The overall aim of this proposal is the acquisition of the remaining pre-clinical data required for submission of an Investigational New Drug (IND) application for a human clinical trial of XT-101 for the treatment of neuropathic pain. XT-101 is an encapsulated formulation of an expression plasmid DNA encoding human interleukin-10 (IL-10). There is a tremendous unmet clinical need for safe and effective treatment for neuropathic pain. The failure of current therapeutics to treat neuropathic pain effectively may reflect the fact that all of these agents explicitly target neurons. Over the last two decades, there has been a growing understanding of the importance of glial activation in the development and persistence of neuropathic pain, with exponentially increasing numbers of publications across years documenting the critical importance of glial dysregulation in animal models pathological pain, including neuropathic pain. Critical to the rationale for XT-101 is the fact that it is now solidly documented across animal models that glial dysregulation of pain is created and maintained by the perseverant release of glial pro-inflammatory products in spinal cord. The most important of these spinal glial pro-inflammatory products, for pathological pain in general and for neuropathic pain in particular, are pro- inflammatory cytokines. XT-101, by inducing prolonged production and release of the powerful anti- inflammatory cytokine, IL-10, targets the activated glial cells and glial proinflammatory products that are responsible for supporting and amplifying neuropathic pain signals. XT-101 has been shown to be highly efficacious in the leading animal models for neuropathic pain.
The specific aims for this project are to 1) Develop and implement good manufacturing practice (GMP) process for production of XT-101, 2) Complete all remaining pre-clinical studies necessary to support the filing of an IND with the FDA, and 3) Prepare and file an IND with the FDA for XT-101 in a neuropathic pain indication. To achieve these aims, the project proposes a series of studies, including standard toxicology studies that will demonstrate the safety of XT-101 in appropriate animal models and provide information to guide human dosing. Based on our pre-IND meeting with the FDA, we expect that the data obtained from the successful completion of these studies, along with the substantial existing data supporting the safety and efficacy of XT- 101, will be sufficient to support the filing of an IND with the FDA.
Neuropathic pain afflicts over 6 million Americans and has devastating personal, economic and social impacts. 40% to 60% of patients with neuropathic pain receive no relief or inadequate relief from existing therapies, with those most severely affected being the least likely to be helped. The successful development of XT-101 will provide a safe, efficacious, non-opioid treatment option for patients afflicted with neuropathic pain.