Immunotherapeutic Approaches to Alzheimer’s: How We Got Here and Where Insights Are Leading

Trials now focusing on prodromal AD, mild AD dementia

By Jeffrey Cummings, MD, ScD; James Leverenz, MD; and Babak Tousi, MD

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Immunotherapies may transform Alzheimer’s disease (AD) therapeutics by harnessing the power of the immune system to rid the brain of toxic proteins. In fact, immunologic approaches to AD are the focus of four active clinical trial programs across the Cleveland Clinic Lou Ruvo Center for Brain Health trial network, which includes sites in Las Vegas, Cleveland, and Weston, Florida. This article outlines the path that’s led to current immunotherapeutic approaches to AD and identifies a few remaining hurdles on the road to clinical success.

Rationale and early setbacks

Immunotherapy refers to treatments that involve immunologic mechanisms to exert disease-modifying effects on the underlying processes leading to cell death. Monoclonal antibodies are typically produced artificially outside the body and infused intravenously on a regular basis. Subcutaneous administration is also being explored. An alternate immunotherapeutic approach is active vaccination, in which the patient is inoculated with an amyloid protein fragment and produces an immunologic response, with the induced response intended to remove the amyloid accumulating in the brain.

The immunotherapeutic approach to AD began in 1999 when immunization with amyloid-beta protein attenuated development of AD-type pathology in transgenic animal models of AD that were engineered to overproduce the amyloid protein. In 2001, a human study of AN1792, an active vaccine against amyloid, was initiated. The study was terminated when 6 percent of enrolled patients developed allergic encephalitis; cross-reactivity of the antigen with normal brain tissues was identified as the likely cause. Autopsy of a small number of enrolled patients found evidence of amyloid removal from the brain but no disease modification.

After this setback, scientists pursued the alternate approach of passive immunotherapy with monoclonal antibodies in an effort to avoid the adverse effects observed with AN1792. The figure below contrasts the essentials of active and passive immunization in the setting of AD.

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The first passive immunotherapy tested in AD was bapineuzumab, a monoclonal antibody targeting the N-terminal portion of the amyloid-beta protein. The primary outcomes of this trial showed no drug-placebo difference, but a subanalysis appeared to suggest that those who were not carriers of the apolipoprotein e4 allele (ApoE-4), a gene known to exert effects in AD, showed positive effects on cognitive testing. A subsequent trial failed to identify any therapeutic benefit in either ApoE-4 carriers or noncarriers.

A new type of side effect was seen in this trial — development of amyloid-related imaging abnormalities — that appears to be nearly unique to immunotherapy, represents interruption of the blood-brain barrier, and is usually asymptomatic but has important and permanent stroke-like consequences in some patients. These changes are now routinely monitored with MRI in immunotherapy trials.

Proliferation of candidate therapies

These early experiences with immunotherapy have served to advance and refine immunologic approaches to AD treatment. The result is 14 types of immunotherapy now in various stages of clinical testing for AD (Table 1) in an attempt to replicate the therapeutic responses observed in animals. Most of these immunotherapies are monoclonal antibodies directed against the amyloid-beta protein, while one (AADvac1) is a vaccine directed against the tau protein, two are polyclonal antibodies and three are active vaccines. Information on the therapeutic effects of the six agents in phase 3 trials will be available within the next few years.

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The imperative — and challenge — of early intervention

Experience with monoclonal antibodies indicates that they may have their greatest effects when given early in the disease course, as suggested by the Solanezumab Study Group and others. Trials are currently focusing on prodromal AD, before there is any functional deficit, and mild AD dementia.

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Yet this poses a challenge, as very mildly affected individuals are difficult to enroll in trials since they may not realize their memory deficits are signs of AD. The challenge is heightened by the fact that phase 3 trials tend to be large (> 1,000 patients) and long (18-month double-blind phase followed by an open-label extension). Many individuals with mild memory loss will be excluded when amyloid imaging shows them to be free of amyloid deposits in the brain (the hallmark finding of AD). The “screen fail” rate of these trials can be as high as 75 to 80 percent, and clinical trial sites must screen many patients to enter a few into trials.

Cleveland Clinic Lou Ruvo Center for Brain Health is committed to helping address these enrollment challenges through its active clinical trial programs for four immunotherapies — aducanumab, solanezumab, crenezumab and albumin/immunoglobulin — across its clinical sites in three distinct regions of the U.S. We are hopeful these trials may result in the development of the first successful immunotherapies for AD.

Dr. Cummings is Director of Cleveland Clinic Lou Ruvo Center for Brain Health.

Dr. Leverenz is Cleveland Director of the Lou Ruvo Center for Brain Health.

Dr. Tousi is Head of the Clinical Trials Program at the Lou Ruvo Center for Brain Health.