Study Rationale: Parkinson’s disease (PD) is characterized by the hallmark accumulation of toxic clumps of alpha-synuclein, particularly a modified form of the protein called pS129. Acurex has developed a small molecule therapeutic that lowers pS129 alpha-synuclein levels and prevents axonal degeneration in multiple PD-relevant models. Our lead compound, CU-12991, is approximately one hundred times more potent at eliminating pS129 alpha-synuclein aggregates than any other publicly disclosed drug. This study therefore aims to further evaluate our lead compound in both in vitro and in vivo pharmacokinetic models, including in well-established rodent models of PD and in PD patient induced pluripotent stem cell (iPSC)-derived dopaminergic neurons.
Hypothesis: This proposal aims to complete the preclinical pharmacology package — including absorption, distribution, metabolism, excretion and toxicology (ADMET) — for CU-12991 or a backup compound; these studies will produce a lead compound ready for IND-enabling studies.
Study Design: This proposal will further characterize our lead compound in ADMET/PK and PD pharmacology studies to identify a candidate drug suitable for IND-enabling studies. To accomplish these analyses, we will scale up production of the compound, conduct in vitro ADMET characterization of dosing and safety and multispecies in vivo ADMET characterization and evaluate the compound in appropriate animal models.
Impact on Diagnosis/Treatment of Parkinson’s disease: Preclinical cellular models of PD indicate that our compound will be a best-in-class, disease-modifying PD therapeutic. A new therapeutic for PD could transform the treatment landscape of the disease by slowing, halting or potentially reversing aspects of neurodegeneration in people with PD.
Next Steps for Development: If successful, this project will produce a compound with suitable dosing, safety and tolerability characteristics to move forward into further clinical development, including IND-enabling studies, animal model efficacy studies and ultimately nominating a clinical candidate and submitting an IND.