>…I think IVIG treatment is ridiculous. All IVIG is is purified immunoglobin g. There's no selection for specificity. In other words you get a grab bag of IgG.<
“Winnowing out the particular antibodies within Gammagard that work best could be key for fashioning a new Alzheimer's weapon from Baxter's drug. There is no way supplies could meet the demand of the vast and growing Alzheimer's population, according to researchers. But it may be possible to isolate the effective antibodies and manufacture them through other means.”
CHICAGO, April 17 /PRNewswire-FirstCall/ -- New York-Presbyterian Hospital/Weill Cornell Medical Center and Baxter International Inc. (NYSE: BAX ) announced results of a six-month, placebo-controlled Phase II study of 24 patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID [Immune Globulin Intravenous (IGIV)] for the treatment of mild-to-moderate Alzheimer's disease today at the American Academy of Neurology (AAN) annual meeting in Chicago. The study met the primary endpoint criteria favoring GAMMAGARD LIQUID and GAMMAGARD S/D over placebo on measures of cognitive function and global impression of change, which are common measures of outcome in Alzheimer's disease clinical trials. The study also met secondary endpoints that measured changes in beta-amyloid and anti-amyloid antibody levels in blood and cerebrospinal fluid. Results show findings indicative of potential efficacy and tolerability. Key findings throughout six months included: measurements of clinical outcome, behavioral outcome and cognitive performance in Alzheimer's patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID compared to placebo. Twelve-to-18 month data will be available later this year.
Secondary endpoint results suggest that levels of antibodies against beta-amyloid were observed to have increased in the blood and cerebrospinal fluid of patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID, while the levels of beta-amyloid increased in the blood. Beta-amyloid is a substance thought to contribute to the degeneration of the brain in Alzheimer's disease. Clearing this substance from the central nervous system, therefore is hypothesized to help remove or reduce the building blocks of Alzheimer's.
The primary and secondary endpoint data were reported by the lead researcher for the trial, Dr. Norman Relkin, director of the Memory Disorders Program and behavioral neurologist and neuroscientist at New York-Presbyterian/Weill Cornell Medical Center, and associate professor of clinical neurology at Weill Cornell Medical College in New York City.
"This was the first placebo-controlled clinical trial of GAMMAGARD for Alzheimer's disease and the results are clearly promising," Dr. Relkin commented.
Baxter supported the study and provided GAMMAGARD LIQUID and GAMMAGARD S/D for the trial. GAMMAGARD S/D and GAMMAGARD LIQUID, marketed as KIOVIG in the European Union, contain a broad spectrum of immunoglobulins (antibodies) and are indicated as an immunoglobulin replacement therapy that boosts the immune system in patients with primary immunodeficiency disorders. The precise mechanisms of GAMMAGARD S/D and GAMMAGARD LIQUID's effects in Alzheimer's disease are not known.
"These study results reflect Baxter's support of innovative science and commitment to meeting a critical, unmet medical need," said Hartmut J. Ehrlich, MD, vice president of global research and development for Baxter's BioScience business. "While results of Baxter's mid-stage development work in Alzheimer's disease treatment are promising, further investigation in a larger Phase III study is required."
Phase II Study Design
In the double-blind, placebo-controlled Phase II study, 24 patients in the United States with mild-to-moderate Alzheimer's disease, who were maintained on standard treatment therapy, were randomly assigned to receive GAMMAGARD LIQUID (eight patients), GAMMAGARD S/D (eight patients) or saline placebo (eight patients) for six months. The study included a comparison of four dosing regimens of GAMMAGARD, with doses ranging from 0.2 g/kg every two weeks to 0.8 g/kg every month. The safety and tolerability of the treatment and clinical outcomes of 24 patients were assessed at the beginning of the study and after three and six months. The study is an ongoing, open-label study extended to 18 months to examine the long-term effects of the treatment.
Cognitive, behavioral and functional measures were collected at baseline, three months and six months of treatment. The primary endpoints of the Phase II trial were cognitive function (as measured by the ADAS-cog) and global impression of change (as assessed by the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) change rating). The secondary endpoints measured changes in beta-amyloid and anti-amyloid antibody levels in blood and cerebrospinal fluid. Safety and tolerability of GAMMAGARD S/D and GAMMAGARD LIQUID treatment in Alzheimer's patients were also assessed relative to placebo.
Phase II Study Results
In August 2007, Baxter and New York-Presbyterian/Weill Cornell announced preliminary Phase II results based on six-month data, indicating the study provided encouragement to carry out a Phase III trial. The criteria for going forward with a Phase III trial were favorable outcomes in GAMMAGARD S/D and GAMMAGARD LIQUID-treated patients relative to those given placebo. The final results of the study re-affirm the decision of Baxter and the ADCS to pursue a multi-center, Phase III study evaluating the role of GAMMAGARD LIQUID for the treatment of patients with mild-to-moderate Alzheimer's disease. The decision was based on results of two completed, open-label clinical studies and the preliminary six-month interim analysis of the Phase II trial.
The Phase II study follows an earlier Phase I study in eight patients carried out at New York-Presbyterian/Weill Cornell that was published in the journal Neurobiology of Aging in February 2008.
Cognitive Function and Global Impression of Change Findings (Primary Endpoints)
After six months, the group of patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID averaged 1.52 points higher than placebo-treated patients (+0.27 versus -1.25) on the ADCS-CGIC score, a commonly used measure of outcome in Alzheimer's disease clinical trials. The ADCS-CGIC is used in Alzheimer's trials to assess clinically relevant overall changes in Alzheimer's disease patients determined by patient and caregiver interviews.
Patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID had fewer behavior-related adverse events during the six-month trial and had a more favorable behavioral outcome as measured by the Neuropsychiatric Inventory, a scale used to measure behavioral problems in Alzheimer's patients. The average change in ADAS-Cog score -- a common cognitive testing measure -- at six months of treatment was numerically improved in patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID than placebo (-0.38 versus +2.61), although this difference did not reach statistical significance in the relatively small number of patients studied.
Levels of Beta-Amyloid (Secondary Endpoints)
Dr. Relkin also reported observations that levels of antibodies against beta-amyloid increased in the cerebrospinal fluid and blood of patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID, while the levels of beta-amyloid in the blood increased. The antibody and beta-amyloid levels were assessed using ELISA immunosorbant assay, a method used to detect antibodies, and observations were analyzed using parametric statistical analysis.
Tolerability
The study also met its endpoint in assessing the tolerability of GAMMAGARD S/D and GAMMAGARD LIQUID in Alzheimer's patients. The only treatment-related adverse events that occurred at a greater frequency with GAMMAGARD S/D and GAMMAGARD LIQUID treatment as compared to placebo were rash and a transient drop in blood count (in most cases, hemoglobin (Hgb) levels returned to within 1 Hgb unit of baseline within three to six months).
Dr. Lisa Mosconi, assistant professor of psychiatry at New York University Medical Center, worked with the New York-Presbyterian/Weill Cornell group on the analysis of brain imaging data from the study and also presented findings at the AAN meeting. She reported that GAMMAGARD-treated participants had observable changes in brain metabolism. While energy metabolism in the brain was an exploratory endpoint in the study it was preserved or improved in 10 out of 13 patients after six months of GAMMAGARD S/D and GAMMAGARD LIQUID treatment.
"Brain metabolism usually decreases progressively in patients with Alzheimer's disease," said Dr Mosconi. "The changes on PET scans of these Alzheimer's patients after six months of GAMMAGARD S/D and GAMMAGARD LIQUID are encouraging."
The Phase II study also evaluated brain metabolism in patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID compared to those who received placebo based on 18F-fluoro-deoxyglucose Positron Emission Tomography (PET) (FDG-PET) scans, which are sometimes used in the diagnosis of Alzheimer's disease. Across brain regions usually affected by Alzheimer's disease, in this study the GAMMAGARD S/D and GAMMAGARD LIQUID groups were observed to show 16 percent higher brain metabolism after treatment compared to placebo (12-18 percent increase in the hippocampi, 14-17 percent increase in parieto-temporal cortices and 21-24 percent increase in the thalami).
Phase III Study
The Phase III study is sponsored by the National Institutes of Health (NIH) and Baxter. The study protocol was submitted to the U.S. Food and Drug Administration for review, with the intention of initiating patient recruitment later in 2008. The trial will include approximately 35 leading academic centers in the United States that are members of the Alzheimer's Disease Cooperative Study (ADCS). The involvement of the ADCS and NIH in the conduct of the Phase III trial will ensure the highest level of independent scientific evaluation of the potential role of GAMMAGARD S/D and GAMMAGARD LIQUID in the treatment of Alzheimer's. <<
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