New Alzheimer’s Research: Disease Modification Therapies

Director, Farber Institute for Neurosciences, Thomas Jefferson University Chair,
Medical and Scientific Advisory Council, Alzheimer’s Association

This interview was conducted on May 18, 2007 by Peter Cook

Introduction

Alzheimer’s is one of the most pressing crises currently facing American healthcare. “One out of every two adults who reaches the age of 85 will suffer from Alzheimer’s,” says Sam Gandy, MD. “The main intervention for 15 years now has been cholinesterase inhibitors, which offer temporary symptomatic relief for Alzheimer’s patients, but do not slow brain deterioration and have no long-term impact on the disease’s prognosis.”

Dr. Gandy, who has studied selective disease vulnerability—with a particular focus on neurological disorders—for his entire career, is one of a number of doctors studying disease modification for Alzheimer’s.

“This is a time of great excitement in the field of Alzheimer’s research,” he says. “For the first time we’re identifying and testing substances that address the underlying causes of this disorder; substances that appear to slow—and in some cases even halt or reverse—the progression of Alzheimer’s.”

Disease Modification

As Dr. Gandy explains, the difference between disease modification and symptomatic relief is that in the latter the treatment interacts with the disease’s underlying pathology. “Take diabetes, for example. Treatment involves supplying the patient with insulin, but nothing is done to address the pancreas, where insulin is actually made; current treatment just helps the body compensate for a deficiency.” Similarly, the cholinesterase inhibitors allow the brain to compensate for a deficiency of the neurotransmitter acetylcholine, which is linked to the symptoms of Alzheimer’s. Cholinesterase breaks down acetylcholine between nerve cells, and cholinesterase inhibitors slow this process down. However, Alzheimer’s targets the cells that produce acetylcholine, and when these are gone, cholinesterase inhibitors no longer have any effect.

“The principle of disease modification,” Dr. Gandy says, “is to identify and treat the earliest cause of a disease possible. Alzheimer’s is a disease of cell death, so disease modification entails staving off that cell death.”

The pathology of Alzheimer’s involves accumulation of abnormal structures—proteins—that build up either between nerve cells (amyloid plaques) or within nerve cells (neurofibrillary tangles). As Dr. Gandy explains, “amyloid is a short peptide—or piece of a protein—that, normally, is produced and relatively quickly broken down. In Alzheimer’s patients, the amyloid essentially folds back on itself in a locked position, exposing a particularly sticky part of the peptide. Once exposed, it begins bonding with other amyloids, and soon you have a large clump, or plaque, which then begins attacking the brain.” The disease modifying therapies that are currently undergoing clinical trials are aimed at preventing this amyloid buildup.

Disease Modifying Therapies

Currently, there are 3 main disease-modifying therapies under investigation. Tramiprosate, a tablet formation, is in phase III clinical trials, and the results will be announced very soon.

“There’s a great deal of excitement about this treatment,” Dr. Gandy says. “This is the first medication specifically aimed at breaking up amyloid plaque that has made it this far in clinical trials.”

Tramiprosate is the product of an evolution of understanding both in genetics—which pointed the way toward amyloid folding—and structural biology—which recently developed the techniques required to address that folding. “There’s also growing evidence that protein folding is an element in a number of late onset brain diseases, including Parkinson’s,” Dr. Gandy says. “This is no longer a problem just for basic biochemistry, but an important problem in molecular pathology as well.”

Another tablet formulation, R-flurbiprofen, is also in phase III testing, the results of which are expected to be announced some time in 2008. R-flurbiprofen was derived originally from ibuprofen. “It’s long been recognized that people with arthritis who take anti-inflammatories have an apparent lower risk for Alzheimer’s,” Dr. Gandy says. “Originally, we suspected that this was due to inflammation playing some part in Alzheimer’s, but it turns out these drugs target a particular amyloid subtype that is, in essence, especially sticky.” The amyloid implicated in plaque formation comes in two lengths: either 40 or 42 amino acids long. It turns out that it is the 42 amyloid that is particularly sticky, and it is just this amyloid that ibuprofen affects. Once this was recognized, researchers were able to develop a derivative of ibuprofen that targeted the 42 amyloid without the side effects of nonsteroidals, such as stomach upset and stomach bleeding.

A third treatment, currently in phase II testing, is a vaccine against amyloid plaque formation. “This vaccine has been around for 5 or 6 years, and was first discovered in a mouse model,” Dr. Gandy says. “Essentially, the vaccine is made up of an amyloid substance which spurs the body to produce antibodies that help the brain clear amyloid plaques away.” The vaccine appeared safe in animal trials, and in phase I testing, but in phase II, 5% of the 300 patients developed an acute but non-fatal encephalitic reaction to the vaccine. “This slowed testing on the treatment, of course, but researchers later discovered that one group of amyloid amino acids is required to stimulate antibody production, and a different group are responsible for encephalitis, and trials have been reinitiated with the refined vaccine,” Dr. Gandy says.

An alternative type of vaccination, called passive immunization, is now undergoing phase III trials. “Passive immunization involves producing antibodies in a laboratory using recombinant DNA techniques, and then infusing patients with these every several weeks or months, rather like chemotherapy,” Dr. Gandy explains. “The major benefit is that treatment can be stopped quickly if there are any adverse events—there’s no going back with a regular—or active—vaccination.”

Dr. Gandy believes it will be a year or two before the results of these vaccination trials are obtained and released. “Alzheimer’s is a slow disease, and there’s a great deal of variation from patient to patient, so even if a treatment is working, it takes 6 months to a year to see any notable effects.”

Conclusion

“It is predicted that by 2015 Alzheimer’s alone will consume the entire medicare budget,” Dr. Gandy says. “This disease is a major challenge to public health, and it’s only going to get more severe. However, at a time when the clinical and societal impact of Alzheimer’s is more evident than ever, and researchers have finally identified a number of extremely promising treatments, NIH funding for Alzheimer’s research has been cut for the first time in 30 years.” Dr. Gandy stresses that now, as researchers are just beginning to make breakthroughs, further research into the causes and treatment of Alzheimer’s is more important than ever.

Disclosure: Dr. Gandy is on the speaker’s bureau of SMART and Wyeth/Elan; has received grant support from Eisai, Pfizer, The Robert Atkins Foundation, and Wyeth; and has received honoraria from Eisai, Pfizer, and Roche.