Results Of 9-month Phase II Study Of Gammagard Intravenous Immunoglobulin

The nine-month results show significantly better global outcomes, cognitive performance and daily functioning in patients treated with IGIV compared to initially placebo-treated patients.

Just last April, at the American Academy of Neurology (AAN) meeting in Chicago, the six-month outcomes of the double-blind, placebo-controlled Phase II trial were presented. Now, interim data from the extension of that study show persistence of benefits for Alzheimer's patients treated continuously over 9 months. This is the first study to show persistence of benefits for Alzheimer's from IGIV with continuous treatment for 9 months. Previous studies discontinued therapy after 6 months.

The lead researcher for the trial is Dr. Norman Relkin, a behavioral neurologist and neuroscientist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. Dr. Relkin is director of the Memory Disorders Program at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and Associate Professor of Clinical Neurology at Weill Cornell Medical College in New York City.

Working in collaboration with Dr. Relkin is Dr. Diamanto Tsakanikas, the neuropsychologist for the Phase II study. Dr. Tsakanikas is Clinical Assistant Attending Neuropsychologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and an Instructor of Neuropsychology in the Department of Neurology & Neuroscience at Weill Cornell Medical College.

Baxter International Inc. supported the study and provided GAMMAGARD Liquid and GAMMAGARD S/D for the trial. GAMMAGARD contains a broad spectrum of immunoglobulins (antibodies), and is indicated as an immunoglobulin replacement therapy in patients with primary immunodeficiency disorders.

In the double-blind, placebo-controlled Phase II study, 24 patients in the United States with mild to moderate Alzheimer's disease were randomly assigned to receive GAMMAGARD LIQUID (eight patients), GAMMAGARD S/D (eight patients) or saline placebo (eight patients). In the open-label extension of this study, all patients were treated for a total of 18 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.

Cognitive, behavioral and functional measures were collected at baseline and every three months thereafter. The primary endpoints of the Phase II trial were cognitive function, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale score (ADAS-Cog), and global function, as assessed by the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change rating (CGIC). Safety and tolerability of IGIV treatment in Alzheimer's patients were also assessed relative to placebo. Secondary endpoints included effects on biomarkers related to beta amyloid, a peptide related to Alzheimer's disease.

In today's presentation at ICAD, Dr. Relkin reported that subjects who received uninterrupted IGIV therapy for 9 months demonstrated significantly better cognitive and overall clinical outcomes compared to initially placebo-treated subjects. Dr. Relkin also reported that uninterrupted treatment with IGIV resulted in further improvements in activities of daily living.

Statistically significant differences favoring IGIV treatment were observed on the CGIC at 3, 6 and 9 months. After nine months, the group of patients treated with GAMMAGARD averaged 1.4 points higher than initially placebo-treated patients on the CGIC, a commonly used measure of overall outcome in Alzheimer's clinical trials. At six months, the same group of patients had averaged 1.2 points higher than placebo-treated patients on the CGIC.

On the ADAS-Cog, a test of cognition, change scores numerically favored the IGIV-treatment at 3, 6 and 9 months, with the difference reaching statistical significance at 3 and 9 months. The average change in ADAS-Cog score at nine months of treatment favored treatment with GAMMAGARD by 5.4 ADAS points. The average change in ADAS-Cog score at six months of treatment had favored GAMMAGARD by 2.6 ADAS points. In an analysis by dose arm, subjects receiving 0.4g IGIV/kg/2 weeks improved over baseline on ADAS-Cog scores in 4 of 4 cases at 9 months. None of the subjects given placebo initially showed comparable improvements.

The scientists also measured activities of daily living (ADL) — the actual performance of each subject in common daily activities, as reported by caregivers. ADL is broken down into three increasing levels of severity: 1) independence, 2) supervision/required verbal reminders or instruction, and 3) physical assistance for daily tasks — including eating, toileting, bathing, grooming, dressing, reading, travel and using common household appliances. The research team found that experimental subjects either slightly improved or slightly declined over the study period. However, subjects in the placebo group showed a greater drop in ADL score.

The IGIV group showed minimal decline in carrying out daily tasks and performed better than initially placebo–treated patients on measures of activities of daily living. On average, there was a 7-point difference (-9.6 ADL point score in the placebo group compared to -2.5 ADL point score in the experimental group) between the IGIV (at all doses administered) and the placebo group. There was an 11-point difference between the 9-month performance of the IGIV group (+2 ADL points) and that of the placebo group (-9 ADL points). “Effects on daily function of this magnitude can make a difference in the lives of Alzheimer's patients and their caregivers,” Dr. Tsakanikas commented.

Last year, in August 2007, NewYork-Presbyterian/Weill Cornell announced preliminary results of the Phase II study, indicating that the study provided further encouragement for carrying out a Phase III trial.

The latest results of the Phase II trial re-affirm the decision, initially announced in August 2007, to move to a Phase III study evaluating the role of Gammagard LIQUID for the treatment of patients with mild to moderate Alzheimer's disease with a nine-month primary outcome endpoint. The decision to move to Phase III was based on the 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 Dr. Relkin's earlier Phase I results in eight patients that were recently published in the journal Neurobiology of Aging (Feb. 2008). Although the findings of the Phase I and II trials are encouraging, both studies were small and must be evaluated in larger, sufficiently powered studies.

The Phase III trial will be sponsored jointly by the National Institutes of Health (NIH) and Baxter Healthcare, and additional studies may be required. The study protocol was submitted to the U.S. Food and Drug Administration for review, with the intention of initiating patient recruitment later this year. The trial will include about 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 in the treatment of Alzheimer's patients.

This study was supported by Baxter Healthcare, the Citigroup Foundation and The Clinical Translational Science Center (CTSC) of Weill Cornell Medical College.