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

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.