Investigational drugs that decrease the body's load of both soluble and fibrillar amyloid β (Aβ) could change a diagnosis of Alzheimer's disease from a death sentence to that of a chronic but manageable illness.
All of these compounds are still in preclinical or clinical trials, but their potential to redefine the prognosis of Alzheimer's patients is remarkable, researchers say–akin to the benefits that protease inhibitors have wrought for those with HIV-AIDS.
“The first protease inhibitor for AIDS was not a very good drug, but it provided a proof of principle that paved the way for the current drugs, which have revolutionized HIV-AIDS treatment,” said Michael Wolfe, Ph.D., of Brigham and Women's Hospital and Harvard Medical School, Boston.
Similarly, although these first Aβ-modulating agents that target proteases “are not perfect right now, I believe they will pave the way for more effective drugs that will completely change the way we view Alzheimer's therapy.”
Perhaps the most exciting component of drugs that modify Aβ is their potential to change the course of Alzheimer's, according to Dr. Samuel Gandy, chief scientific adviser for the Alzheimer's Association. “We're on the verge of knowing whether antiamyloid strategies will slow or prevent cognitive decline,” he told this news organization.
Methods of Action
The drugs all aim to decrease levels of Aβ peptides, but they do so in different ways, Dr. Wolfe said in an interview.
Aβ–some forms of which aggregate into the characteristic Alzheimer's brain plaques–is produced when the enzymes β- and γ-secretase cut the amyloid precursor protein into different lengths. Inhibitors of γ-secretase stop that cleavage, lowering Aβ levels by keeping the precursor protein intact. Selective amyloid-lowering agents (SALAs) also work on γ-secretase: They change the point where the protein is cut, preventing the formation of the toxic, longer-chain Aβ-42. Both γ-secretase inhibitors and SALAs are designed to reduce soluble Aβ levels, with the aim of preventing plaque formation.
The third agent under development–an Aβ antagonist–is designed to maintain Aβ peptides in a soluble state. It apparently stops heparin from binding to Aβ, an interaction thought to trigger Aβ aggregation, Dr. Wolfe said. This compound, which is furthest along the developmental pipeline, not only reduces soluble Aβ, but has been shown in animal models to reduce the load of already-formed Aβ-42 plaques.
Safety and Efficacy
Some serious safety issues plagued the γ-secretase inhibitors during early preclinical development, Dr. Wolfe said. The enzyme also plays a key role in cell signaling from the Notch receptor: Blocking it entirely had significant effects on this pathway, which mediates cell differentiation and proliferation. Immune cells and tissues with high cellular turnover–including gut tissue–were most severely affected.
The SALAs don't block γ-secretase, but rather modify the enzyme's activity in a way that avoids the Notch problem. But, Dr. Wolfe said, early SALAs just weren't very effective in cell cultures. “Even the one in clinical trials requires very high doses,” to achieve a significant effect. “They're apparently very safe, however,” he added.
The Aβ antagonists have likewise shown little or no toxicity in humans, even at very high doses, he said.
Tramiprosate: A β Antagonist
Of all the Aβ modulators, tramiprosate (Alzhemed, Neurochem Inc.) is closest to clinical use. Its initial 18-month phase III trial, which includes 1,052 North American patients with mild to moderate Alzheimer's, is set to conclude in January 2007. A similarly sized European trial is underway.
Findings from in vitro experiments have shown that the drug inhibited Aβ-42-induced cell death by 38%. In animal studies, it reduced Aβ-42 plasma levels by 31% and plaque burden by 24% (Neurobiol. Aging 2006, May 1;[Epub ahead of print]doi:10.1016/j.neurobiolaging.2006.02.015).
The findings of a phase II study of 58 patients with mild to moderate Alzheimer's, who were followed for almost 3 years, are consistent with those early results. Over the first 3 months of that trial, patients on the highest dose of tramiprosate had a significant decrease in mean levels of Aβ-42 in cerebrospinal fluid compared with placebo patients.
“The reductions varied depending on the dose given, but the average decrease was up to 30%, which reproduced quite nicely what we saw in the animal studies,” said Denis Garceau, Ph.D., Neurochem's senior vice president of drug development.
Tramiprosate also has some ability to stabilize disease progression and perhaps even modify its course, he said. After 20 months on the drug, about 70% of the patients with mild Alzheimer's who were still receiving tramiprosate showed either stabilized or slightly improved cognitive measures.
There were no significant adverse effects; the most frequent were mild to moderate gastrointestinal symptoms that resolved spontaneously.