Alzheimer’s Association Prompts FDA to Broaden Trials

September 9, 2011

The Alzheimer’s Association announced in July that the FDA had accepted its recommendations to modify exclusion and monitoring criteria for clinical trials of agents that affect β-amyloid protein in the brain.

The Alzheimer’s Association announced in July that the FDA had accepted its recommendations to modify exclusion and monitoring criteria for clinical trials of agents that affect β-amyloid protein in the brain. The FDA had increased restrictions in its research guidelines 1 year before, prompting formation of an expert Work Group at the 2010 Alzheimer’s Association International Conference to prepare a response.

The group of scientists from several pharmaceutical manufacturers, academic research centers, and the Association worked under the auspices of the Association’s long-standing “Research Roundtable.” Their recommendations and summary of relevant research was posted online to coincide with the press announcement, in advance of publication in the Association journal and 1 week before the 2011 annual conference.1

“The working Group’s timeline was as inspiring as its process,” declared Maria Carrillo, PhD, Alzheimer’s Association Senior Director, Medical and Scientific Affairs. “We’ve gone from concept to consensus to publication in less than 1 year, reflecting the urgent need to move the field forward.”

In the editorial accompanying the Work Group’s publication, Carrillo and coauthors wrote, “Importantly, broadening the restrictions would allow a better understanding of the potential risks and benefits of amy-loid-lowering treatment and would advance the development of treatments for AD [Alzheimer disease] without clinical or scientific evidence indicating that doing so would compromise trial participant safety.”2

One class of agents for reducing the β-amyloid component of senile plaques uses antibodies to increase the clearance of the protein from the brain. Other agents being assessed inhibit the formation of β-amyloid or its aggregation into plaques. These drug developments can potentially mitigate the course or even the onset of illness and yield products that are alternatives to, or are synergistic with, the current palliative medications for conserving acetylcholine neurotransmitter function against inexorable loss of neuronal integrity.

Co-sponsored by Pfizer, Johnson & Johnson, and Elan, the agent furthest along in clinical testing, bapineuzumab, is a humanized monoclonal antibody that targets β-amyloid protein. It is closely followed in the development and testing pipeline by solanezumab from Lilly and ponezumab from Pfizer. Preclinical testing suggests that solanezumab and ponezumab have potential to prevent or clear plaque formation; in phase 2 studies, bapineuzumab has been shown to reduce levels of cortical fibrillar β-amyloid.3 Direct imaging of effects on senile plaques is at hand with the development of positron emission tomography (PET) plaque imaging agents Amyvid (florbeta-pir) from Lilly and PET manufacturer Siemens, and flutemetamol from Johnson & Johnson and General Electric.

Adverse effects vs therapeutic promise

Whether promising mechanisms translate to improved cognitive out-comes remains to be determined in adequately sized phase 3 trials. Unfavorable outcomes, however, can occur early in clinical testing and can be difficult to differentiate as adverse effects of therapy or untoward responses to illness. The 2 amyloid-related imaging abnormalities detected in the MRI monitoring of clinical trial participants that prompted the FDA to revise its guidelines are mi-crohemorrhage and vasogenic edema.

Microhemorrhage in the brain has been identified previously and described in the Alzheimer’s Association announcement as a common age-related condition that occurs even in apparently neurologically healthy individuals, but more frequently in those with AD, and is associated with amyloid accumulation. Vasogenic edema was first identified in the MRI monitoring with bapineuzumab and is posited to occur as mobilization of β-amyloid increases permeability of brain capillary endothelial cells. The detection of vasogenic edema in patients who receive a γ-secretase inhibitor to reduce the formation of β-amyloid suggests a link to more than a single class of amyloid-affecting agents.4

There appears to be a causal relationship between vasogenic edema and treatment, with increased incidence occurring at higher dosages of bapineuzumab. It is possible, however, that vasogenic edema can occur spontaneously “as part of the aging brain’s natural effort to clear β-amyloid.”5

In response to reports of amyloid-related imaging abnormalities, however, the FDA revised its guidelines in 2010 to exclude patients with more than 2 existing brain microhemorrhages at baseline and to discontinue testing in patients who develop either microhemorrhage or vasogenic edema. In the view of the Work Group, these restrictions were imposed before data demonstrated their necessity, and their imposition confounds obtaining these data.

“The Work Group believed it was obviously important to protect clinical trial participants from potential adverse outcomes related to amyloid-related imaging abnormalities,” the authors of the recommendations explained. However, “they thought that it was also important not to be unnecessarily stringent in excluding participants with amyloid-related imaging abnormalities, based on the current literature and publicly available information.”1

The Work Group recommendations accepted by the FDA include raising the exclusion cutoff to 4 microhemorrhages at baseline and allowing patients who develop microhemorrhage to continue trial participation in the absence of worsening symptoms. In addition, the Work Group recommended consideration of dose reduction when an amyloid-related imaging abnormality develops; minimum standards for MRI protocols and frequency of use to monitor for amyloid-related imaging abnormalities; and future research on the prevalence of amyloid-related imaging abnormalities, the relationship between microhemorrhage and vasogenic edema, and how factors these may affect clinical outcomes.



1. Sperling RA, Jack CR Jr, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367-385.
2. Schindler RJ, Carrillo MC. Output of the working group on magnetic resonance imaging abnormalities and treatment with amyloid-modifying agents. Alzheimers Dement. 2011;7:365-366.
3. Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061-2070.
4. Sperling R, Bronen R, Greenberg S, et al. Three cases of apparent vasogenic edema (VE) from a phase 2 clinical trial of the gamma secretase inhibitor BMS-708163 in patients with mild-to-moderate AD. Alzheimer’s Association International Conference; July 16-21, 2011; Paris.
5. Sperling RA, Salloway S, Fox NC, et al; Bapineuzumab 201 Clinical Trial Investigators. Risk Factors and Clinical Course Associated With Vasogenic Edema in a Phase II Trial of Bapineuzumab. 2009. Accessed August 2, 2011.