# A Phase 3 Pivotal Trial of AGB101 to Slow Progression in MCI due to Alzheimer's Disease

> **NIH NIH R01** · AGENEBIO, INC. · 2021 · $2,844,834

## Abstract

This is a submission for partial support of a pivotal Phase 3 study responsive to PAR-18-028. The
clinical trial uses a novel approach to Alzheimer’s disease in patients at high risk for dementia. It will
test the efficacy of a low-dose formulation of the SV2a antagonist levetiracetam (AGB101) to slow
disease progression in patients with amnestic Mild Cognitive Impairment (aMCI) due to Alzheimer’s
disease (AD). The entire Phase 3 program will include 830 patients randomly assigned to either
AGB101 or placebo and followed for 78 weeks using the Clinical Dementia Rating sum of boxes
(CDRsb) as a sole primary efficacy measure as agreed upon with the FDA at the End of Phase 2
meeting. As partial support for the trial under a public private partnership, the funds requested in this
application support a substudy of 160 patients (out of the total 830), who will follow the full phase 3
protocol with the addition of tau PET imaging at baseline and endpoint to assess the effect of AGB101
on the spread of tau pathology. Extensive clinical and preclinical data support the hypothesis that
neural overactivity is a critical driver of neuropathology leading to neuronal death in early AD and
strongly support the hypothesis that hippocampal overactivity is a driver of the spread of tau
pathology. This overactivity is most prominent in patients with clinical MCI and deposited amyloid as
determined by amyloid PET imaging (aMCI due to AD). As described in the application, extensive
preclinical data also show that the antiepileptic drug levetiracetam given in low, but not at the much
higher doses used to treat epilepsy, restores hippocampal activity to normal levels and prevents
neurodegeneration; other antiepileptic drugs that are not SV2a antagonists do not have this
neurobiological effect. A Phase 2 study measuring hippocampal activity during a pattern separation
memory test in patients with aMCI found that AGB101 normalized hippocampal activity and improved
performance on this highly specific memory test for assessment of hippocampal function. Most
importantly, the proposed substudy will provide a robust test of the ability of AGB101 to restore normal
hippocampal activity when given chronically and the relationship of this normalization to the spread of
tau pathology as assessed in tau PET imaging together with a longitudinal series of 3T MRI structural
imaging optimized for the medial temporal lobe circuits the define early Braak staging. Thus, alongside
partial support for the Phase 3 trial, with possible registration of a new therapeutic by 2021, support
under this award will potentially contribute to biomarker development by testing the hypothesis that
excess neural activity drives disease progression, specifically the spread of tau pathology.

## Key facts

- **NIH application ID:** 10170206
- **Project number:** 5R01AG061091-04
- **Recipient organization:** AGENEBIO, INC.
- **Principal Investigator:** RICHARD Charles MOHS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,844,834
- **Award type:** 5
- **Project period:** 2018-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170206

## Citation

> US National Institutes of Health, RePORTER application 10170206, A Phase 3 Pivotal Trial of AGB101 to Slow Progression in MCI due to Alzheimer's Disease (5R01AG061091-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10170206. Licensed CC0.

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