Dr Lynn KramerLynn Kramer, MD
Preliminary analysis from the ongoing open-label extension (OLE) of the BAN2401-G000-201 clinical trial (NCT01767311) suggests that negative amyloid positron emission tomography (PET) persists over time in patients treated with Eisai’s investigational Alzheimer disease agent, BAN2401.1

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, which were accepted to the American Academy of Neurology (AAN) 2020 Annual Meeting, were collected by Lynn Kramer, MD, chief clinical officer, Neurology Business Group, Eisai, and colleagues.

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.1,2

In the core study, the mean baseline PET SUVR for the 10mg/kg biweekly group was 1.36 (n = 14). In this preliminary analysis, the mean PET SUVR change from core baseline to OLE baseline was −0.29 (n = 12), which was comparable to the mean change of −0.30 (n = 13) observed from baseline to 18 months treatment in the core study, despite a mean time off study drug of 29.4 months.
 
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“BAN2401, a humanized IgG1 monoclonal antibody, selectively binds Aβ protofibrils over monomers (≥1000-fold) and fibrils (≥10-fold),” Kramer et al. wrote. “BAN2401 treatment demonstrated brain amyloid reduction in the core phase 2 study, with up to 81% subjects returning on visual read from amyloid positive to negative at 18 months in the 10mg/kg biweekly group.”

Kramer and colleagues noted that eligible patients for this assessment were those who fulfilled OLE inclusion/exclusion criteria, with all subjects required to be amyloid positive at baseline in core study, based on PET visual read or CSF. Amyloid PET status was determined at OLE baseline. “Due to timing of OLE implementation, there was no limitation on time off drug prior to entering OLE,” they wrote.

The core, double-blind, placebo-controlled, parallel-group phase 2 trial randomized 856 patients with mild cognitive impairment (MCI) caused by either AD or mild Alzheimer dementia, to either placebo, or 1 of 5 active treatment arms, consisting of 3 biweekly doses (2.5 mg/kg, 5 mg/kg, or 10 mg/kg) and 2 monthly doses (5 mg/kg or 10 mg/kg). Results showed that the highest dose, 10 mg/kg administered biweekly, resulted in a slowing of disease progression after 18 months compared to placebo. In that group, the amyloid PET analysis also showed significant reductions of amyloid PET SUVR and amyloid PET image visual read of subjects converting from positive to negative for amyloid in the brain.2

Safety results also showed that the therapy was acceptably tolerable. The most common treatment-emergent adverse event (AE) reported was infusion-related reactions, most being mild to moderate, and Amyloid-Related Imaging Abnormalities (ARIA). ARIA edema did not occur in >10% of patients in any treatment arms, nor <15% of patients with APIOE4 at the highest dose, per protocol safety and reporting methods.

Despite a number of failures, including recent negative assessments in the Alzheimer space, Eisai has continued to push along with its investigational amyloid agents. In December 2019, Harald J. Hampel, MD, PhD, MA, MSc, vice president and chief medical officer, Neurology Business Group, Eisai, told NeurologyLive that the company plans to stay the course on the amyloid theory in light of the many signals pointing in other directions, in part due to Biogen’s plans to pursue regulatory approval for aducanumab, an investigational treatment for early Alzheimer as well as previously presented BAN2401 data. “This news strengthens the relevance of the amyloid biochemical pathway in the pathophysiology of Alzheimer and for targeted disease-modifying therapy,” he said.

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REFERENCES
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 May 11, 2020. investors.biogen.com/news-releases/news-release-details/eisai-and-biogen-announce-positive-topline-results-final.