli, an analyst at Bloomberg Intelligence in London. “It is unlikely that one therapy will achieve strong efficacy in all patients. So, the more we have -- especially of cheaper drugs with low toxicity -- to add to our arsenal, the better.”
Most of the pharmaceutical research money for Alzheimer’s is going to drugs that aim to either remove, neutralize or stop the production of amyloid, according to Woodward. The deferiprone study will mark a return to an approach explored, with encouraging results, in Canada more than three decades ago.
Rare Success
Doctors in Toronto in the mid-1980s found that twice-daily shots of desferrioxamine mesylate -- used for managing excess iron levels in the blood of thalassemia sufferers -- reduced the rate of cognitive decline by 50 percent over two years. Ironically, the study of 48 probable Alzheimer’s patients was conducted to investigate the role of another metal, aluminum.
“It remains one of the only positive clinical trials for Alzheimer’s disease,” said Scott Ayton, a research fellow with the Florey Institute of Neuroscience and Mental Health in Melbourne, who is also working on the deferiprone study.
The Canadian research wasn’t replicated or followed up at the time amid growing interest in targeting amyloid, he said. In the past few years, evidence supporting iron’s pernicious role in Alzheimer’s disease has mounted.
Three Years
Patients with more iron in their brains deteriorate first and fastest, and those with low iron seem to have slower or delayed progression of the disease, Ayton and colleagues showed in a seven-year study published in Nature Communications in 2015.
They hypothesized that a drug called a chelator that binds to iron, enabling it to be lured from tissues, could lower levels in the brain, possibly delaying the onset of Alzheimer’s by up to three years in people experiencing mild cognitive impairment, the early stages of the disease. Deferiprone, an oral iron chelator, is sold by Canada’s ApoPharma Inc. under the brand name Ferriprox for patients with thalassemia, an inherited blood disorder.
Iron composition in the body is regulated by signals that tell cells how much of the metal to take up. Cells can be programmed to die by drawing in toxic levels in a molecular process known as ferroptosis.
Parkinson’s Effect
Inappropriate ferroptosis signaling may cause nerve cells, or neurons, to recruit lethal amounts of the metal ions and die, causing neurodegeneration, Ayton said.
In the trial slated to start next month, cognitive decline will be compared alongside measurements of iron in key parts of the brain using a new MRI technique called quantitative susceptibility mapping, he said.
ApoPharma is providing a special formulation of the drug and the accompanying placebo for the randomized, controlled trial, according to Jordan Berman, global director of corporate communications for Apotex Inc., a Toronto-based affiliate. Interest in the study arose from the “growing recognition that excess free iron in the brain appears to be a contributor to the progression of Alzheimer’s disease,” Berman said.
People shouldn’t rush to using deferiprone without supervision because it hasn’t been specifically studied in Alzheimer’s patients yet, and it isn’t without side effects. The drug may cause agranulocytosis, a dangerous lowering of white blood cells that puts patients at risk of serious infections, according to Berman. Participants in the Alzheimer’s trial will be monitored for that.
“Iron is required because it’s quite a powerful element,” Ayton said. “But the same reason that makes it very powerful also makes it very dangerous.”
To contact the reporter on this story: Jason Gale in Sydney at j.gale@bloomberg.net.
To contact the editors responsible for this story: Brian Bremner at bbremner@bloomberg.net, Marthe Fourcade, John Lauerman
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