Development of a topical fixed-dose combination drug for peripheral neuropathic pain.

PROJECT SUMMARY An estimated 30 million people in the United States suffer from some form of peripheral neuropathy, a condition that develops as a result of damage to the peripheral nervous system. The top two major causes of peripheral neuropathy in the US are diabetes mellitus (both T1DM and T2DM) and chemotherapeutic agents. Currently, there are no FDA-approved treatments to prevent or reverse diabetic peripheral neuropathy (DPN) and chemotherapy-induced peripheral neuropathy (CIPN) other than those that simply treat the symptomatic pain. The founders of WinSanTor have demonstrated that peripheral neuron growth is restrained by cholinergic activation of the M1 receptor (M1R) via regulation of mitochondrial respiration. M1R antagonists promote neuronal growth and prevent and/or reverse multiple indices of neuropathy and associated neuropathic pain in nonclinical models of diabetes and CIPN, after chronic administration. Consistent with this, a pilot clinical trial by our academic collaborator using the non-selective muscarinic receptor antagonist oxybutynin, confirmed reversal of intra-epidermal nerve fiber (IENF) loss in subjects with type 2 diabetes after 5 months of dermal topical treatment, with concurrent reduction of pain. M1R antagonists offer a potentially disease-modifying therapeutic approach for DPN and CIPN. While muscarinic antagonists have been shown to reverse pain after chronic administration (5 months), they do not have acute (minutes to hours following a single application) anti- pain effects. An ideal therapeutic approach would combine both acute palliative and chronic disease-modifying properties, both to retain patient compliance and also block chronification of pain – the concept that ongoing acute pain permanently modifies sensory processing systems. Given the potent effects of topical analgesics such as lidocaine in acutely alleviating pain in some diabetic and CIPN patients, and the promising disease- modifying effects of topical pirenzepine on neuropathic pain, we propose to develop a fixed-dose combination (FDC) product that offers acute pain relief to disrupt the chronification of pain and establish patient medication compliance that also prevents and/or reverses established degenerative neuropathy and associated neuropathic pain. FDC products, which contain two or more separate active ingredients that target different pathways, are a proven way of addressing indications with complex etiology, and offer enhanced efficacy and/or improved disease management than either monotherapy alone. Furthermore, FDCs reduce patient treatment burden and improve compliance, due to the acute pain relief potential. To develop this novel FDC product, we propose to 1) develop an FDC of lidocaine and pirenzepine topical formulation, and 2) test the treatment regime of co-administration of topical lidocaine 5% and pirenzepine 4% in reversing indices of neuropathy and neuropathic pain in mouse models of diabetes and CIPN. The success of Phase I will provide strong support for a Phase II project, where additional pharmacology safety and toxicology studies, as well as CMC work, will be conducted to support an FDA IND submission.PROJECT NARRATIVE Thirty million Americans suffer from some type of peripheral neuropathy, a condition that develops as a result of damage to the peripheral nervous system and is frequently associated with pain. There are no current FDA- approved treatments that target the pathological processes underlying peripheral neuropathy and provide pain relief. WinSanTor is developing a novel fixed-dose combination product that offers acute pain relief to disrupt the chronification of pain and establish patient medication compliance and also prevents and/or reverses established degenerative neuropathy and associated neuropathic pain caused by diabetes and chemotherapy.