Study Rationale: The complexity of Parkinson’s disease (PD) has contributed to the poor success rate in drug development. At Neumora we seek to understand this complexity by identifying the biological drivers for disease in specific patients and then linking them to therapeutic approaches using contemporary computational methods. Lysosome dysfunction has been linked to the pathogenesis of PD, with many genetic risk factors having direct impact on lysosome biology. Mutations in GBA1 are the most common genetic cause of PD, which is driven by partial loss-of-function of the lysosomal glucocerebrosidase enzyme (GCase). Restoration of GCase function is predicted to slow PD disease progression, therefore the development of small molecule activators of the GCase enzyme permits the testing of this therapeutic hypothesis in the clinic.
Hypothesis: Our work seeks to advance Neumora’s small molecule activator of the GCase enzyme, NMRA-GBA001 toward the clinic to test the therapeutic hypothesis that increases in lysosomal function will slow disease progression for PD patients carrying a GBA1 mutation, as well as a group of idiopathic PD patients with reduced GCase function.
Study Design: In order to progress NMRA-GBA001to human trials, we need to conduct appropriate studies to support development of translational endpoints and IND-filing. These studies include 1) translational biomarker development to support target engagement, as well as, for downstream lysosomal function that is indicative of our drug having an effect in the brain. 2) Demonstrating that our small molecule enters the CNS and engages the target when dosed in pre-clinical models. 3) Studies evaluating long-term toxicity and safety of NMRA-GBA001 in small and large pre-clinical models, as well as manufacture and characterization of a batch of NMRA-GBA001 to conduct these studies.
Impact on Diagnosis/Treatment of Parkinson’s disease: The advancement of NMRA-GBA001, a potential best-in-class GCase modulator/activator, provides the field with the best chance to test whether increasing neuronal lysosomal function can slow PD disease progression. In addition, as noted below, Neumora has the potential to develop an enrichment approach for idiopathic PD patients to identify those who would gain the most benefit.
Next Steps for Development: In parallel to the grant funded activities, Neumora is advancing other efforts to support clinical development plans for NMRA-GBA001, including development of a Precision Approach to enable expansion of the GCase activation therapeutic hypothesis into idiopathic PD patients. The team is already planning for clinical development, including discussions with CROs and centers that could execute studies, including the Center for Human Drug Research (CHDR), who has a large GBA1 patient population, as well as, deeply characterized PD population in the Netherlands. The next steps following the proposed studies include manufacture of drug product to support human clinical trials to enable IND filing to advance NMRA-GBA001 into Phase 1 evaluation in healthy volunteers and PD patients.