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In what could prove to be an important development in the search for a treatment of Alzheimer's disease, NewYork-Presbyterian Hospital/Weill Cornell Medical Center physician-scientists say the results of an initial (Phase I) clinical study provide encouraging evidence that antibodies derived from human plasma can capture the beta-amyloid protein in blood and exert positive effects on patients' thinking abilities. Beta-amyloid is a central component of the senile plaque in the brains of Alzheimer's patients, and its toxicity against brain cells is believed to be a prime cause of the illness.

The study's investigators, however, caution that it's still far too early to hail IVIg as anything but "promising," and they do not currently recommend that physicians treat Alzheimer's patients with IVIg.

But, while preliminary, the findings – which are being reported on Tuesday, April 12, at 4 p.m., at the annual meeting of the American Academy of Neurology (AAN) in Miami – do suggest the value of initiating larger, controlled Phase II clinical trials, and preparation for such trials are currently underway.

Intravenous immunoglobulin (IVIg) – an antibody product derived from human plasma and FDA-approved to treat other conditions, but not Alzheimer's – has been found to contain antibodies that latch onto beta-amyloid proteins in the blood. Previous studies have shown that antibodies against beta-amyloid can draw this protein out of the nervous system and reduce the burden of amyloid on the brain.

In the Phase I clinical trial, eight Alzheimer's patients were treated with IVIg (Gammagard S/D Immune Globulin Intravenous Human), donated by Baxter Healthcare Corporation, and, to date, seven have undergone cognitive testing after six months of therapy. Cognitive function stopped declining in all seven patients and improved in six of the seven patients.

IVIg therapy was well-tolerated, with patients experiencing only minor and infrequent side effects, such as chills following the infusion.

"If these results are confirmed in larger, controlled trials, we might have a safe Alzheimer's treatment capable of clearing the amyloid protein away," says senior researcher Dr. Marc E. Weksler, The Irving Sherwood Wright Professor of Geriatric Medicine and Professor of Medicine at Weill Medical College of Cornell University in New York City. Dr. Weksler is also an Attending Physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"These initial results are really encouraging," adds lead researcher Dr. Norman R. Relkin, Director of the Memory Disorders Program at NewYork-Presbyterian/Weill Cornell and Associate Professor of Clinical Neurology and Neuroscience at Weill Cornell Medical College. "Immune therapy for Alzheimer's disease has shown tremendous promise in the laboratory but has been difficult to translate into clinical practice. IVIg has the advantages of a well-established safety record and the benefits of containing antibodies that healthy individuals produce naturally as they age."

Dr. Weksler explains, "The search for an Alzheimer's vaccine is not new. The field exploded in 1999 when it was reported that mice bred to develop an Alzheimer's-like illness stopped depositing plaque after being immunized with beta-amyloid."

Researchers moved as quickly as possible to test out this type of "active" immunization – where the body builds its own antibodies against a particular target – in humans. "Unfortunately, about 6 percent of patients in that study developed encephalitis, a dangerous brain-swelling, so the trial was stopped," said Dr. Weksler.

The NewYork-Presbyterian/Weill Cornell team then turned to what vaccine developers call "passive immunization," where doctors deliver ready-made antibodies into the bloodstream.

In 2002, Drs. Weksler and Relkin, and Dr. Paul Szabo, a Weill Cornell molecular biologist, published a study showing that Alzheimer's patients had lower levels of anti-amyloid antibodies in their blood than cognitively normal individuals their age.

The question arose whether giving antibodies from healthy individuals to those with Alzheimer's would be beneficial.

To test this possibility, the NewYork-Presbyterian/Weill Cornell team chose IVIg, an antibody product derived from human plasma. IVIg received FDA-approval decades ago for the treatment of immune disorders in children and adults, and has been safely used in hundreds of thousands of patients.

Furthermore, upon close investigation, the team realized IVIg contained antibodies to several forms of beta-amyloid, including those thought to play a central role in the development of Alzheimer's.

At this time, they learned that a pilot study of IVIg by Dr. Richard Dodel and colleagues was already in progress in Germany with five Alzheimer's patients and appeared to be showing promising results.

"We set out to determine whether IVIg could alter the trafficking of beta-amyloid in the persons with Alzheimer's disease, and to determine what dose and frequency of treatment could be safely used for this purpose," said Drs. Relkin and Weksler.

In the current NewYork-Presbyterian/Weill Cornell study, eight patients with mild to moderate Alzheimer's disease, averaging 74 years of age, received one to four IVIg infusions per month at varying doses. Because the researchers wanted to track circulating levels of beta-amyloid and beta-amyloid antibodies, patients also underwent regular blood tests, as well as spinal taps to collect samples of spinal fluid. Patients were also given standard tests of memory and cognition to assess ongoing changes in mental function.

Levels of anti-beta-amyloid antibodies and beta-amyloid increased significantly in blood after each IVIg infusion.

"This indicates that antibodies in IVIg alter the dynamics of beta-amyloid trafficking in the blood. We also determined that IVIg affects the forms of amyloid that are thought to be most toxic to brain cells," Dr. Relkin explained. "These effects depended on the dose and frequency at which IVIg was administered."

While it's too early to say for sure that IVIg is the optimal form of passive immunotherapy for Alzheimer's disease, Drs. Weksler and Relkin are very encouraged by the significant improvements in patients' thinking ability, as measured by cognitive testing, following treatment with IVIg.

"Although this is not a sufficiently large study or one designed to prove effectiveness, it does appear that our patients did considerably better than expected with this treatment," Dr. Relkin comments.

Adds Dr. Weksler: "Our results – and those of Richard Dodel's team in Germany – provide a clear rationale for carrying out further studies of IVIg as a potential treatment for Alzheimer's."

But both physician-scientists remain cautious.

"Right now, we'd advise doctors against treating Alzheimer's patients with IVIg. There's still too much we don't know – especially the treatment's long-term effectiveness," they say. "We need to confirm these findings in larger, controlled trials before we can say anything definite."

This research was carried out with support from Baxter Healthcare Corporation, the Institute for the Study of Aging, the Dana Foundation, the Alzheimer's Association, the Elyachar Foundation, the O'Neill Trust, and the National Institutes of Health. Additional funding was provided by the Max and Lila Stern Family Fund and by gifts from the Flanzer, Koplow, and Scribner families.

Co-researchers included Dr. Tuna Burgut, Basia Adamiak, and Carmen Monthe – all of NewYork-Presbyterian/Weill Cornell; Dr. Kelvin Lee of Cornell University, Ithaca; Dr. Yansheng Du and Xing Wei of Indiana University School of Medicine; Drs. Linda and Steven Younkin of the Mayo Clinic, Jacksonville; and Dr. Richard Schiff of Baxter Healthcare Corporation.

Frequently Asked Questions About IVIG and Alzheimer's

What is IVIg?
IVIg stands for IntraVenous Immunoglobulin. It is a product of human blood that is derived from the plasma of thousands of healthy volunteers. IVIg contains antibodies, which are the proteins that help protect the body against disease.

Why is IVIg being studied as a treatment for Alzheimer's?
It was recently discovered that IVIg contains antibodies that bind to beta amyloid (Aß). Aß is a protein that many scientists believe is important in causing Alzheimer's. IVIg may help to promote the clearance of Aß from the brain and block Aß's toxic effects on brain cells.

Is IVIg a new treatment?
IVIg was originally approved by the U.S. Food and Drug Administration for treating immune disorders in children and has been available for more than 30 years. IVIg is FDA-approved for the treatment of patients with primary immunodeficiencies, immune thrombocytopenic purpura (ITP), B-cell chronic lymphocytic leukemia (CLL), Kawasaki syndrome, and immunodeficiency associated with pediatric HIV and bone marrow transplantation.

Neurologists also use IVIg in the treatment of multiple sclerosis and motor neuropathy, though IVIg is not approved for these conditions. It is not currently approved to treat Alzheimer's disease, but is under study for that purpose.

How is IVIg treatment given?
IVIg is administered by an infusion into a vein, a process that typically takes several hours. It is believed that infusions have to be carried out at least once or twice a month in Alzheimer's patients.

Is IVIg safe?
Several hundred thousand persons have received IVIg over the years, and it is generally well-tolerated. There may be added risks to its use in elderly individuals with Alzheimer's, but many older persons have received IVIg without difficulty.

Because it is derived from human blood, IVIg carries with it a very small risk of communicable diseases such as Hepatitis and HIV. However, in the United States there have been no documented cases of transmission of these diseases by IVIg over the past 10 years.

Other possible risks relating to use of IVIg include kidney failure, stroke, lung problems, heart failure, allergic reactions and other problems. The likelihood of these complications occurring can be reduced by screening out persons who have known risk factors and administering the IVIg in modified forms.

Is IVIg costly?
IVIg is very expensive compared to medications currently in use to treat Alzheimer's disease. One month of treatment typically costs $5000 - $10,000 – including the expense of the IVIg itself, the infusions and other costs.

How effective is IVIg in Alzheimer's?
So far, only two clinical studies have been carried out examining the effects of IVIg in Alzheimer's disease at a mild to moderate stage of the illness. Collectively, a total of 13 patients were treated in these two studies, which is too small a number to establish whether or not the treatment works. IVIg was well-tolerated by the AD patients treated and none were noted to decline in their thinking abilities over 6 months of treatment. A majority of the patients improved on simple measures of thinking ability.

Many more persons with Alzheimer's will need to be treated in blinded studies that incorporate placebo controls before the usefulness of IVIg can be determined.

There are different "brands" of IVIg. Are they all the same?
The various manufacturers of IVIg use different preparation processes, which could affect the usefulness of their product for treating Alzheimer's. The various brands of IVIg have not yet been compared in actual Alzheimer clinical trials, so it is not known whether they are all equivalent. Products made by Baxter Healthcare and Octapharma have been tested and both yielded positive effects.

How long will IVIg need to be given if it proves effective in treating Alzheimer's?
It is not known how long treatment will need to be continued at this time.

Can my doctor prescribe IVIg for Alzheimer's?
In theory, since IVIg is commercially available, it can be prescribed by a licensed physician. However, since the optimal dosing, preparation and patient for this treatment have yet to be determined, it is not recommended that physicians use IVIg for this purpose at this time except in experimentally controlled clinical studies (trials). Since it is not approved to treat Alzheimer's disease, Medicare and third-party payers may choose not to pay for this treatment.

How can I get involved in a study of treatment with IVIg for Alzheimer's?
A Phase I study is underway at the Weill Cornell Medical College in New York but is closed for enrollment. Phase II studies are currently being planned and new patients for that study will be recruited in 2005. If you or someone you know wishes to be considered for such a trial, please contact Basia Adamiak at [email protected].