IN PRELIMINARY STUDY, IVIG SHOWS PROMISE FOR ALZHEIMER DISEASE
MIAMI BEACH—Intravenous immunoglobulin (IVIg) shows promise for halting – and perhaps even reversing – the cognitive decline of Alzheimer disease, a preliminary dose-finding study suggests. But the six-month phase I trial was performed in just eight patients and it is way too soon to even think about recommending the treatment to patients, the researchers stressed.
“Our small study suggests that this already approved antibody product may be useful for treating Alzheimer disease,” said Norman R. Relkin, MD, Director of the Memory Disorders Program at New York-Presbyterian Hospital/Weill Cornell Medical Center in New York City.
Reporting here at the AAN Annual Meeting, Dr. Relkin said that cognitive function improved in six of seven Alzheimer disease patients given IVIg for six months.
Dr. Relkin said his group was interested in IVIg because, as a product prepared from pooled human blood, it contains a high level of anti-amyloid beta antibodies. Alzheimer disease patients have low levels of these anti-amyloid antibodies in their circulation, compared with healthy people of the same age, he said. The anti-amyloid antibodies attack and latch onto beta amyloid, drawing the proteins out of the blood and blocking the toxic burden of amyloid on brain cells, he explained.
A DOSE FINDING STUDY
In the phase I, dose-finding study, the researchers gave IVIg to eight patients, including a man who had been diagnosed with mild to moderate Alzheimer disease. The patients, whose average age was 74 years old, had an average score of 23.5 points on the 30-point Mini-Mental Status Examination (MMSE) scale.
The patients were randomized to receive one of four dosing regimens: 0.4 g/kg every two weeks, 0.4 g/kg every week, 1.0 g/kg every two weeks, or 2.0 g/kg every month.
Anti-amyloid antibody levels increased significantly in plasma after each IVIg infusion in a dose-dependent fashion. Also, anti-amyloid antibody levels rose incrementally with successive treatments, the study showed.
Of the seven patients who completed six months of treatment, none have shown a decline in cognitive function and six improved in cognitive function, Dr. Relkin said.
“This is fairly dramatic as we would have expected a decline in cognitive function over six months,” Dr. Relkin said. “In six months, one would expect a 1.5-point decline in MMSE scores. Our patients showed a 3-point increase.”
“IVIg is helping to stabilize and even improve cognitive status,” he said. The participants experienced only minor and infrequent side effects, such as chills following the infusion.
The study was funded primarily by Baxter Bioscience, which manufactures IVIg as Gammagard, with support from several other organizations, including the NIH and the Alzheimer's Association. A separate study in Germany, in which five patients were given IVIg, showed similar results, he said (J Neurol Neurosurg Psychiatry 2004; 75: 1472–1474).
Together, the two small studies “give us strong encouragement,” Dr. Relkin said. But, he stressed, “We want to be cautious, these preliminary data do not provide a rationale for treating Alzheimer patients with IVIg.”
For starters, no one knows how long a person has to stay on the treatment, he said. MMSE scores went back to baseline in two of three patients taken off IVIg for a washout period, he said. “You may have to take IVIg for life or at least a critical amount of time to clear the amyloid.”
Also, since IVIg is derived from pooled blood, the supply is limited. The cost is high – nearly $7,000 a year at the doses used in the study – about the same as dialysis for people with failing kidneys, he said.
A phase Ib study is now evaluating the long-term effects of the treatment, he said. Dr. Relkin said investigators have reason to believe that there may be multiple types of antibodies within IVIg that exert therapeutic effects in Alzheimer disease. “We are trying to refine IVIg in the hope of creating a more cost-effective and plentiful future treatment,” he said.
Commenting on the study, other investigators agreed that larger, placebo-controlled studies are needed before any firm conclusions can be drawn.
“Six months and eight patients is not evidence one way or another. Even without treatment some Alzheimer patients do better on tests at six months,” said Lawrence S. Honig, MD, PhD, Associate Professor of Clinical Neurology at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University. Dr. Honig was not involved with the study.
“IVIg is also extremely expensive and not totally without side effects,” he said. “Unless animal data suggest this is a reasonable strategy in Alzheimer disease, it might make more sense to proceed with specific antibody trials.”
Using IVIg – which contains millions of human antibodies in addition to beta amyloid antibodies – to treat the disease is like picking a random book off the shelf and hoping it is the one you want to read, he said.
Dr. Honig and others are getting ready to conduct a manufacturer-sponsored phase II trial of a new compound known as AAB-001, a humanized monoclonal antibody that binds to and clears beta amyloid protein from the blood.
AAB-001, which is being developed by the Elan Corporation and Wyeth Pharmaceuticals, is a synthetic, highly purified preparation of anti-beta amyloid antibodies, he said. “This more targeted passive immunization approach makes a lot more sense.”
ARTICLE IN BRIEF
- ✓ In what was primarily a safety trial of a treatment for Alzheimer disease, six patients who completed six months of treatment with IVIg improved in cognitive function, while none of the patients showed evidence of cognitive decline.