New therapies and clinical trials S. Rosenzweig-Lipson 1, ,*R. Barton 1, M. Gallagher 2, R. Mohs 1. 1AgeneBio, Inc – Baltimore (United States), 2Johns Hopkins University – Baltimore (United States) *Corresponding author(s). Email: sharon.rosenzweig-lipson@agenebio.com (S.Rosenzweig-Lipson)

Abstract:

Background:

No effective therapies exist to halt or reverse Alzheimer’s disease (AD). With a predicted prevalence of AD cases rising to >100 million worldwide by 2050, the need for such therapies is urgent. The prevalence of patients with AD dementia, who represent the greatest human and economic burden, could be dramatically reduced by preventing or delaying progression in early phases of the disease, such as Mild Cognitive Impairment (MCI) due to AD (prodromal AD). There is now strong evidence from preclinical models and human patients that neuronal circuits become hyperactive in prodromal AD contributing to the accumulation and spread of Alzheimer’s pathology and to subsequent cognitive decline. Hippocampal hyperactivity is most pronounced in patients with amnestic MCI and deposited amyloid as determined by amyloid PET imaging (MCI due to AD). AgeneBio is developing therapeutics to reduce hippocampal overactivity and slow progression to Alzheimer’s dementia.

Extensive clinical and preclinical data support the hypothesis that neural overactivity is a critical driver of AD neuropathology, including the deposition of amyloid and spread of tau along connectional pathways. AGB101 (low dose levetiracetam) demonstrates efficacy on a range of molecular, synaptic, electrophysiological, functional and behavioral endpoints across models (age-related memory impairment, amyloid, tau) and species (flies, mice, rats, aMCI in humans). In a Phase 2 study measuring hippocampal activity during a pattern separation memory test in patients with aMCI, AGB101 normalized hippocampal activity and improved performance on this highly specific memory assessment of hippocampal function. The HOPE4MCI trial (currently in progress) is investigating the effects of AGB101 (220 mg) vs placebo in patients with MCI due to AD.

Objectives: Primary objective: To assess the efficacy of AGB101 (low-dose levetiracetam, 220 mg, extended release tablet) compared to placebo in subjects with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) using Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores.

Secondary objectives: To assess the efficacy of AGB101 compared to placebo on: 1) FAQ and MMSE scores 2) neuronal injury, as measured by a change in the entorhinal cortex thickness Additional secondary objectives: To assess the efficacy of AGB101 compared to placebo on: 1) CDR (global, memory box), BPS-O task, and ISLT scores 2) hippocampal volume 3) the levels of tau protein in the brain using the tau PET ([18F]MK-6240)

Methods: This is a multicenter, randomized, double-blind, placebo-controlled, 78-week, fixed-dose study evaluating AGB101 versus placebo as a treatment for slowing the progression of MCI due to AD. A total of 830 subjects will be randomized (415/treatment group).

Inclusion criteria: Subjects must meet all of the following inclusion criteria at screening: 1) Subjects between 55 and 85 years old (inclusive) in good general health 2) Have a study partner who has sufficient contact with the subject to be able to provide assessment of memory changes, who can accompany the subject to the screening and all major clinic visits for the duration of those visits, and who is able to provide an independent evaluation of the subject’s functioning. 3) Have MCI due to AD as defined by all of the following criteria and consistent with the National Institute on Aging-Alzheimer’s Association criteria – MMSE scores between 24 and 30 (inclusive) – A memory complaint reported by the subject or his/her study partner. – Evidence of lower memory performance based on the delayed recall portion of the ISLT. – A Clinical Dementia Rating (CDR) score of 0.5 with a memory box score of ≥ 0.5. – Essentially preserved activities of daily living. – Cognitive decline not primarily caused by vascular, traumatic, or medical problems (alternative causes of cognitive decline are ruled out). 4) Evidence of an amyloid-positive PET scan

Results: The HOPE4MCI trial is currently underway. Sites are currently enrolling in the US and Canada with plans to expand to Europe. Up to date subject demographics, screen failure information, safety and dropout information will be presented at the meeting.

Conclusions: HOPE4MCI represents the first and only Phase 3 clinical trial targeting the reduction of hippocampal overactivity for slowing the progression of MCI due to AD.t The HOPE4MCI trial is supported, in part, by R01AG061091 to RM and R01AG048349 to MG.