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Alzheimer’s Disease
New Horizons in the Treatment of Alzheimer’s Disease—Immunotherapeutics
a report by
Edward Tobinick, MD
Director, Institute for Neurological Research (INR)
The inability of pharmacologically based therapeutic molecules, such as the The current AAC-001 trial was designed for patients with mild to moderate AD
cholinesterase inhibitors and memantine, to effectively prevent clinical and a Mini-Mental State Examination (MMSE) score of 16–26. Because of the
deterioration in Alzheimer’s disease (AD) over the long term has stimulated the similarity of the mechanism of action of this agent to AN-1792 there remains
search for more effective therapeutic approaches that may have the ability to significant concern regarding the safety of this vaccine. For this reason, the
show significant disease-modifying activity. Immunotherapeutic approaches occurrence of severe skin lesions in a single patient receiving the vaccine has
are perhaps the most exciting potential therapeutic options on the near currently (May 2008) resulted in the halting of all clinical trials of this agent, but
horizon. The most closely watched therapeutic approaches falling into this class there is the possibility that testing will resume.
that may become available in the reasonably near term include: two
experimental therapeutics designed to directly attack A-beta, AAC-001 and Passive Anti-amyloid Immunotherapy with Bapineuzumab
bapineuzumab; another immunotherapeutic whose mechanism of action is Bapineuzumab is a humanized monoclonal antibody to A-beta being
still being delineated, but which also contains anti-amyloid antibodies, namely developed by Elan/Wyeth.
4
The rationale is that passive A-beta antibodies
intravenous immunoglobulin; and a fourth therapeutic, which, although it may may have the potential to bind and reduce brain A-beta. Bapineuzumab is
address certain amyloid-mediated mechanisms, takes a completely novel currently being trialed in two separate studies in patients with probable
therapeutic approach to treating AD, namely peri-spinal etanercept. AD: one for ApoE4-positive carriers and one for ApoE4-negative carriers.
These studies are both for selected participants with mild to moderate AD
Active Anti-amyloid Immunotherapy with AAC-001 with MMSE scores ranging from 16 to 26. The study of ApoE4-positive
A-beta is widely hypothesized to be the major therapeutic target in AD. carriers (clinicaltrials.gov identifier NCT00575055) is planned to include
Unfortunately, there has not yet been a single agent designed to directly 800 enrollees. The ApoE4 negative carrier study (clinicaltrials.gov identifier
target amyloid that has been successfully brought through phase III clinical NCT00574132) is planned to include 1,250 enrollees at 200 study sites.
trials. One potential approach is active anti-amyloid immunotherapy. One Both trials were begun in December 2007 and are scheduled for
preliminary clinical trial involving this approach studied 30 participants completion in December 2010 (the final data collection date for the
and found that those study participants immunized with A-beta peptide primary outcome measure).
who actively generated anti-A-beta antibodies (20 of the participants)
exhibited a slower rate of decline of certain cognitive functions over a These are placebo-controlled studies; the active comparator will consist of
study period of one year.
1
There has been considerable interest in AAC- 0.5mg/kg infusions given over a period of 60 minutes every 13 weeks for a
001 (clinicaltrials.gov identifier NCT00498602), which is an active anti- total of 18 months for the ApoE4-positive patients, and doses of 0.5, 1.0,
amyloid vaccine undergoing clinical trial testing by Elan/Wyeth. It is a or 2.0mg/kg (three groups) for the ApoE4-negative patients.
modified version of AN-1792,
2
a previous anti-amyolid vaccine tested
several years ago by this same consortium, but whose clinical There is some concern regarding the risk of brain microhemorrhages, which
development was stopped because of severe meningoencephalitis that have been seen in transgenic mice treated with passive A-beta vaccines.
5
In
occurred in 18 of 300 study participants.
3
a 30-patient randomized, double-blind, placebo-controlled, single-
ascending-dose trial of bapineuzumab treated with infusions ranging from
0.5 to 5mg/kg, three of 10 patients treated at the 5mg/kg dose developed
Edward Tobinick, MD, is Director of the Institute for
Neurological Research (INR), a private medical group, and
magnetic resonance imaging abnormalities, consisting predominantly of
directs the INR’s active, patented, off-label, anti-tumor high signal abnormalities on fluid attenuated inversion recovery sequences,
necrosis factor treatment program and its physician training
which resolved by 12 weeks post-dose.
4
With multiple doses, one might be
program. He is also an Assistant Clinical Professor of
Medicine at the University of California, Los Angeles (UCLA)
concerned that these effects could be augmented. The study designers
and in 2007 was appointed to the Editorial Board of the were apparently more concerned about safety in the ApoE4 positive
Journal of Neuroinflammation. He invented and was the first
carriers, hence the reduced dosing levels in these patients. The phase III trials
to publish on the use of etanercept delivered by peri-spinal
administration for the treatment of selected neurological disorders. Dr Tobinick completed
are currently recruiting study participants.
medical school at the Univerity of California, San Diego School of Medicine in La Jolla,
California, and post-graduate training at UCLA.
Intravenous Immunoglobulin
E:
etmd@ucla.edu
Intravenous immunoglobulin (IVIg) is used off-label for a variety of disorders
involving neurological inflammation, including myasthenia gravis, certain forms
34 © TOUCH BRIEFINGS 2008
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