Development of oral KCC2 enhancer drug for treatment of painful diabetic neuropathy

Abstract: there is a need for more effective drug treatments for diabetic neuropathic pain (DNP), which affects one-third of people with diabetes. Current analgesics have unpredictable efficacy and debilitating side effects that can outweigh pain relief. Despite its impact on quality of life, there are no disease-modifying treatments for DNP. In recent years, growing evidence shows that neuropathic pain in diabetic neuropathy and other disorders is caused by spinal disinhibition secondary to hypofunction of KCC2, a CNS-specific chloride transporter that is essential for neuronal responses to inhibitory neurotransmission. KCC2-enhancing treatments are effective in animal models of neuropathic pain, including diabetic rats, with analgesic effects in both males and females. Therefore, treatments that restore KCC2 function and neuronal chloride homeostasis within dorsal spinal cord could directly address central pathological mechanisms of DNP, therapy alleviating neuropathic pain and improving quality of life of DNP patients. Axonis therapeutics is advancing a first-in- class oral KCC2 enhancer drug, AXN-006-01-3, towards clinic with GLP-toxicology studies planned for Q4 2022. In this phase 1 sbir application, we aim to complete key proof of concept studies to show that AXN- 006-01-3 can treat neuropathic pain in a DNP model. Additionally, impaired hrdd is a biomarker of spinal disinhibition, and correlates with drug analgesic efficacy, in both DNP models and patients. Because hrdd impairments reflect KCC2 hypofunction and respond to KCC2 treatments, we will examine hrdd as a translational, electrophysiological biomarker of our KCC2-enhancing small molecule drug for DNP. Finally, we will investigate PK/PD relationships using a confocal-based neuronal KCC2 biomarker.