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Samson, Kurt

doi: 10.1097/01.NT.0000434606.56800.f2
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Investigators reported that, in a phase 3 trial, intravenous immunoglobulin in either of two doses did not result in any statistically significant difference in the rate of cognitive decline, compared with the placebo group.

An eagerly awaited phase 3 clinical trial of intravenous immunoglobulin (IVIG) did not meet its endpoints of reducing cognitive decline and preserving functional abilities in mild to moderate AD patients. However, preliminary observations did demonstrate encouraging signs in two small subgroups of participants.

Final results of the Gammaglobulin Alzheimer's Partnership (GAP) Study were presented in mid-July at the Alzheimer's Association International Conference (AAIC) in Boston.

GAP was a randomized, 18-month, double-blind, placebo-controlled trial involving 390 people that was conducted at 45 centers in the US and Canada. A total of 275 subjects completed the trial, while 22 discontinued treatment but were evaluated for the length of the study.

Two different doses of IVIG were tested — 400 mg/kg or 200 mg/kg — for 18 months. One group received the higher dosage, one the lower, and the third a placebo. Compared with the placebo group, treatment with either dose did not result in any statistically significant difference in the rate of cognitive decline, however antibodies from treatment did reach the central nervous system. IVIG had no effect on tau and phosphorylated tau levels.

Subgroup analysis indicated a dose-dependent reduction in amyloid-beta in the blood and brains of a small group of patients with the apolipoprotein E4 (APOE4) genotype, and some patients with mild dementia did not decline as rapidly on cognitive tests as untreated subjects. The study was not powered to show statistical significance in these subgroups, but the researchers said they are considering additional trials limited to such patients.

The US Food and Drug Administration (FDA) has approved IVIG as a treatment for a number of disorders, ranging from blood cancer to Kawasaki disease, but it has not been approved for AD.

AD patients, their families, and the medical community had followed the trial closely because the phase 2 trial found treatment was well tolerated and some patients showed significant improvement in cognition and global clinical measures of AD. These findings were presented at the annual meeting of the American Academy of Neurology in April 2010.

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At a news conference, principal investigator Norman Relkin, MD, PhD, director of the Memory Disorders Program at Weill Cornell Medical College, was asked why the subgroup analyses showed some treatment benefits, but not the entire study population. He said that there are three possible explanations.

“I think it was the luck of the draw,” he said. “First, I believe that in the phase 2 study we had more APOE4 carriers. Second, in large trials there is always the likelihood that not all subjects actually had AD, but rather dementia due to other causes.”

Other unidentified biomechanisms could also be involved, he continued, or APOE4 might interfere with other antibodies in the cerebrospinal fluid.

The third possibility is that it was “a statistical fluke” caused by unique characteristics of the subjects selected for the study. It is too soon, however, to plan a follow-up trial with restricted subjects matching the profile of those in the subgroups that did show signs of a positive response.

“I believe what we have shown is just the tip of the iceberg. We are looking closely at the data, but it is going to be some time before we know how to go forward with a trial in the two subgroups. I am still optimistic that there are signals in this study that are worth further study.”



He added that the patients who did respond in the phase 2 study are still doing well, and some have been followed for more than eight years.

“Our results suggest that IVIG can target amyloid-beta and that the antibodies it contains can reach the brains of people with AD when administered through the bloodstream.”

He cautioned, however, that the subgroup analyses do not provide grounds for prescribing IVIG in AD patients who are APOE4 carriers.

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Reisa Sperling, MD, professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital in Boston, was disappointed not only with GAP but also with the fact that other phase 3 trials of potential AD therapies have also proven negative or even harmful.

“I can say that I am disappointed that another phase 3 trial failed to meet its endpoint, but I never thought it was practical given that it had to be administered every two weeks and supplies of IVIG are limited,” she told Neurology Today in a telephone interview.

Dr. Sperling is a researcher with the Harvard Aging Brain Study at Massachusetts General Hospital's Memory Disorders Unit and is also part of the Alzheimer's Disease Cooperative Study, which was involved in the trial; however, her laboratory was not a GAP research site.

She noted that even the in the subgroup analyses in the moderate group with the APOE4 gene, the response was not that robust.

“None of the findings support treatment of AD patients with IVIG, and in order to launch a phase 3 trial in the subgroups they will need to look closely at the data again and determine whether there is enough evidence to support such a study.”

She also pointed out that some patients with AD dementia do not have amyloid-beta and do not decline as rapidly as typical AD patients with APOE genes. Still others have amyloid-beta but no dementia.

“All of this adds noise as we try to understand this disease. There are therapies targeting amyloid-beta, but if a patient does not have evidence of amyloid-beta or tau we still need to understand what is going on.”

Even negative results help provide insights of its utility in even small groups of patients, she added, saying she and other researcher will continue studying the effects of IVIG.

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Michael W. Weiner MD, director of the Center for Imaging of Neurodegenerative Disease at the University of California, San Francisco, said the concept of using IVIG remains viable.

“This is an exciting avenue for investigation, not only because it is already approved by the FDA for other disorders, but because it targets amyloid-beta,” he told Neurology Today, adding that it would also sidestep the need to find safer monoclonal antibodies. Several promising monoclonal antibodies to amyloid-beta have shown promise in early trials, but later caused immune system problems, some of them severe.

“Everyone is disappointed,” Dr Weiner told Neurology Today in a telephone interview. “Dr. Relkin has played a central role in studying IVIG in AD patients.The secondary subgroup analyses showed some benefits, especially in individuals with the APOE gene, but such analyses are ‘very common’ in clinical trials when a study fails to meet its primary endpoints.”

“Researchers often find some subgroups that did respond, which I guess it is the ‘glass half full or half empty’ phenomenon,” he said. “But this is no reason for any AD patient with the APOE4 phenotype to go out seeking IVIG treatment.”

He also noted that there is no guarantee that another phase 3 trial limited to these subgroups will yield positive results.

“If another trial can be conducted and the preliminary findings can be replicated it would be encouraging, but very often when a subgroup analysis shows some benefits in one trial, they cannot be reproduced again.”

The GABP study was conducted by Baxter in collaboration with the Alzheimer's Disease Cooperative Study (ADCS), a clinical trial consortium supported by the National Institute on Aging.

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Researchers not involved with the phase 3 trial of IVIG for Alzheimer's disease said despite its failure to meet primary endpoints, they were encouraged to keep exploring the viability of the therapy, based on promising work in animal models. Several other researchers presented findings at the Alzheimer's Association International Conference in mouse models of Alzheimer's disease (AD) and in human embryonic neurons that offer new insight into the ability of IVIG to protect the brains of patients with AD. The investigators include evidence that it may help reduce hippocampal neurofibrillary tangle pathology while increasing neuroplastic gene expression, and found signs that it can protect human fetal neuron cells against oxidative stress.

Scott Counts, PhD, assistant professor of neurological sciences at Rush University Medical Center in Chicago, presented a preliminary analysis of CA1 neurons in mice with amyloid-beta, tau, and neurofibrillary tangles that were treated with IVIG for three months.

He reported a 15 percent decrease in activation of an antibody that reacts to the tau phosphorylation event involved in formation of tangles among treated mice. Further analysis showed a 40-50 percent increase in plasma levels of several modulators of neuronal plasticity, including synaptophysin, homer-1, nestin, and neurofilament-H.

“Our findings, although preliminary, suggest that IVIG reduces hippocampal NFT [neurofibrillary tangle] pathology while up-regulating neuroplastic gene expression in this model of AD,” Dr. Counts told Neurology Today.

“IVIG is like a black box. It seems to have some protective effect on neurons, but what is the mechanism? That is the question.”

In another study, Debomoy Lahiri, PhD, a researcher at Indiana University School of Medicine's Stark Neuroscience Institute in Indianapolis, reported that IVIG provided a protective and restorative effect when cultures of human embryonic progenitor neurons were exposed to oxidative stress.



Neuronal growth, recovery, and restoration were observed when these nascent neurons were treated with IVIG either before, during, or after being challenged with reactive oxidative species, which mimic the cellular stress of oxygen free radicals in the body. As people age they are more vulnerable to damage from oxygen free radicals, including damage to neurons and synaptic proteins.

The team found that IVIG was well tolerated, preserved the challenged cells, rescued those in distress, and allowed for normal neurogenesis — the progenitor cells were able to grow into mature neurons.

This increase in neuronal viability suggests that IVIG increases metabolic activity and perhaps the number of viable neurons, Dr. Lahiri told Neurology Today.

“Our results suggest that IVIG is beneficial in preserving and protecting neurons against oxidative insult as well as benefiting neuronal viability,” Dr. Lahiri noted. “The next step is to investigate the exact mechanisms by which IVIG saves that [neuronal viability] that allows these neurons to mature.”

Kurt Samson

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•. AAIC abstracts/releases on IVIG for Alzheimer's disease — clinical and basic research:
    •. Pubmed archive on IVIG for Alzheimer's disease:
      © 2013 American Academy of Neurology