Preclinical development of a novel therapeutic for Parkinson's disease

Project Summary Parkinson’s Disease (PD) is the second most common neurodegenerative disorder, afflicting ~1 million Americans. Levodopa is the gold-standard symptomatic treatment for PD by elevating dopamine levels in the brain. Though the most effective treatment, prolonged levodopa use leads to 1) the debilitating side effect, levodopa-induced dyskinesia (LID), and 2) diminished levodopa efficacy which leads to fluctuations of PD symptoms, known as “wearing-off”. These concerns are two of the greatest unmet needs in PD and affect how doctors prescribe dosages and treatment options, impacting the efficacy of the necessary medications for PD. After 5 years of levodopa usage, 40% of PD patients will develop LID and/or fluctuations. Not only having a clinical impact, but PD patients with such complications require nearly $60,000 of additional therapeutics every year. Using Sinopia Biosciences’ computational platform, we studied gene expression changes due to levodopa administered to 6-OHDA lesioned PD-like mice. Applying our computational workflow, we identified a small molecule (SB-0107) that was selected based on: 1) having one of the top scores from our platform, 2) its novel mechanism of action, 3) previous clinical exposure to elderly patients, 4) its predicted CNS penetration properties, and 5) its potential for patent protection. Subsequently, we demonstrated the compound’s unique and potentially transformative pharmacology for treating both the symptoms of PD and complications of levodopa (i.e. LID). In both rodent and primate models, SB-0107 shows large effect sizes. Further, we observed in a cognitive deficit primate model of PD that SB-0107 improves performances in the tested cognitive tasks. Thus, SB-0107 represents a promising candidate for advancement to the clinic for PD. In this Fast-Track proposal, we will advance the compound by completing preclinical development studies for anticipation of IND submission.Project Narrative Levodopa is the primary treatment for Parkinson’s Disease, a neurodegenerative disease that afflicts 1 million Americans. Unfortunately, levodopa has serious side effects and loses its efficacy over time. Using Sinopia Biosciences’s computational drug discovery platform, we identified a small molecule that we subsequently tested and validated in relevant rodent and primate models, providing a unique mechanism for treating Parkinson’s Disease. This proposal will complete preclinical drug development for this compound in order to advance to the clinic.