FDA Phase 1 Development of a Novel Nonopioid Cell and Tissue Permeable Peptide Therapeutic for Epigenetic Reprogramming of Neuropathic Pain

Neuropathic pain (NeP) affects an estimated 7-10% of the population. In the most severe cases, pain can be disabling, severely affecting a patient’s quality of life and ability to work, therefore causing economic strain. The lack of effective therapeutic options has led physicians to prescribe opioids, contributing to the opioid crisis. A limitation of most of current therapeutic strategies is that they address only the symptoms, but do not target the pathophysiological mechanism that leads to the development of NeP. We have developed a novel, first-in-class therapeutics, ASCT-83, which targets a key molecule that controls the epigenetic changes that lead to the transition from acute to chronic pain: the repressor element-1 (RE1)-silencing transcription factor (REST), a master repressor of neuronal genes. ASCT-83 is a first-in-class and new drug modality (a cell and tissue penetrating peptide), that promotes REST degradation to restore normal neural gene expression. Importantly, in a pre-clinical model, ASCT-83 has also shown the potential added benefit of improving the motor function resulting from peripheral nerve injuries. We have completed the pre-clinical efficacy and safety studies for ASCT-83, and submitted an IND which has received Safe to Proceed letter from the Food and Drug Administration (FDA). Our long-term goal is to develop ASCT-83 into a marketed drug for a treatment for NeP. Our rationale is that, by restoring normal gene expression, ASCT-83 will alleviate NeP. The objective of the proposed study is to fulfill the FDA guidance recommendations for Phase 2 clinical trials, to establishing ASCT-83 reproductive and clinical safety, and derisking ASCT-83 for eventual partnership with a large pharmaceutical company. This objective will be met through the following specific aims: Aim 1. Determine safety and tolerability of ASCT-83 in healthy adults in a Phase 1 single and multiple ascending dose (SAD and MAD) first-in-human clinical trial. Aim 2. Assess fertility and early embryonic development (FEED) toxicity in rat. Aim 3. Determine ASCT-83 safety in sub-chronic general toxicology studies in rat and dog. The successful completion of the proposed studies will allow for the initiation of Phase 2 clinical trials for administration of ASCT-83 in NeP patients.