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The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc.The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results.The focus of this article is on the innovative design of the study.The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.

Current synaptic vesicle 2A (SV2A) positron emission tomography (PET) imaging agents include the nanomolar affinity probes [11C]UCB-J and [18F]UCB-H derived from the anti-epileptic drug levitaracetam (Keppra®). An industry-utilized “de-risking” approach was used to carry out initial pharmacological characterization and to assess potential next-generation candidates amenable to F-18 radiolabeling for preliminary evaluation. Radioligand binding methods were employed in mammalian brain homogenates to determine the SV2A affinity (Kd) and maximal binding capacity (Bmax) of [3H]UCB-J. Novel leads were then screened to identify compounds minimally with comparable binding affinities with UCB-J in order to select a F-18-labeled candidate for subsequent in vivo assessment in rat. In parallel, mammalian brain tissue section autoradiography was performed to assess specific SV2A distribution. [3H]UCB-J bound with high affinity to a single population of sites in the rat brain (Kd = 2.6 ± 0.25 nM; Bmax = 810 ± 25 fmol/mg protein) and control human cortex (Kd = 2.9 ± 0.54 nM; Bmax = 10,000 ± 640 fmol/mg protein). Distribution of specific SV2A binding was shown to be homogeneous throughout the rodent brain and primarily in gray matter regions of rodent and human brain sections. Analog screening identified MNI-1038, MNI-1126/SDM-8, and SDM-2 as having comparable binding affinities with the currently available PET ligands. Subsequent [18F]MNI-1126/[18F]SDM-8 dynamic micro-PET imaging in rats revealed in vivo uptake and accumulation in the brain with favorable kinetics. Chase studies using 30 mg/kg levetiracetam confirmed that in vivo brain uptake of [18F]MNI-1126/[18F]SDM-8 was reversible. Taken together, these data suggest [18F]MNI-1126/[18F]SDM-8 (since renamed as [18F]SynVesT-1) characterized via an in vitro screening cascade provided a measurable in vivo SV2A specific signal in the rodent brain. This tracer as well as the close analog [18F]SDM-2 (since renamed as [18F]SynVesT-2) is currently undergoing further evaluation in preclinical and clinical studies.

BACKGROUND/OBJECTIVES: Elenbecestat, an oral BACE-1 inhibitor that has been shown to reduce Aβ levels in cerebrospinal fluid, was investigated in two global phase 3 studies in early AD. Here we report on differences observed in characteristics of APOE ε4 and amyloid positive subjects in the large screening cohort. DESIGN: Screening was performed in 5 sequential tiers over a maximum of 80 days, as part of placebo controlled, double blind phase 3 studies. SETTING: Subjects were evaluated at sites in 7 regions (29 countries). PARTICIPANTS: Overall, 9758 subjects were screened. INTERVENTION: All screened subjects that were eligible received either placebo or 50 mg QID elenbecestat post randomisation. MEASUREMENTS: Gender, disease staging, APOE ε4 status, amyloid status, amyloid positron emission tomography (PET) standard uptake value ratio (SUVr) and amyloid PET Centiloid (CL) values were determined for screened subjects; by country and region. RESULTS: In this program, 44% of subjects were APOE ε4 positive. Frequency of females was similar in both APOE ε4 positive and negative groups. However, early mild AD subjects were slightly higher in the APOE ε4 positive group compared with the APOE ε4 negative group. 56% of subjects were amyloid positive. The mean age in the amyloid positive group was slightly higher than the amyloid negative group. The gender distribution was similar between amyloid groups. A lower number of mild cognitive impairment was observed in the amyloid positive group along with a higher number of early mild AD. APOE ε4 positive subjects were higher in amyloid positive group compared to the amyloid negative group. China had the lowest APOE ε4 and amyloid positivity rates with Western Europe and Oceania performing best. Subjects received florbetapir, florbetaben or flutemetamol amyloid PET tracer. Amyloid negative and positive subjects CL values were normally distributed around their respective means of 1.5 CL and 83 CL. However, there was an appreciable overlap in the 20-40 CL range. CONCLUSIONS: In this large cohort of cognitively impaired subjects, subject demographics characteristics were comparable regardless of APOE genotype or amyloid positivity. APOE ε4 positivity and amyloid positivity varied by country and by geographical region.