New Horizons in the Treatment of Alzheimer’s Disease—Immunotherapeutics

New Horizons in the Treatment of Alzheimer’s Disease—Immunotherapeutics

Tobinick Edward
Published: US Neruology - Volume 4 - Issue I
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The inability of pharmacologically based therapeutic molecules, such as the cholinesterase inhibitors and memantine, to effectively prevent clinical deterioration in Alzheimer’s disease (AD) over the long term has stimulated the search for more effective therapeutic approaches that may have the ability to show significant disease-modifying activity. Immunotherapeutic approaches are perhaps the most exciting potential therapeutic options on the near horizon. The most closely watched therapeutic approaches falling into this class that may become available in the reasonably near term include: two experimental therapeutics designed to directly attack A-beta, AAC-001 and bapineuzumab; another immunotherapeutic whose mechanism of action is still being delineated, but which also contains anti-amyloid antibodies, namely intravenous immunoglobulin; and a fourth therapeutic, which, although it may address certain amyloid-mediated mechanisms, takes a completely novel therapeutic approach to treating AD, namely peri-spinal etanercept.

Active Anti-amyloid Immunotherapy with AAC-001
A-beta is widely hypothesized to be the major therapeutic target in AD. Unfortunately, there has not yet been a single agent designed to directly target amyloid that has been successfully brought through phase III clinical trials. One potential approach is active anti-amyloid immunotherapy. One preliminary clinical trial involving this approach studied 30 participants and found that those study participants immunized with A-beta peptide who actively generated anti-A-beta antibodies (20 of the participants) exhibited a slower rate of decline of certain cognitive functions over a study period of one year.1 There has been considerable interest in AAC- 001 (clinicaltrials.gov identifier NCT00498602), which is an active antiamyloid vaccine undergoing clinical trial testing by Elan/Wyeth. It is a modified version of AN-1792,2 a previous anti-amyolid vaccine tested several years ago by this same consortium, but whose clinical development was stopped because of severe meningoencephalitis that occurred in 18 of 300 study participants.3

The current AAC-001 trial was designed for patients with mild to moderate AD and a Mini-Mental State Examination (MMSE) score of 16–26. Because of the similarity of the mechanism of action of this agent to AN-1792 there remains significant concern regarding the safety of this vaccine. For this reason, the occurrence of severe skin lesions in a single patient receiving the vaccine has currently (May 2008) resulted in the halting of all clinical trials of this agent, but there is the possibility that testing will resume.

Passive Anti-amyloid Immunotherapy with Bapineuzumab
Bapineuzumab is a humanized monoclonal antibody to A-beta being developed by Elan/Wyeth.4 The rationale is that passive A-beta antibodies may have the potential to bind and reduce brain A-beta. Bapineuzumab is currently being trialed in two separate studies in patients with probable AD: one for ApoE4-positive carriers and one for ApoE4-negative carriers. These studies are both for selected participants with mild to moderate AD with MMSE scores ranging from 16 to 26. The study of ApoE4-positive carriers (clinicaltrials.gov identifier NCT00575055) is planned to include 800 enrollees. The ApoE4 negative carrier study (clinicaltrials.gov identifier NCT00574132) is planned to include 1,250 enrollees at 200 study sites. Both trials were begun in December 2007 and are scheduled for completion in December 2010 (the final data collection date for the primary outcome measure).

These are placebo-controlled studies; the active comparator will consist of 0.5mg/kg infusions given over a period of 60 minutes every 13 weeks for a total of 18 months for the ApoE4-positive patients, and doses of 0.5, 1.0, or 2.0mg/kg (three groups) for the ApoE4-negative patients.

There is some concern regarding the risk of brain microhemorrhages, which have been seen in transgenic mice treated with passive A-beta vaccines.5 In a 30-patient randomized, double-blind, placebo-controlled, singleascending- 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 magnetic resonance imaging abnormalities, consisting predominantly of high signal abnormalities on fluid attenuated inversion recovery sequences, which resolved by 12 weeks post-dose.4 With multiple doses, one might be concerned that these effects could be augmented. The study designers were apparently more concerned about safety in the ApoE4 positive carriers, hence the reduced dosing levels in these patients. The phase III trials are currently recruiting study participants.

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