With the help of Cure Alzheimer’s Fund, we now have conducted a series of optimization studies, which have allowed for fine tuning of dose selection. Furthermore, Amylyx now is completing our IND-enabling studies to bring AMX0035 to clinic. Recently, a series of biomarkers of inflammation, oxidative stress and cellular death have been studied clinically as potential endpoints to make trials easier and cheaper in both AD and ALS. We propose evaluating AMX0035 in a stringent mouse model of innate inflammation that expresses these same biomarkers to make a highly translatable evaluation in this model. Using a phenotypic model that expresses clinic-validated biomarkers hopefully will solve the longstanding issue of a lack of translatability in neurology from mouse models to patients. This study should thus both provide confidence in our drugs and choice of biomarkers, as well as provide a pathway for future drug development.
In Alzheimer’s disease (AD) and other neurodegenerative diseases (ND) such as ALS, neurological inflammation and cell death form a vicious cycle that is one of the main causes of decline. Mitochondrial and endoplasmic reticulum stresses mediate these pathways, accelerating inflammation and triggering apoptosis. Therefore, we developed a combination therapeutic of repurposed compounds to simultaneously reduce endoplasmic reticulum stress and mitochondrial dysfunction to halt the cycle of inflammation and cell death. To date, we have shown that our therapeutic, AMX0035, reduced inflammation and oxidative cellular death in cellular models and reduced soluble amyloid beta in a transgenic mouse model, likely by immunological clearance. While AMX0035 is a promising candidate, a series of optimization studies is needed before it will be ready for IND-enablement. We propose evaluating AMX0035 in the G93A SOD1 mouse model of ALS, a series of in vitro dose optimization studies, healthy rats for pharmacokinetics, and a stringent rat model of innate immune response. The individual components of AMX0035 are clinically well tolerated and easily dosed in our expected dose range, which will facilitate rapid translation to and evaluation in the clinic. The proposed studies therefore will enable us to bring this promising new drug candidate to patients suffering from AD and ALS.