ARTICLE IN BRIEF
IV immunoglobulin did not show a benefit for early or moderate Alzheimer's disease in a large multicenter trial.
Even while targeted antibody therapies continue to attract the greatest hopes for treatment of Alzheimer's disease (AD), intravenous immunoglobulin (IVIG) — a tried-and-true antibody treatment for other neurologic disease — has failed to show any benefit for early or moderate AD in a large multicenter trial, according to a paper published in the April 5 online edition of Neurology.
The idea behind the trial was a solid one, according to Paul Aisen, MD, professor of neurology and director of the Alzheimer's Therapeutic Research Institute at the Keck School of Medicine at the University of Southern California in Los Angeles, who helped lead the trial. Antibody-based therapy against amyloid-beta (Abeta) remains the most promising clinical strategy for AD, and human immunoglobulin contains small quantities of anti-Abeta antibodies. Moreover, unlike the murine or humanized monoclonal antibodies under study, those from human blood are polyclonal and bind to multiple conformations of Abeta, including the oligomeric and fibrillar forms that are thought to be especially pathogenic.
Furthermore, IVIG has a long safety record, and small studies in AD, though underpowered to provide any definitive evidence, have suggested a possible benefit on cognition that correlated with a change in plasma Abeta levels. “That was encouraging, and so we felt there was good justification for the multicenter trial,” Dr. Aisen said.
The study enrolled 390 patients with mild to moderate AD at 41 sites in North America beginning in December 2008. Participants met clinical criteria for probable AD dementia and had Mini-Mental State Examination scores between 16 and 26.
Subjects were randomized to receive either 0.2 g/kg or 0.4 g/kg IVIG, or placebo, every two weeks for 18 months. This was lower than the usual therapeutic dose in other neurologic conditions, which ranges up to 2g/kg, partially due to cost and supply, Dr. Aisen noted. To avoid confounding, randomization was stratified by apolipoprotein E4 status and stage of disease.
The primary outcome measure was change from baseline on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and on the 23-item Alzheimer's Disease Cooperative Study Group Activities of Daily Living Scale (ADCS-ADL). A subgroup of participants also underwent amyloid imaging with florbetapir at baseline and 18 months.
There were no differences in outcome among the three groups on either of the primary outcome measures. The ADAS-cog score rose by about eight points and the ADCS-ADL score fell by about 11 points in each group. There was no difference in effect between patients with mild versus moderate AD. “The most important result of the study is simply that it was negative for both its primary outcomes,” Dr. Aisen said. “We had hoped for a benefit on progression, but we didn't see it.”
The researchers did observe an increase in immunoglobulin levels in the cerebrospinal fluid in patients receiving active treatment, suggesting the antibodies were reaching the central nervous system. They also saw a statistically significant and dose-dependent reduction in plasma levels of Abeta-42 at 18 months, with a decline of 7.91 ng/ml in the high-dose group, 3.51 ng/ml in the low-dose group, and 1.35 ng/ml in the placebo group. Both active-treatment reductions, but not the placebo reduction, were significant compared to baseline values.
“The reduction in plasma Abeta-42 suggests target engagement, but the mechanism is unclear,” Dr. Aisen said. It is possible that the antibody bound to Abeta circulating in the plasma without affecting brain levels of the protein, a possibility supported by the imaging results, which showed no significant decline in brain amyloid, although, Dr. Aisen cautioned, the imaging subgroup was too small to be informative, give the differences seen among the three groups. There was no change in the plasma levels of Abeta-40.
“In my view, monoclonal anti-amyloid antibodies hold greater promise than IVIG in Alzheimer's disease,” Dr. Aisen concluded.
“This is likely to be the last word on intravenous immunoglobulin in Alzheimer's disease,” said Thomas Wisniewski, MD, FAAN, professor of neurology at the New York University School of Medicine and director of the Alzheimer's Disease Center at the NYU Langone Medical Center, who was not involved in the study.
There were multiple factors stacked against the likelihood of success with IVIG in AD, he noted. “The mixture of mildly and moderately affected patients, the low concentration of the relevant antibodies in the immunoglobulin mixture, and the lack of an image-based inclusion criterion all reduced the likelihood of success,” he said.
On the other hand, he noted, the most promising antibody currently in clinical trials is aducanumab, which is derived from a naturally produced antibody to Abeta, so on theoretical grounds, there may be some reason to expect an outsized benefit from antibodies in IVIG. But the natural concentration is “orders of magnitude lower,” he pointed out. “This was not likely to work.”
“Intravenous immunoglobulin is an intriguing therapeutic concept for Alzheimer's disease,” commented Howard Chertkow, MD, professor of neurology and neurosurgery at McGill University and director of the Jewish General Hospital/McGill Memory Clinic in Montreal, Canada. It has a good safety and efficacy record in neurology, “and if it was shown to be effective, one could start therapy tomorrow.”
And while the amalgam of antibodies within a sample makes it a “messy” treatment, “we don't know for sure what the cause of Alzheimer's disease is, so maybe a messy treatment for a messy disease makes sense.”
As for the negative results, Dr. Chertkow commented, “This study had the right number of patients and no methodological errors to be able answer the question it addressed. It is a very well-done failed study, and a negative answer in a well-done study is still a step forward.”
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