New drug may restore memory with Alzheimer’s disease
Reported December 25, 2007
A 2006 study by MetLife found that adults over age 55 fear Alzheimer’s disease more than cancer, and with good reason. Alzheimer’s creeps up on patients and their families, robbing more than half of all Americans over age 85 of their memory and ability to care for themselves.
But what is perhaps most frightening is that available treatments for the disease are by and large ineffective.
Research from Georgetown University several years ago suggested that a new class of anti-Alzheimer’s molecule, spirostenols, might undo some of the characteristic pathophysiology of Alzheimer-affected brains. Further testing showed that one such molecule, Caprospinol, actually reversed the course of an Alzheimer-like condition induced in rats. Today, Samaritan Pharmaceuticals (Las Vegas, NV), is gearing up for human clinical studies with this compound, also known as SP-233.
Buildup of beta-amyloid plaque in the brain has been recognized as a hallmark sign of Alzheimer’s for close to a century. Significant research points to this buildup as a causative factor in the development and progression of the disease. Until recently this hypothesis could not be tested definitively because of a lack of treatments that eliminate beta-amyloid plaques.
Samaritan Pharmaceutical scientists, working with leading researchers from Georgetown and McGill Universities, have demonstrated in a rat animal model, used to test new innovative drugs for Alzheimer’s disease, that Caprospinol clears amyloid plaque from the brain and restored memory. More impressively, treated rats perform as well or better in standardized behavioral tests than healthy control animals. In addition to eliminating plaque, Caprospinol appears to reverse the damage to memory and cognition that amyloid plaque causes.
Dr. Vassilios Papadopoulos, of McGill University Health Center, an adviser to Samaritan, and the discoverer of anti-Alzheimer’s spirostenols recently published a paper reviewing current development-stage approaches to treating Alzheimer’s disease (Recent Patents on CNS Drug Discovery, 2007, 2, 113-123). In this article, he identified amyloid plaque as a key target for therapy. The paper also summarized the research on acetylcholinesterase inhibitors as well as beta-amyloid aggregation inhibitors, of which Caprospinol is an example.
The rat studies were conducted by treating rats with a method of inducing an Alzheimer’s-like condition in test animals within four weeks. Rats treated in this fashion gradually lose cognitive skills, as well exhibiting a host of pathophysiologic brain changes indicative of Alzheimer’s. Then treatment of sick rats with Caprospinol brought about significant positive changes in brain pathology. Neuritic plaques, neurofibrillary tangles, astrogliosis, microgliosis, neuronal death, and tissue shrinking were all either reversed or markedly improved.
Why another Alzheimer’s drug?
One might ask why the world needs another Alzheimer’s disease drug. The answer lies in the relatively poor performance by existing Alzheimer’s medications.
Of the five Alzheimer’s disease drugs approved in the U.S., four (Razadyne?, Exelon?, Aricept?, and Cognex?) are inhibitors of cholinesterase, an enzyme that shuts down the activity of the neurotransmitter choline. Cholinesterase inhibitors are approved for mild to moderate Alzheimer’s. The fifth medication, Namenda?, is an antagonist of the N-methyl D-aspartate receptor which regulates glutamate, another neurotransmitter. None of these agents cure Alzheimer’s disease or significantly change the course of the disease. The best that some patients can expect is a delay in symptom progression and/or improvements in some memory and behavioral functions.
Enhancement of neurotransmitter activity is a logical approach to treating AD. However, there are problems with cholinesterase and glutamate-acting agents. The first is that they do not address the underlying pathology of Alzheimer’s, treating only the symptoms and not the disease. The second, related shortcoming is that the most responsive patients get worse. The positive benefits of drug treatment are, disappointingly, measured in weeks or at best, months. Alzheimer’s drugs also tend to be quite expensive, and organ toxicities are not uncommon.
Based on the chemical structure of cholesterol, Caprospinol is an entirely new anti-Alzheimer’s compound and works completely different than the currently approved neurotransmitter agents. Although the exact mechanism has not yet been elucidated, molecular modeling experiments suggest that Caprospinol inserts itself inside the folded structure of the beta-amyloid peptide, preventing amyloid molecules from joining together into the highly neurotoxic amyloid-derived diffusible ligands (ADDLs). It is this mechanism that researchers believe causes amyloid plaque wash out of the brain. Scientists also hypothesize that through binding, Caprospinol prevents ADDLs from entering neuronal mitochondria, the energy-producing structures in all living cells.
Samaritan has recently received the go-ahead from the U.S. Food and Drug Administration to test Caprospinol on a small group of patients in a Phase I human safety trial. Thus far results from animal toxicology tests are extremely encouraging. No toxicity was observed in animal studies. Although it is a steroid, the drug does not appear to interfere with the body’s steroid receptors or liver function either. And since it does not affect with the cytochrome P450 enzyme system, investigators believe that SP-233 should cause no unanticipated interactions with other medications that Alzheimer’s patients are likely to be taking. Acting in the liver, the P450 enzymes are responsible for metabolizing and helping to eliminate drugs and other chemicals.
The Phase I trial on Caprospinol is expected to begin in Q2 2008.
