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

Published Online: June 4th 2011 US Neurology, 2008;4(1):34-36 DOI: http://doi.org/10.17925/USN.2008.04.01.34
Authors: Edward Tobinick
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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 anti-amyloid 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, 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 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.

Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIg) is used off-label for a variety of disorders involving neurological inflammation, including myasthenia gravis, certain forms of multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy.6 In 2002, naturally occurring antibodies directed against A-beta were detected in IVIg preparations and found to be present in both serum and cerebrospinal fluid (CSF) after intravenous infusion.7 These same investigators later conducted a pilot study utilizing monthly IVIg infusions in five patients with AD treated over six months. A-beta in the CSF decreased by 30% compared with baseline, and the Alzheimer’s Disease Asssement Scale–cognitive subscale (ADAS-Cog) improved by 3.7±2.0 points.8 Scores on MMSE did not show a significant change.8 Most recently, at the just concluded American Academy of Neurology annual meeting, the results of a placebo-controlled, phase II clinical trial of IVIg for the treatment of 24 patients with probable AD (MMSE 14–26) was discussed. Subjects received infusions every two to four weeks at dosages ranging from 0.2g/kg/2weeks to 0.8g/kg/month, with assessment of ADASCog and clinical global impression of change (CGIC).9 IVIg resulted in increased anti-amyloid antibody levels and decreased CSF beta-amyloid.9 Global outcomes, as measured by CGIC, were slightly improved (0.27 GCIC points for IVIg versus 1.25 for placebo), but ADAS-Cog, although favoring the active group, did not reach statistical significance.
The results were interpreted as encouraging the initiation of a phase III clinical trial. In this trial, the only adverse event that was increased in the active group was skin rash. A review of IVIg therapy reports that most adverse events are mild and transient, but severe adverse reactions can occur.10 Acute renal failure, usually occurring in the first 10 days after IVIg administration, is usually reversible, and thromboembolic complications are also a risk.10 As a pooled blood product, there is a small risk of transmission of viral diseases, and hemolytic anemia, death, and transfusion-related acute lung injury have been reported.10 A phase III clinical trial is scheduled to begin soon.

Peri-spinal Etanercept

Tumor necrosis factor-alpha (TNFα) is a cytokine that is well recognized as a key mechanism of disease.11 In 1999, excess TNF in the CSF of patients with AD was found at a level 25 times that of controls.12 Although initially it was thought by the group that made this discovery that TNF was playing a neuroprotective role, they later determined that excess TNF in patients with mild cognitive impairment was associated with progression to AD.13 The present author conceived of the use of etanercept, a potent anti-TNF therapeutic, as a treatment for neurological disorders, including AD, in the late 1990s.14,15 Etanercept is a recombinant dimeric fusion protein consisting of the extracellular ligand-binding portions of two human p75 TNFα receptors linked to the Fc fragment of human IgG1. Etanercept binds to TNF and blocks its interaction with cell surface TNF receptors, thereby reducing the biologic effect of excess TNF. The medical community now has more than one million patient-years of experience using etanercept for treatment of a variety of inflammatory disorders in which TNF plays a prominent role.16 Accumulating basic science and epidemiological, genetic, and clinical data supports a central role of excess TNF in the pathogenesis of AD.17–29
Etanercept does not cross the blood–brain barrier when administered systemically.30 A previous clinical trial utilizing systemically administered etanercept for the treatment of AD failed to show benefit.31 Peri-spinal administration of etanercept, however, was hypothesized to have the ability to traverse the blood–dural barrier, as demonstrated by the ability of this novel treatment approach to reduce the symptoms of lumbar and cervical radiculopathy.32,33 A prospective, open-label, six-month pilot study of peri-spinal etanercept administered weekly to a cohort of 15 patients with probable AD ranging in severity from mild to severe was performed.34 The average age of the patient population was 76.7 years. The mean baseline MMSE was 18.2 (n=15), the mean baseline ADAS-Cog was 20.8 (n=11), and the mean baseline severe impairment battery (SIB) was 62.5 (n=5).
There was significant improvement with treatment, as measured by all of the primary efficacy variables, through six months: MMSE increased by 2.13±2.23, ADAS-Cog improved (decreased) by 5.48±5.08, and SIB increased by 16.6±14.52.34 The methods used involving peri-spinal administration of etanercept were hypothesized to utilize the cerebrospinal venous system to enable therapeutically effective delivery of etanercept to the central nervous system.35,36 Most recently, peri-spinal etanercept was demonstrated to result in rapid clinical improvement, beginning within minutes, in an 81-year-old physician with probable AD.37,38 It was hypothesized that this rapid improvement may have been related to amelioration of the effects of excess TNFα on synaptic mechanisms and the role of TNF as a gliotransmitter.25,37,39
The proper use of peri-spinal etanercept for the treatment of AD requires that dosage and dosing intervals be individualized for each patient. This requires experience with the use of peri-spinal etanercept in the treatment of patients with dementia. At this point, until there is more widespread clinical experience utilizing this patented treatment approach, the proper performance of peri-spinal injection of etanercept, and disease management utilizing peri-spinal etanercept, both require specialized and specific physician training and experience and should not be attempted without such training.40 Potential adverse effects of the use of peri-spinal etanercept for the treatment of AD (off-label use) include all of the risks inherent with the use of etanercept for its labeled indications, which include, but are not limited to, death, infection, decreased blood counts, congestive heart failure, lymphoma, demyelinating disease, and reactivation of tuberculosis. Purified protein derivative skin testing prior to initiation of etanercept treatment is mandatory, and a black box warning highlighting the risk of tuberculosis, sepsis, and severe infection has been added to the package insert. The initiation of randomized, placebo-controlled clinical trials will add much-needed additional clinical data. ■

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