# Development of Oral KCC2 Potentiator AXN-027 as a Novel Anti-Epileptic Drug for Mesial Temporal Lobe Epilepsy

> **NIH NIH R43** · AXONIS THERAPEUTICS, INC. · 2024 · $323,001

## Abstract

Development of oral KCC2 potentiator AXN-027 as a novel anti-epileptic drug for mesial
temporal lobe epilepsy
Abstract:
Patients with mesial temporal lobe epilepsy (mTLE) have spontaneous recurrent seizures (SRS) that are often
refractory to commonly used antiepileptic drug (AEDs). New targets and therapies are thus urgently required to
address this drug resistance in ~40% of patients. Loss of excitation/inhibition (E/I) balance in neuronal circuits is
a pathological hallmark of epilepsy. KCC2 is a CNS-specific potassium/chloride cotransporter that maintains low
intracellular chloride in neurons, and is critical for enabling GABAergic inhibition. However, KCC2 hypofunction
occurs in patients with both idiopathic and acquired epilepsy, while KCC2-deficient mice have increased seizure
susceptibility and mTLE pathologies. The resulting abnormally high chloride in neurons is thought to lead to
pathological excitatory responses to GABA, and limit efficacy of GABA-acting AEDs. Increasing KCC2 function
via genetic, viral and pharmacological approaches protects against epileptic seizures in vivo and in vitro.
Therefore, a KCC2-potentiating treatment could restore E/I balance, rescue pharmacoresistance, and treat SRS
in mTLE patients. But there are no FDA-approved drugs that selectively potentiate KCC2.
 AXONIS’ are developing proprietary compounds that selectively potentiate KCC2 function by binding to
KCC2, increasing KCC2 surface clustering, and increasing KCC2 chloride extrusion. AXONIS’ lead KCC2
potentiator, AXN-027, is a highly optimized orally-bioavailable compound selected from extensive structure-
activity relationship work driven by potency and CNS-favorable ADME/PK properties. In this Phase 1 SBIR, we
will use a well-characterized intrahippocampal kainate-induced mouse model of mTLE with chronic SRS and
electroencephalogram (EEG) to investigate anti-seizure efficacy of AXN-027, which will enable development of
a first-in-class KCC2-potentiating AED to treat mTLE patients.

## Key facts

- **NIH application ID:** 10922018
- **Project number:** 1R43NS137942-01
- **Recipient organization:** AXONIS THERAPEUTICS, INC.
- **Principal Investigator:** Shane Hegarty
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $323,001
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922018

## Citation

> US National Institutes of Health, RePORTER application 10922018, Development of Oral KCC2 Potentiator AXN-027 as a Novel Anti-Epileptic Drug for Mesial Temporal Lobe Epilepsy (1R43NS137942-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10922018. Licensed CC0.

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