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AAIC 2013 press room, July 13-18: 617.954.3414

Additional Results from Phase 3 Trial of IVIG in Alzheimer's Reported at Alzheimer's Association International Conference

BOSTON, July 16, 2013 – Additional analyses from a negative Phase 3 clinical trial of IVIG (intravenous immunoglobulin) in people with mild to moderate Alzheimer's disease were reported today at the Alzheimer's Association International Conference® 2013 (AAIC® 2013) in Boston.

"We learn more about Alzheimer's disease from every study," said Maria Carrillo, Ph.D., Alzheimer's Association vice president of Medical and Scientific Relations. "Even negative trials provide critical information to the research community for application in future studies to help us find better treatments, which are so desperately needed."

In May 2013, Baxter International announced topline results of the first Phase 3 clinical trial of IVIG as an add-on to established therapy in people with mild to moderate Alzheimer's disease, known as the Gammaglobulin Alzheimer's Partnership (GAP) Study. The drug did not meet either of its primary endpoints.

"These results show us exactly why drugs, in particular those that are approved for one disease that are being tested for another, must go through the very thorough FDA approval process," said Mary Sano, Ph.D., Director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine, Bronx, NY, and a member of the executive committee for the GAP Study. "The FDA process protects people from misguidedly using drugs that are not effective and may be very costly."

Dr. Sano is a member of the Alzheimer's Association Medical and Scientific Advisory Council.

Updated Results from the GAP Phase 3 Trial of IVIG in Mild to Moderate Alzheimer's

In their topline announcement in May 2013, the GAP Study researchers reported that the results were negative on the main outcome measures, which were two well-established tests of cognition and daily functioning – the ADAS-Cog and ADCS-ADL. At the same time, they reported favorable cognitive changes in two pre-specified subgroups: people with Alzheimer's who carried the APOE-e4 Alzheimer's risk gene and those who were moderately impaired. According to the data presentation, the study was not powered to show statistical significance in the subgroups.

At AAIC 2013, Norman Relkin, M.D., Ph.D., of Weill Cornell Medical College and the Cornell Memory Disorders Program, and lead investigator of the GAP study, reported for the first time on additional analyses, including cognitive and biomarker tests. For cognition, the researchers found that study participants in the APOE-e4 carrier subgroup receiving IVIG 400mg/kg/2wk (n=87) had numerically superior results at 18 months relative to placebo on the Modified Mini-Mental State (3MS) Examination (n=66) and the Trails B test (n=77), two out of several measures of thinking ability made in the study.

"Though 3MS and Trails B were not the primary outcome measures in the study, they are well-established cognitive measures and, therefore, may suggest other ways to measure change in future Alzheimer's disease clinical trials," Relkin said.

Biomarker analyses demonstrated that antibodies from the treatment reached the central nervous system. The researchers found:

"It is important to say that the GAP study results do not provide grounds for prescribing IVIG in Alzheimer's disease, even with this positive signal in the APOE-e4 carriers, further confirmatory studies would be needed before clinical use could be recommended," Relkin said.

"The primary clinical outcomes are unequivocally negative, but there are signals in the clinical and biological markers in some subgroups. With the understanding that we cannot draw conclusions about IGIV's effectiveness in these subgroups from these results alone, the effects of IVIG on beta-amyloid and antibody levels in the blood and brain are noteworthy. These results support that IVIG can target beta amyloid and that the antibodies it contains can reach the brains of people with Alzheimer's when administered through the bloodstream."

"Research should continue in people with mild to moderate Alzheimer's; the field should not focus exclusively on early intervention strategies," said Relkin.

The Gammaglobulin Alzheimer's Partnership (GAP) Study was a Phase III, randomized, double-blind, placebo-controlled clinical trial in 390 people with mild to moderate Alzheimer's disease, conducted at 45 centers in the U.S. and Canada. Two different doses of IVIG were tested versus placebo as add-ons to approved Alzheimer's medications. The drug was administered every two weeks for 18 months. Primary study endpoints were changes on two well-established tests of cognition and daily functioning – the ADAS-Cog and ADCS-ADL. The GAP study was conducted by Baxter and the Alzheimer's Disease Cooperative Study, a clinical trial consortium supported by the National Institute on Aging at the National Institutes of Health. Baxter studies of IVIG in mild to moderate Alzheimer's disease were discontinued after the announcement of topline results in May.

APOE-e4 is one of three naturally occurring forms of the APOE gene; the others are APOE-e2 and APOE-e3. Everyone inherits a copy of some form of APOE from each parent. Those who inherit one copy of APOE-e4 have an increased risk of developing Alzheimer's disease. Those who inherit two copies have an even higher risk, but not a certainty. Risk genes increase the likelihood of developing a disease, but do not guarantee it will happen. Researchers have found several genes that increase the risk of Alzheimer's. APOE-e4 is the first Alzheimer's risk gene identified, and remains the gene with strongest impact on risk.

Despite the negative results of the Phase 3 IVIG trial, and because of the successes of IVIG in animal models of Alzheimer's and early stage trials in people, researchers continue to pursue how IVIG may work in the brain to inform ongoing Alzheimer's therapy research.

IVIG reduces tau pathology in a mouse model of Alzheimer's disease

"IVIG may help clear brain amyloid to prevent amyloid plaque buildup, but the poor results so far of clinical trials targeting amyloid raise the possibility that IVIG acts in a different way. Therefore, we tested whether IVIG might target the other characteristic lesion of the Alzheimer's brain, the neurofibrillary tangle," said Scott Counts, Ph.D., of Rush University Medical Center, Chicago.

Counts and colleagues at Rush tested whether IVIG alters the expression of tau tangle-like deposits in the brains of a transgenic mouse model of Alzheimer's that displays tangles as it ages. Three month old mice were treated intravenously with either IVIG or saline every two weeks for either three months or six months. The brains of these mice were then examined to see if IVIG reduced tangle build-up.

"Our preliminary data suggest that IVIG may reduce Alzheimer's-like tangle pathology and increase neuroprotective gene expression in a mouse model of Alzheimer's disease," Counts said.

IVIG may make neurons less vulnerable to damage from reactive oxygen species

In an effort to uncover the mechanism(s) by which IVIG might provide benefit, Debomoy Lahiri, Ph.D., of the Indiana University School of Medicine, and colleagues recently showed that treatment of degenerating rat brain cells with IVIG in a test tube protected the structure of the cells and enabled them to survive longer. They hypothesized that IVIG treatment might also preserve and protect human brain cells.

Lahiri and colleagues created primary human fetal brain neuron (HFN) cultures and treated them with several different doses (5-20mg/ml) of IVIG for 72 hours. The cell cultures were then exposed to reactive oxygen species (ROS) for 24 hours. Separate HFN cultures were treated with different doses of IVIG (5-20mg/ml) but not exposed to ROS.

Reactive oxygen species (ROS) are molecules that form as a natural byproduct of the normal metabolism of oxygen; they have important roles in communication between cells and keeping the body's internal environment stable (homeostasis). However, during times of environmental stress, ROS levels can increase dramatically. This can cause significant damage to cells; it is known as oxidative stress.

The scientists observed that IVIG pre-treatment (10 and 20mg/ml) provided significant protection to brain cells that were subsequently exposed to ROS. They also observed significant increase in cell viability in the neurons when they were treated with 10 and 20mg/ml doses of IVIG alone for four days.

"Our results suggest that IVIG treatments may make neurons less vulnerable to damage from reactive oxygen species," Lahiri said. "Since preventing brain cell loss in Alzheimer's is an important goal of therapy, our results suggest that IVIG may be beneficial for preserving and protecting neurons against oxidative damage."

"This is particularly important because we know that beta amyloid deposits in the Alzheimer's brain indirectly lead to the generation of ROS, including free radicals, that damage and destroy brain cells," Lahiri added.

About AAIC

The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association

The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800-272-3900.

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Proposal ID: 39689
Topic: Therapeutics     Subtopic: Clinical Trials
Presentation: Oral session, Tuesday, July 16, 2013, 2:15 pm ET

Results of the GAP 160701 Study: A Phase 3 Clinical Trial of Intravenous Immunoglobulin for Mild to Moderate Alzheimer's Disease - Norman Relkin on Behalf of the ADCS and Baxter Gap 160701 Study Group

Presenting Author: Norman Relkin (nrelkin@med.cornell.edu), Weill Cornell Medical College and the Cornell Memory Disorders Program.

Background: The Gammaglobulin Alzheimer's Partnership (GAP) 160701 Study is a pivotal Phase 3 clinical trial testing the safety and efficacy of Gammagard® IGIV for the treatment of mild to moderate Alzheimer's disease (AD). This presentation provides the final outcomes of the GAP trial.

Methods: All subjects met NINDS-ADRDA criteria for Probable AD (MMSE 16-26 inclusive). Subjects and their study partners consented to participate in the IRB approved protocol. Subjects were randomly assigned to receive intravenous infusions of IGIV 10% at a dose of 0.4 grams/kilogram/2 weeks or 0.2 grams/kilogram/2 weeks or a low dose albumin placebo. The study medication was administered for 18 months (36 infusions) as an add-on to conventional FDA-approved AD medications. Randomization was balanced for baseline MMSE score and APOE genotype. All subjects underwent clinical outcome and safety assessments as well as serial plasma collection and neuroimaging with MRI. Subsets of participants consented to sub-studies involving collection of CSF, FDG PET or AV-45 PET. The co-primary outcomes were the 18 month change from baseline on the ADAS-Cog and ADCS-ADL. The primary analysis was performed on the Intent-to-Treat cohort. In addition, a completer analysis was performed that included all randomized subjects who completed at least 90% of planned infusions.

Results: A total of 732 persons were screened. 390 persons meeting NINDS-ADRDA criteria for Probable Alzheimer's Disease were randomized. 279 subjects (72.3%) completed 18 months of treatment. An additional 22 subjects (5.1%) discontinued study medication before 18 months but completed evaluation visits through month 18. The remaining 88 subjects (22.6%) discontinued study medication and evaluation visits prior to 18 months. Mean age of the study participants was 70.3 years (range 50-89), including 213 females and 177 males. The mean baseline MMSE score was 21.3. At time of enrollment, 381 subjects were receiving cholinesterase inhibitors and 283 were taking memantine. More than 14000 infusions were provided to subjects collectively over the course of the study. The last study visit was completed in December 2012.

Conclusions: Final study outcomes will be presented at the AAIC meeting.



Proposal ID: 37653
Topic: Basic Translational Science     Subtopic: Molecular and cell biology
Presentation: Poster session, Monday, July 15, 2013, 11:45 am ET

IVIG reduces tau pathology and increases neuroplastic gene expression in the 3xTg mouse model of Alzheimer's disease

Presenting Author: Scott Counts (scott_e_counts@rush.edu)
Scott Counts, Sylvia Perez, Elliott Mufson, Rush University Medical Center, Chicago, Illinois, United States.

Background: Current FDA-approved treatments for Alzheimer's disease (AD) offer short-term clinical benefits but fail to alter disease progression. Phase III trials testing the efficacy of Abeta immunotherapy have not improved cognition in people with mild AD. More recently, intravenous immunoglobulin (IVIG) treatment has emerged as an alternative AD immunotherapy. In this regard, placebo-controlled, double blind phase II clinical trials with IVIG demonstrated good tolerability and improved cognitive outcomes in patients with mild/moderate AD. However, the mechanisms underlying the effect of IVIG upon cognitive outcomes remain unknown. IVIG contains antibodies to Abeta causing a shift of Abeta protein concentration from the cerebrospinal fluid to blood, suggesting a brain amyloid clearance mechanism. However, the suboptimal results of clinical trials of anti-amyloid monoclonal antibodies raise the possibility that IVIG acts via an amyloid-independent mechanism.

Methods: We tested whether IVIG alters the expression of tau neurofibrillary tangle (NFT)-like deposits within hippocampal CA1 neurons of the 3xTg mouse model of AD. Three month old mice were treated intravenously with either IVIG (10%, 400 mg/kg) or saline every two weeks for either three months or six months. At sacrifice, blood was drawn for plasma gene expression profiling and brains processed for immunohistochemistry using the AT-180 antibody, which recognizes the T231 tau phosphorylation event involved in NFT formation.

Results: Preliminary quantitative densitometric analysis of CA1 neurons following three months of treatment revealed a small but significant ~15% decrease in AT-180 immunoreactivity with IVIG compared to saline-treated 3xTg mice (p < 0.01, n = 10/group). Expression profiling studies showed that IVIG treatment resulted in a 40-50% increase in plasma levels of several modulators of neuronal plasticity, including synaptophysin, homer-1, nestin, and neurofilament-H (p < 0.05, n = 6/group).

Conclusions: Preliminary data suggest that IVIG reduces hippocampal NFT pathology and up-regulates neuroplastic gene expression in the 3xTg mouse model of AD.



Proposal ID: 39290
Topic: Therapeutics     Subtopic: Others; Neurogenesis
Presentation: Poster session, Wednesday, July 17, 2013, 11:45 am ET

Effect of IVIg in Preserving Human Primary Neurons & Protecting Them Against Oxidative Stress

Presenting Author: Debomoy Lahiri (dlahiri@iupui.edu)
Debomoy Lahiri, Balmiki Ray, Indiana University School of Medicine, Indianapolis, Indiana, United States

Background: Neurons in Alzheimer's disease are more vulnerable to toxic stimuli, including reactive oxygen species (ROS). A promising treatment strategy for AD is to preserve and protect neuronal cells from oxidative damage. We have recently shown that treatment with intravenous immunoglobulin (IVIg) protects neuronal viability and synaptic proteins in degenerating primary rat hippocampal neurons. We hypothesized that IVIg treatment would preserve, protect and increase human neurons. Here, we report a potent neuropreservatory effect of IVIg against ROS-mediated neuronal damage in primary human fetal brain neuron (HFN) cultures.

Methods: HFNs were cultured (Long et al., JBC-2012) and treated with different doses (5-20mg/ml) of IVIg (Gammagard, Baxter) for 72 h. Glycine and Buminate (Baxter) were added to the cultures separately as vehicle and placebo, respectively. Following IVIg treatments, media were removed, and fresh media with 50µM H2O2 (ROS), without the addition of IVIg, was added into the wells. Cells were harvested after 24 h of ROS exposure, and morphology recorded by imaging and immunocytochemistry (ICC). Separately, HFN cultures were treated with different doses of IVIG (5-20mg/ml) along with the vehicle and placebo. Effects of IVIg alone on neurons were assessed by cellular viability assay (CTG), and on cellular morphology/neurite lengths by ICC.

Results: We succeeded in growing viable HFN cultures from the human fetal brain as assessed by ICC. We observed that IVIg (10 and 20mg/ml) pre-treatment provides significant protection to neurons subsequently challenged with ROS. We also observed significant increase in cell viability in the neurons when they were independently treated with 10 and 20mg/ml doses of IVIg for four days, suggesting increased metabolic activity of exiting neurons or increased neuronal mass.

Conclusion: IVIg treatments make neurons less vulnerable to ROS-mediated damage. Pre-treatment with IVIg alone protected neurons when they were post-treated with ROS. We also observed increased viability of neurons following IVIg treatments. IVIg increases metabolic activity and perhaps the number of viable neurons. Since preventing neuronal loss in AD is an important goal to obtain therapeutic efficacy, our results suggest that IVIg is beneficial for preserving and protecting neurons against oxidative insult and for its effect on increased neuronal viability.

(Acknowledgments: We sincerely thank Dr. Michelle Gilmor for her advice and Nipun Chopra for technical help, and Baxter for research support.)

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Make history at AAIC 2013 • Boston, MA • July 13-18, 2013