There is an urgent need to find and accelerate approval of Alzheimer?s disease (AD) prevention therapies. Aducanumab is an antibody that binds selectively to amyloid-? (A?) oligomers and fibrils. In a Phase 1b trial of clinically affected AD patients with A? plaques, it dramatically reduced A? plaque burden and appeared to slow cognitive decline. Alzheimer?s Prevention Initiative (API) and Anti-Amyloid Treatment in Asymptomatic Alzheimer?s (A4) Trials leaders have come together to propose a 24-month, multicenter, double blind, placebo- controlled prevention trial of aducanumab using AD biomarker endpoints as primary outcomes, along with cognitive/clinical, safety, and tolerability outcomes, in cognitively unimpaired 65-80 year-old A? PET+ persons stratified for presence or absence of the APOE4 allele. We will continue the blinded, randomized treatment past 24 months until we learn the results of the ongoing Phase 3 aducanumab program in persons with early AD. If the Phase 3 program shows significant cognitive and/or clinical benefit and also shows that aducanumab?s A? PET effects, alone or in combination with downstream biomarker effects, are associated with clinical benefit, and our 24-month trial showed identical biomarker effects, the findings would be used to support aducanumab?s ?accelerated approval? in unimpaired A?+ persons based on those biomarker effects; in doing so, it would advance the potential use of surrogate biomarker endpoints to rapidly test prevention therapies in almost everyone at biomarker or genetic risk. At that point, participants would receive open-label treatment and Biogen would conduct post-marketing studies following FDA?s guidance to confirm that the treatment?s 24-month biomarker are associated with subsequent clinical benefit, as required under the FDA?s accelerated approval provisions. Our deliberately ambitious proposal is intended to 1) find an approved prevention therapy as early as 2023, ahead of the National Plan to Address AD?s goal to ?prevent AD by 2025,? and 2) advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical AD stages when some treatments may have their greatest benefit. However, if the Phase 3 program does not show significant benefit, the stakes would be even higher for our trial, since the question would remain whether intervention before clinical stages of AD is necessary to attain benefit. We would modify the trial by using the Preclinical Alzheimer Composite Endpoint-Revised (PACC-R) as the primary outcome and continuing blinded treatment until the last participant?s 48-month visit, clarify whether the treatment?s 24 month biomarker effects are associated with subsequent cognitive benefit, and seek to achieve our goals by 2025. Regardless of the Phase 3 results, the proposed trial offers an unprecedented chance to find, approve and support the availability of prevention therapies as soon as possible. It would capitalize on a public-private partnership, NIH support, $5-10M in philanthropy, access to aducanumab and most of the financial support from Biogen, provide a public resource of data and samples, and have the maximum public benefit.
Leaders from the Alzheimer?s Prevention Initiative (API) and Anti-Amyloid Treatment in Asymptomatic Alzheimer?s (A4) Trials have come together to conduct a potentially license-enabling prevention trial, using clinically informative Alzheimer?s disease biomarkers and other assessments to evaluate the promising amyloid plaque-busting antibody treatment aducanumab in cognitively unimpaired 65-80 year-old persons with a positive amyloid PET scan. The deliberately ambitious proposal is intended to 1) find an approved Alzheimer?s prevention therapy as early as 2023, ahead of the National Plan to Address Alzheimer?s Disease goal to ?prevent Alzheimer?s disease by 2025; 2) introduce the use of these biomarkers to test and approve prevention therapies in almost everyone who, based on their biological tests or genetic risk, are at increased risk; and 3) help make it possible to conduct prevention trials in at risk persons even before they have extensive amyloid plaques, when some treatments may have their greatest benefit. It is intended to capitalize on a public-private partnership with the makers of aducanumab, NIH support, $5-10 million dollars in philanthropy; enable us to secure access to this promising drug and secure most of the financial support from our industry partner; provide a public resource of data and biological samples to help the field find even better ways to test prevention therapies; have the maximum public benefit; and prevent Alzheimer?s disease as soon as possible.