Long-term, non-clinical toxicology for advancing CMS121 to Phase 2 trials for AD

Abstract Our goal is to advance CMS121 to a Phase 2 clinical trial by conducting the long-term non-clinical toxicology studies needed to support a long-term course of daily administration to subjects with mild to moderate Alzheimer's Disease (AD). CMS121 is a small molecule that has shown efficacy in multiple mouse models of

Alzheimer's Disease (AD) and offers a novel therapeutic approach for treatment of AD in humans. While the recently approved drugs for AD reduce Aβ plaque load, their effects on the key clinical hallmarks of the disease, such as impaired memory and loss of executive function, are not yet clear. Thus, there is a

continued need for additional AD drug candidates, especially ones that address these debilitating features of AD. We believe that an effective AD drug will have to demonstrate powerful effects against multiple pathological processes. A truly disease-modifying drug with long-term therapeutic benefits and immediate cognitive benefits

would be a tremendous benefit to the millions affected by AD. CMS121 was derived using a novel approach to AD drug development and interacts with targets distinct from those of other AD drugs and drug candidates, thereby providing an altogether new approach to disease treatment. CMS121 was developed in conjunction with Salk Institute scientists. The parent compound, identified from a

broad screen of compounds for neuroprotective activity, was modified to obtain a series of derivatives with vastly superior protective and pharmacologic characteristics. The derivative, CMS121, prevents and reverses a number of the behavioral symptoms associated with AD in both genetic and sporadic mouse models of AD.

Studies of the mechanism of action show that CMS121 affects multiple, specific regulators of lipid synthesis and metabolism, resulting in a reduction in fatty acid synthesis and lipid peroxidation and an enhancement of mitochondrial homeostasis. All of these features are altered in AD brains and these alterations are associated

with neuroinflammation. Furthermore, a restoration of these alterations to normal levels has been shown to be beneficial in multiple models of AD. A Phase 1 clinical trial of CMS121 is now wrapping up as the last dosing was concluded a few weeks ago (December, 2022). The completion of data compilation is in progress. The next step in the evaluation of CMS121

as a therapeutic for AD is a Phase 2 trial, in which subjects with mild cognitive impairment (MCI)/early AD will be dosed for longer durations of daily administration to assess clinical benefits. A longer term treatment is very likely necessary to see improvement in cognition and other parameters for a disease that is characterized by a

slow progression, particularly at the early stages. Before proceeding to the longer duration Phase 2 trials, a long- term toxicology study in animals is required by the FDA to provide critical safety information. The studies proposed in this application are a 6-month rat and a 9-month dog toxicology study, in which dosing will be

administered daily over those periods. The results will guide the dosing and testing design of the Phase 2 human trial.