Major Finding: Treatment with a range of doses of IVIG for 18 months resulted in a mean increase of 6.7% in lateral ventricular volume, which was significantly lower than the 12.3% increase observed with placebo.
Data Source: A double-blind, randomized, placebo-controlled phase II trial of 24 patients with mild to moderate Alzheimer's disease.
Disclosures: Baxter Healthcare sponsored the study of IVIG, with additional support from the Citigroup Foundation and the National Institutes of Health. Dr. Relkin reporting no relevant disclosures besides receiving a research grant from Baxter Healthcare to study IVIG.
TORONTO – Intravenous immunoglobulin therapy reduced brain atrophy in patients with mild to moderate Alzheimer's disease in a small phase II trial. The finding suggests that specific IgG antibody components found in the blood product might be treatment candidates for the disease.
“Relative to what we have available right now [to treat Alzheimer's disease], this is a very promising outcome, and it's associated with a reduction in the rate of brain atrophy comparable with age-matched normals,” Dr. Norman Relkin said during a poster presentation.
Enlargement of the cerebral lateral ventricles is known to occur as a consequence of brain atrophy in Alzheimer's disease (AD). This increase in ventricular volume is correlated with cognitive decline and increases in Alzheimer's disease neuropathology.
Dr. Relkin and his colleagues compared intravenous immunoglobulin (IVIG) therapy against placebo in a 6-month, double-blind, randomized study of 24 patients with mild to moderate AD. In a 12-month extension phase of the study, 16 patients who originally were randomized to IVIG continued to receive the same doses of IVIG, whereas 8 placebo-treated patients were re-randomized to one of four doses of IVIG. The investigators used an IVIG product produced by Baxter Healthcare called Gammagard.
IVIG exhibited a dose-dependent effect on brain atrophy in which higher doses resulted in less atrophy. Among 14 IVIG-treated patients who underwent volumetric MRI at baseline and after 18 months, the yearly increase in lateral ventricle volume measured with volumetric MRI was lowest in patients treated with 0.4 mg/kg every 2 weeks (2.4%) and highest in those treated with 0.2 mg/kg every 2 weeks (11.2%). The doses of IVIG given to patients ranged from 0.2 mg/kg every 2 weeks to 0.8 mg/kg every 4 weeks.
The volume of the lateral ventricles increased by a mean of 6.7% per year during treatment with IVIG (all doses combined), which was significantly lower than the 12.3% annual rate of increase observed in six placebo-treated patients. Only the 0.4 mg/kg dose of IVIG given every 2 weeks resulted in significantly less change in total brain volume than did treatment with placebo (−0.62% vs. −2.24%, respectively).
“In addition to the brain imaging, we have previously shown changes in cerebrospinal fluid and plasma amyloid levels … and levels of cerebral metabolism changing in response to treatment,” said Dr. Relkin, director of the Memory Disorders Program at New York–Presbyterian Hospital/Weill Cornell Medical Center.
The reduction in brain atrophy was significantly correlated with improvement in clinical outcomes at 18 months on the Clinical Global Impression of Change and the cognitive subscale of the Alzheimer's Disease Assessment Scale. Patients' baseline characteristics were not correlated with volumetric MRI outcomes.
“This is a 'kitchen sink' approach, so the next step is to find what is in [IVIG] that is causing the therapeutic effect. … We know that it has a fairly good complement of antiamyloid antibodies. Those are prime candidates, but we don't know for sure yet that those are ones responsible for a therapeutic effect,” Dr. Relkin said in an interview.
In addition to an ongoing, multicenter, phase III study of IVIG in 360 patients with mild to moderate AD, Dr. Relkin and his colleagues are testing subsets of antibodies within IVIG in cell culture–based studies and preclinical animal models to see which components are therapeutically relevant. “We are not encouraging people to use [IVIG] off-label for Alzheimer's disease, even though it has been safe and well tolerated in these small studies,” he said. “It has never been studied in the Alzheimer's population before.”
Baxter Healthcare sponsored the phase I and II studies of IVIG, with additional support from the Citigroup Foundation and the National Institutes of Health. The phase III trial is cosponsored by Baxter and the NIH. Dr. Relkin reported no relevant disclosures besides receiving a research grant from Baxter Healthcare to study IVIG.
The outcome is associated with a reduction in the brain atrophy rate, comparable with age-matched normals.
Source DR. RELKIN
After 18 months, the ventricular enlargement rate was greater with placebo (left) than it was with IVIG (right).