Phase 3 Study of BAN2401 in Preclinical Alzheimer Disease Announced

Reisa Sperling, MD

Eisai and Biogen, in conjunction with the Alzheimer’s Clinical Trials Consortium (ACTC), have announced the launch of a phase 3 clinical study of the investigational Alzheimer disease agent BAN2401, to assess the therapy in those with preclinical Alzheimer disease.¹

Dubbed AHEAD 3-45, the study is a public-private partnership between the ACTC and Eisai, and is funded by the National Institute on Aging. It will be conducted at sites in the US, Japan, Canada, Australia, Singapore, and Europe, and aims to enroll 1400 participants who will be treated with BAN2401 for 216 weeks. A common screening period will be conducted, after which patients will be randomized to 1 of 2 trials: A3 and A45.

“It is hoped that initiating treatment much earlier in the disease process may be advantageous in preventing future cognitive decline. The AHEAD 3-45 should provide critically important answers about the optimal time to intervene with anti-amyloid therapy,” said co-principal investigator Reisa A. Sperling, MD, director, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, in a statement.

The first of the trials, A45, will enroll cognitively unimpaired participants who have elevated levels of amyloid and will seek to assess BAN2401’s ability to prevent cognitive decline and suppress the progression of brain AD pathology. The primary end point is the change from baseline in the Preclinical Alzheimer Cognitive Composite 5 (PACC5) at 216 weeks. Its secondary end points are changes from baseline in brain amyloid levels as measured by amyloid positron emission tomography (PET), as well as brain tau levels as measured by tau PET and Cognitive Function Index.

The second trial, A3, will include those without cognitive impairment who have intermediate amyloid levels and are at high risk for further amyloid-beta accumulation. The A3 primary end point is the change from baseline in brain amyloid levels as measured by amyloid PET, while the secondary end point is the change from baseline in brain tau levels as measured by tau PET.

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“The mission of the ACTC includes the development of public-private partnerships to conduct trials of promising candidate therapies,” Paul Aisen, MD, professor of neurology, and director, Alzheimer's Therapeutic Research Institute, University of Southern California, in a statement. AHEAD 3-45 is the type of collaboration we need in the fight against Alzheimer's disease.”

Both A3 and A45 will include exploratory end points in a subset consisting of additional clinical assessment scales, imaging, blood biomarkers, and cerebrospinal fluid (CSF). An amyloid, tau, neurodegeneration (ATN) biomarker panel of imaging and biofluid markers will be used for the assessment of effects on the progression of pathophysiologic changes. Those include Aβ 1-42, Aβ 1-40, t-tau, p-tau, neurogranin, and neurofilament light chain.

“The initiation of AHEAD 3-45 with BAN2401, focused on therapies for the earliest stages of the AD continuum through our collaboration with the ACTC group, marks an exciting time for us," said Lynn Kramer, MD, chief clinical officer, Neurology Business Group, Eisai, in a statement. “This represents a next step in developing precision therapies for AD using biomarker panels as part of our human health care mission; we are committed to making a difference for patients, their families, and health care professionals across the globe.”

BAN2401 is a humanized, monoclonal, anti-amyloid-beta protofibril antibody, which selectively binds to neutralize and eliminate toxic Aβ protofibrils that are thought to be a causative factor for Alzheimer. Currently, it is being studied in a pivotal phase 3 clinical study in symptomatic early Alzheimer (Clarity AD; NCT03887455), following the outcome of the phase 2 study (Study 201; NCT01767311).

Preliminary analysis from the ongoing open-label extension (OLE) of Study 201 suggests that negative amyloid positron emission tomography (PET) persists over time in patients treated with BAN2401.² The analysis included the first 111 patients and showed that visual reads of amyloid PET remained negative from the end of core treatment until the open-label baseline—consistent with PET standard uptake value ratio (SUVR)—despite the subjects being off BAN2401 treatment for a range of 9 to 52 months. The data were accepted to the American Academy of Neurology (AAN) 2020 Annual Meeting.

Of the 111 patients in the analysis, 84 were BAN2401-treated subjects, with a mean duration of time off the study drug of 23.7 months (range, 9.2—52.5). All of those who were amyloid-negative and treated with BAN2401 who entered the OLE were also amyloid negative at the extension baseline (n = 36; mean, 32.1 months off treatment). In the core phase 2 study, 80% (68 of 84 patients) of all BAN2401-treated subjects were amyloid negative at OLE baseline by visual read.^2,3

REFERENCES

1. Initiation Of New Phase III Clinical Study (AHEAD 3-45) Of BAN2401 Preclinical (Asymptomatic) Alzheimer's Disease [press release]. Tokyo, Japan: Eisai; and Cambridge, MA: Biogen Inc. Published July 13, 2020. Accessed July 14, 2020. eisai.mediaroom.com/2020-07-13-Initiation-Of-New-Phase-III-Clinical-Study-AHEAD-3-45-Of-BAN2401-Preclinical-Asymptomatic-Alzheimers-Disease.

2. Swanson CJ, Zhang Y, Dhadda S, et al. Persistence Of BAN2401-Mediated Amyloid Reductions Post-treatment: A Preliminary Comparison of Amyloid Status Between the Core Phase of BAN2401-G000-201 and Baseline of the Open-Label Extension Phase in Subjects with Early Alzheimer’s Disease. Neurology. 2020;94(15 Suppl): 1330.

2. Eisai and Biogen announce positive topline results of the final analysis for BAN2401 at 18 months [press release]. Tokyo, Japan: Eisai; and Cambridge, MA: Biogen Inc. Published July 5, 2018. Accessed July 14, 2020. investors.biogen.com/news-releases/news-release-details/eisai-and-biogen-announce-positive-topline-results-final.