21 Mar 2019

Today, Biogen and Eisai announced they would terminate the Phase 3 ENGAGE and EMERGE trials of aducanumab for early Alzheimer’s disease. A futility analysis run by an independent data-monitoring committee concluded that that trials would not reach their primary endpoint, the slowing of cognitive decline as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Aducanumab is a monoclonal antibody that helps clear Aβ from the brain. The trials had recruited more than 3,200 patients around the world.

Researchers and clinicians in the field were disappointed but not wholly surprised by the news. “This is heartbreaking news for affected people, their families, and even for our colleagues at Biogen who advanced this study in an extremely thoughtful way. While this news is important for the field, we look forward to learning more from the data when it becomes available," said Eric Reiman, Banner Health, Phoenix.

“This tells us that removal of amyloid in people with disease is too late,” wrote John Hardy, University College London. “Amyloid is a disease trigger. Once the neurodegenerative disease process is up and running, it is up and running.” His thoughts were echoed by others in the field.

“Even though this trial was in the early symptomatic phase of AD, it is still in the phase when Aβ is no longer likely to be the driving process but where tau and inflammation probably are,” noted David Holtzman, Washington University, St. Louis. “I think Aβ is still a good target for the primary and maybe secondary prevention trials of AD, before tau and inflammation have started driving the disease,” he added.

Aducanumab energized the field in 2015 when researchers at the International Conference on Alzheimer’s and Parkinson’s Diseases in Nice, France, showed PET scans from the Phase 1b PRIME trial indicating the antibody all but cleared amyloid plaques from the brain. In this small trial it even appeared to slow cognitive decline as judged by the CDR-SB and the MMSE (Mar 2015 conference news). That data, including much discussion of the underpowered cognitive data, were subsequently published in Nature.

Was this the biological equivalent of “irrational exuberance,” to borrow from a retired Federal Reserve chairman? It now seems warnings at that time were prescient (Sep 2016 news and comments). “The feeling that the early reports on the clinical efficacy of aducanumab were always presented in an overoptimistic way, appears now to have been right,” wrote Bart de Strooper, Dementia Research Institute, London. “The disappointment in the field remains, however, huge,” he added. Hardy agreed. “As many people said at the time, the original Phase 1 trial should never have been published in Nature. Phase 1 trials are simply not for outcome measures. I would say that Nature should make a statement about this and learn from it,” he wrote.

What is the future now for aducanumab and similar anti-Aβ immunotherapies? “I think this solidifies the opinion that amyloid-targeted therapies do not have a clinical effect at the symptomatic stages of the disease process,” wrote Ron Petersen, Mayo Clinic, Rochester, Minnesota. “Might they work prior to the development of symptoms? Maybe, but with no symptomatic signal, it is risky to continue in that space. We clearly need other targets, and tau is the leading candidate for now.”

Biogen has halted the Phase 2 EVOLVE safety study of aducanumab and the long-term extension of PRIME. The company press release says a planned Phase 3 secondary prevention trial will be reassessed once the data from ENGAGE and EMERGE are evaluated. As of this writing, Biogen’s stock price was down 28 percent.—Tom Fagan