# Preclinical and early clinical development of a GABA-A a5 PAM

> **NIH NIH U01** · AGENEBIO, INC. · 2024 · $1,100,000

## Abstract

The overall objective of this UO1 application is to advance the development of BPN-27473, a potent, selective
and orally active GABA-A α5 Positive Allosteric Modulator (PAM) for the treatment of Mild Cognitive
Impairment due to Alzheimer’s Disease (MCI due to AD). As yet, no treatment has shown significant and
reliable therapeutic efficacy on the progression of AD in patients making this an area of extremely high unmet
need. There is strong support from preclinical AD models and human patients, particularly in this early stage
of AD, that neuronal circuits in the hippocampus become excessively active contributing to neuronal pathology
and brain dysfunction. AgeneBio’s GABA-A α5 PAM program represents a novel approach to addressing the
excess hippocampal activity in this patient population at high risk for dementia.
The concept that reduction of hippocampal overactivity is therapeutically beneficial is supported by recent
preclinical and clinical studies using the atypical antiepileptic levetiracetam. Ranging from research on age-
associated memory impairment in rodents to clinical studies in patients with amnestic MCI, beneficial effects on
key circuits in the medial temporal lobe/hippocampus and on memory performance have been demonstrated
by treatment at low doses of levetiracetam that reduce hippocampal overactivity. The strong hippocampal
localization of GABA-A α5 receptors coupled with its role to control tonic inhibition make GABA-A α5 PAMs
well suited to reduce the excess hippocampal activity in MCI due to AD.
BPN-27473 has been well characterized and is a potent, highly selective and orally active GABA-A α5 PAM
that meets discovery in vitro and in vivo criteria. BPN-27473 shows good in vivo receptor occupancy and
studies in rats with age-associated memory loss (a model which shows hippocampal overactivity) demonstrate
that BPN-27473 is effective on improving memory performance after both acute and chronic administration. A
rat dose-range finding study has shown that doses > 15-fold the MED do not have limiting safety or toxicity
liabilities. A suitable scaleup process to enable manufacture large quantities of material has been
demonstrated.
The current proposal will expand both non-GMP and GMP scale up of BPN-27473 manufacture to enable
sufficient supplies for the completion IND-enabling safety studies in rats and dogs/monkeys. Formulation and
drug product development will be completed to have a suitable dosage form for Phase I studies. A pre-IND
meeting will be requested from the FDA and the IND will be submitted. A Phase 1 single ascending dose study
in healthy elderly volunteers will be completed. These studies will enable a thorough understanding of the
safety and tolerability of BPN-27473 and its utility for further clinical development.

## Key facts

- **NIH application ID:** 10914059
- **Project number:** 5U01AG074950-03
- **Recipient organization:** AGENEBIO, INC.
- **Principal Investigator:** Kenneth G Payie
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,100,000
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914059

## Citation

> US National Institutes of Health, RePORTER application 10914059, Preclinical and early clinical development of a GABA-A a5 PAM (5U01AG074950-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10914059. Licensed CC0.

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