CMS121

Mouse studies in Alzheimer's disease models

• The treatment design used APPswe/PS1dE9 transgenic mice: the mice were aged to 9 months, a point at which they already show cognitive impairment, then fed CMS121 at 400 ppm in the diet, about 34 mg/kg a day by the authors' calculation, for 3 months. CMS121 reduced lipid peroxidation and neuroinflammation in the brain and preserved performance on the plus maze test of disinhibition, a two-day water maze and fear conditioning. The same study identified fatty acid synthase as the target and reported that CMS121 lowered brain polyunsaturated fatty acids and inhibited several lipoxygenases (PMID: 32863221, PMID: 39422940).
• SAMP8 mice age rapidly; in this study the mice were aged to 9 months and then fed CMS121 at 400 ppm for 4 months, to 13 months of age, with 9-month-old mice as a young comparison group. CMS121 reduced metabolic and transcriptional markers of aging in the brain and kept Barnes maze and plus maze behaviour at the level of the 9-month-old controls, and it raised acetyl-CoA, inhibited acetyl-CoA carboxylase 1 and increased histone H3K9 acetylation (PMID: 31742554).
• A separate report on the same SAMP8 mouse model looked at brain and kidney: female SAMP8 mice on CMS121 at 400 ppm from 9 to 13 months spent less time in the open arms of the plus maze than untreated old mice, regained kidney weight and avoided the age-related rise in plasma creatinine. Of 38 proteins measured, 10 in brain and 9 in kidney changed with age and were moved back toward young levels by treatment, and the sets barely overlapped between the two organs. In the same paper, CMS121 at 5 micromolar increased survival of male Drosophila by 8.46 percent (p=0.017) (PMID: 33550278).

Other mouse models

• In Huntington's disease models, CMS121 slowed the loss of motor function and increased median lifespan in both R6/2 and YAC128 mice, with the effect on motor decline in YAC128 mice growing as the mice aged, and it reduced disease-driven changes in striatal genes linked to the proteasome and oxidative phosphorylation (PMID: 37864765).
• In db/db mice, a model of type 2 diabetes, six months of CMS121 at 400 ppm did not change food or oxygen consumption, body mass or locomotor activity, but body weight fell about 5 percent, glucose tolerance improved, glycated hemoglobin and insulin fell, blood and liver triglycerides and free fatty acids fell, markers of liver inflammation (nuclear NF-kB, IL-18, C-reactive protein, caspase 3 activity) fell, and urine albumin, clusterin and NGAL fell, which the authors read as protection of the glomerulus and distal tubules (PMID: 37047807).
• Wild-type mice fed CMS121 for 6 months to the age of 7 months gained 40 percent less weight than control mice and had better glucose and lipid measures, lower liver caspase 1, caspase 3 and NOX4, higher Nrf1, TFAM and GLUT4 in fat tissue, a higher resting metabolic rate and higher plasma short-chain acylcarnitines and butyrate metabolites (PMID: 38517358).
• In a study of age-related hearing loss, sixteen female SAMP8 mice were split between control diet and CMS121 at 200 ppm, about 17 mg/kg a day, from 4 weeks of age. At 13 weeks the control group had worse auditory brainstem response thresholds at 12 kHz (56.5 against 39.8, p=0.044) and 16 kHz (64.8 against 43.8, p=0.040), and fewer paired ribbon synapses per inner hair cell (15.7 against 18.4, p=0.014) (PMID: 37097512).

Cell studies

The founding chemistry paper reported fisetin derivatives with greatly improved activity in two cell neuroprotection assays while keeping glutathione maintenance under stress, from a series of more than 160 compounds (PMID: 22192055). CMS121 is used elsewhere as a tool inhibitor of the lipogenic enzymes: it reduced the infectivity of newly released herpes simplex virus type 1 in cell culture when used as a fatty acid synthase inhibitor (PMID: 40327680), reversed the block on acetyl-CoA carboxylase 1 phosphorylation caused by a long noncoding RNA in human umbilical vein endothelial cells under high glucose (PMID: 40273967), reduced lipid accumulation in a cell model of fatty liver disease when used to inhibit the same enzyme (PMID: 38395901), and amplified trained immunity responses in human monocytes given BCG (PMID: 42642930). None of these is a study of CMS121 as a treatment.

Who did the work

Almost all of the efficacy and target work comes from one laboratory, the Cellular Neurobiology Laboratory at the Salk Institute for Biological Studies, with Pamela Maher, Antonio Currais and David Schubert as recurring authors (PMID: 22192055, PMID: 31742554, PMID: 32863221, PMID: 33550278, PMID: 37047807, PMID: 38517358). The development and toxicology review and the phase 1 preprint are coauthored with William Raschke of Virogenics, Inc., the trial sponsor (PMID: 39422940, PMID: 40093210). The hearing study was run with the Department of Otolaryngology at the University of California San Diego (PMID: 37097512).

Genotoxicity tests

CMS121 was negative in a bacterial reverse mutation assay in four Salmonella strains and one Escherichia coli strain, with and without rat liver S9 activation, while all positive controls behaved as expected. It was also negative for structural and numerical chromosomal aberrations in cultured human peripheral blood lymphocytes, with and without S9 activation (PMID: 39422940).

Safety pharmacology in animals

A functional observation battery in rats given single oral doses of 100, 300 or 1,000 mg/kg found no change in any parameter measured. In telemetered dogs given single oral doses of 10, 30 or 100 mg/kg there were no effects on blood pressure, heart rate or body temperature, and respiratory flow function, respiration rate, tidal volume and minute volume did not change at any dose. The 28-day dog study found no electrocardiogram changes (including no significant increase in the corrected QT interval) at doses up to 100 mg/kg a day (PMID: 39422940).

Repeat-dose toxicity in rats and dogs

In a 28-day oral study in rats at 100, 300 and 1,000 mg/kg a day there were no deaths and no adverse effects on clinical observations, ophthalmology, clinical pathology or microscopic examination, although male rats gained less weight at the higher doses; the no-observed-adverse-effect level was set at 1,000 mg/kg a day, the highest dose tested. A 14-day study in dogs at up to 300 mg/kg a day produced vomiting, loose and reddish feces, thinness, reduced activity, smaller spleen and thymus, hepatocellular vacuolation, ileal mucosal hemorrhage, renal cortical tubular degeneration and lymphoid depletion at the top dose, which was taken as the maximum tolerated dose. In the 28-day dog study the top dose was cut from 100 to 75 mg/kg a day in the second week because of weight loss and reduced food intake, and at that dose the dogs had vomiting, watery or loose feces, microscopic kidney changes and, in one animal, higher creatinine and blood urea nitrogen; those kidney findings were judged adverse, so the no-observed-adverse-effect level in dogs was 30 mg/kg a day (PMID: 39422940).

Gaps

No human data exist beyond 7 days of dosing. No published study describes CMS121 in pregnancy, in lactation, in children, in liver or kidney disease, or in combination with any other drug. Because fatty acid synthase is a normal enzyme of lipid synthesis in many tissues, long-term inhibition in people has no safety record.