Neuroprotection is important for future therapies for neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS). The small molecule RT1999 (smilagenin) is a neurotrophic modulator with ample data demonstrating increases in neurotrophic factor release (BDNF and GDNF) in the (central) nervous system upon treatment. RT1999 is an orally active, non-peptide, neurotrophic factor modulator that readily crosses the blood-brain barrier. It modulates neurotrophic factors in vitro and is neuroprotective in a variety of neuronal subtypes including dopaminergic, motor, cortical and sensory neurons in vitro, and which has been developed for Parkinson’s disease (PD) and ALS, with a prior P2B clinical trial in PD. Here, we will show the extensive motor neuron protective effects of RT1999 in 3 different ALS mouse models (SOD1-G93A, pmn, and BGGS), all demonstrating increased motor neuron survival upon RT1999 treatment, as well as its support of peripheral plasticity in the sciatic nerve crush model. These unpublished data form the basis on which RT1999 will enter the Phase 2 EXPERTS-ALS clinical trial later this year.