U01AG084549

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.

Virogenics

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

San Diego, California 921211425 United States

Single Zip Code

Alzheimer's Drug-Development Program (U01 Clinical Trial Optional) (PAR-22-047)

Amendment Since initial award the total obligations have increased 98% from $1,594,649 to $3,156,836.