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

> **NIH NIH U01** · VIROGENICS, INC. · 2024 · $1,594,649

## Abstract

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...

## Key facts

- **NIH application ID:** 10779413
- **Project number:** 1U01AG084549-01
- **Recipient organization:** VIROGENICS, INC.
- **Principal Investigator:** Pamela Anne Maher
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,594,649
- **Award type:** 1
- **Project period:** 2024-09-24 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10779413

## Citation

> US National Institutes of Health, RePORTER application 10779413, Long-term, non-clinical toxicology for advancing CMS121 to Phase 2 trials for AD (1U01AG084549-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10779413. Licensed CC0.

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