“We carefully considered a number of promising anti-amyloid treatments for the A4 trial over the past six months,” said Reisa Sperling, Brigham and Women’s Hospital, who is principal investigator for the A4 trial. “Our committee ultimately reached the decision that solanezumab was the best choice for this first trial in asymptomatic people at high risk for cognitive decline.”

The A4 trial has been highly anticipated by the field at large. Intended to bridge the gap between trials for autosomal-dominant and sporadic AD, it complements the otherwise similar DIAN and API secondary prevention initiatives in people who are genetically destined to develop AD. A4 will not select for people who are at elevated genetic risk, but will enroll people who have the same preclinical biomarker changes observed in longitudinal studies of genetic and sporadic preclinical populations. The trial is funded by the National Institutes of Health and by private sector contributions.

“This trial is going to be incredibly important,” said Gil Rabinovici, University of California, San Francisco. “The preventive trials in autosomal-dominant AD are interesting as proof of concept, but even if the results are positive, the question will remain open about how generalizable the results are to sporadic AD. A4 is going to target the much more common population—older amyloid-positive people who we think are at risk for cognitive decline."

Earlier this week, the National Institute on Aging announced partial funding for the three-year A4 trial as part of its funding of the Alzheimer’s Disease Cooperative Study (ADCS) renewal grant (see ARF related news story). Led by Paul Aisen at the University of California, San Diego, the ADCS will facilitate the A4 trial, and the NIA will fund part of its cost.

Why solanezumab? “It has a good safety profile, which is a big deal when giving a drug to clinically normal people," said Sperling, who directs the Harvard Aging Brain Study at the Massachusetts General Hospital and BWH. Sperling was also encouraged by the evidence of a modest clinical benefit in the mild Alzheimer’s disease dementia patients in the Phase 3 trials (see ARF related news story). "Our confidence level in solanezumab grew after the results were confirmed through an independent, academic analysis by the ADCS released in early October,” she told Alzforum. “We hope that starting treatment much earlier in the disease, before symptoms are present, as well as treating for a longer period of time, will slow cognitive decline and ultimately prevent Alzheimer’s disease dementia.” William Jagust, University of California, Berkeley, agreed. “It suggests that if you moved to asymptomatic individuals, you might have an even greater effect,” he said.

The A4 researchers will use florbetapir (Amyvid®) as the PET amyloid tracer to select participants for the trial. Florbetapir is FDA approved for detecting the presence of amyloid in the brains of patients with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline. Academic centers, including those that will participate in A4, are already set up to use it. Both solanezumab and florbetapir are also being used in an upcoming DIAN treatment trial. Keith Johnson, Massachusetts General Hospital, will lead the PET amyloid imaging aspects of the A4 trial.

“The academic community probably has more experience now with florbetapir than with any other F18 agent,” said Jagust. “There’s also a wealth of data in the academic community using this tracer.”

Christopher Rowe, University of Melbourne, Australia, agreed. “Other tracers are under development that may have higher uptake in amyloid plaques, but they’re not ready for widespread use at this time,” he told Alzforum. “Whether [high uptake] is important for detecting change in amyloid with therapy is not clear, but theoretically, you would expect those [tracers] to be slightly more sensitive at detecting a therapeutic effect on amyloid load," he said.

The solanezumab decision was made a bit easier as researchers have come to acknowledge the A4 trial as the first in a series of preventative trials that may include different anti-amyloid therapies, said Sperling. “We have evolved from thinking of A4 as a single trial to thinking of it as a platform from which we will be able to test multiple drugs over time,” she said. Each trial will inform researchers about how to recruit subjects, conduct studies, and who best responds to treatments. “All of this will inform future trials,” Sperling said.—Gabrielle Strobel and Gwyneth Dickey Zakaib.