Mitofusin agonists for the treatment of neurodegenerative diseases Gerald W Dorn II, MD Mitochondria in Motion, Inc. Washington University in St Louis School of Medicine Abstract: A number of rare neurodegenerative diseases are characterized by mitochondrial fragmentation, dysmotility and dysfunction. Among these are Amyotrophic Lateral Sclerosis (ALS) and Huntington’s Disease (HD), which cause significant morbidity and mortality in affected populations and for which there are no available disease-altering therapies. With Phase I STTR support, Mitochondria in Motion, Inc. (MiM) has developed the first pharmaceutically acceptable small molecule mitofusin activators to treat these and other neurodegenerative conditions with underlying contributory mitochondrial pathology. Mitofusin activation enhances mitochondrial fitness, metabolism and trafficking within diseased neurons, thereby improving homeostatic functioning, conferring resistance to injury and promoting neuronal repair/regrowth. During phase I we hypothesized that intervention with a mitofusin activator would have beneficial effects on etiologically diverse genetic peripheral neuropathies with a mitochondrial component. This notion was validated by phase I studies and MiM is advancing 2 pre-clinical lead mitofusin activators, CPR1-B for sustained activation in genetically heterogenous diseases like ALS and HD not caused by mitofusin (MFN) mutations, and MiM-111 for “burst” activation in Charcot-Marie- Tooth disease type 2A (CMT2A) that is directly caused by mutations in MFN2. Having identified CPR1-B as a clinical candidate in non-CMT2A neuropathies like ALS and HD, our Phase II goals are to initiate non GMP pre-IND studies positioning us for FDA IND approval (Aim 1) and define optimal CPR1-B dosing levels and schedule in ALS and HD mouse models (Aim 2). If successful we will fill an unmet healthcare need and build a commercial enterprise to serve the ~20,000 Americans with ALS and the ~150,000 Americans suffering from or at genetic risk for developing HD, their caregivers and families. Our deliverable in Phase II will be a mitofusin activator positioned for FDA IND approval and phase 1 first-in-human trials.