Yumanity Therapeutics' (YMTX) YTX-7739 Demonstrates Prevention of Motor Function Deficits in Parkinson’s Disease Mouse Model
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Yumanity Therapeutics (NASDAQ: YMTX), a clinical-stage biopharmaceutical company focused on the discovery and development of innovative, disease-modifying therapies for neurodegenerative diseases, today announced results of a study of its lead program, YTX-7739, that demonstrate pharmacological, physiological and behavioral pre-clinical proof of concept in a Parkinson’s disease (PD) mouse model. This oral presentation and two posters will be presented at the 15th Annual International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD™ 2021) Virtual Conference, March 9 to 14, 2021.
“Evidence suggests that α-synuclein pathology is a strong risk factor for Parkinson’s disease,” said Dan Tardiff, Ph.D., interim Head of Research and Scientific Co-founder at Yumanity Therapeutics. “Our proprietary discovery platform led us to the target stearoyl-CoA desaturase (SCD), which when inhibited decreases the toxicity associated with pathogenic α-synuclein. Inhibition of SCD, an enzyme involved in lipid metabolism, has been shown to prevent α-synuclein pathology in multiple models, including patient-derived neurons, in vitro. The results from the current study demonstrate that YTX-7739 has a similar effect in a mouse model of Parkinson’s disease-related pathology. These results lend additional evidence to support our ongoing clinical program in Parkinson’s disease patients.”
The research entitled, YTX-7739, A Clinical Stage Stearoyl-CoA Desaturase Inhibitor for Parkinson’s Disease Improves Behavioral and Pathological Features in an a-Synuclein Mouse Model, conducted in collaboration with the laboratories of Silke Nuber, Ph.D., and Dennis Selkoe, M.D., at Brigham & Women’s Hospital, will be presented at 12:30 p.m. [CET] on March 13 (live discussion March 13 from 5:30 to 6 p.m. CET) by Dr. Tardiff. The study evaluated YTX-7739 vs. control in the PD mouse model. The model was used to evaluate the effect of the drug on motor function as well as survival of neurons and associated biochemical features. The effects of the drug on lipid metabolism were also examined. The investigators found:
- YTX-7739 prevented motor function deficits in the diseased mice after four months of YTX-7739 oral dosing compared to placebo-treated mice.
- YTX-7739 concentrations in the brain reached a level that engaged and inhibited SCD activity consistent with in vitro studies. In addition, SCD inhibition by YTX-7739, which can be measured by a quantitative biomarker, resulted in a decrease in monounsaturated fatty acids in both plasma and brain. Monounsaturated fatty acids may contribute to α-synuclein pathology.
- Multiple biochemical measures of α-synuclein pathology were significantly improved in mice with YTX-7739 as compared to controls, including levels of pathological α-synuclein. The reduction in levels of pathological α-synuclein was also confirmed via histopathological analysis.
- Mice treated with YTX-7739 exhibited enhanced survival of dopaminergic neurons, the type of neuron that selectively dies in the brains of patients with Parkinson’s disease.
The results indicate that YTX-7739 actively engages with its intended target, SCD, in the mouse brain. The observed improvements in pathology and neuron survival, and the resultant correction of motor dysfunction in mice provided added evidence for SCD inhibition as a potential treatment approach for Parkinson’s disease, and further support for the on-going evaluation of YTX-7739 in humans.
Posters to be presented at AD/PD 2021
Non-Clinical Pharmacokinetic and Pharmacodynamic Properties of YTX-7739, a Clinical Stage Stearoyl-CoA Desaturase Inhibitor for Parkinson’s DiseasePoster #: P499 / #1463Topic: Theme C: α-Synucleinopathies / C2.a. Therapeutic Targets, Mechanisms for Treatment: Αlpha-synucleinAuthors: D. Tardiff, M. Lucas, I. Wrona, B. Chang, C. Chung, B. Le Bourdonnec, K. Rhodes, R. ScannevinSummary: YTX-7739 is an inhibitor of SCD, an enzyme that desaturates fatty acids. The objective of the study was to characterize the pharmacokinetic properties of YTX-7739 in rats and cynomolgus macaques and the corresponding pharmacodynamic changes in fatty acid profiles. YTX-7739 was found to be well-tolerated and brain penetrant in both species. It was a potent inhibitor of SCD in vivo where it reduced the levels of unsaturated fatty acids in a dose dependent manner.
A Three-Dimensional Patient-Derived Cortical Neurosphere Model of Parkinson’s DiseasePoster #: P497 / #942Topic: Theme C: α-Synucleinopathies / C2.a. Therapeutic Targets, Mechanisms for Treatment: Αlpha-synucleinAuthors: W. Raja, E. Neves, C. Burke, X. Jiang, P. Xu, V. Khurana, C. Chung, R. ScannevinSummary: The objective of the study was to develop a patient-derived induced pluripotent stem cell PD model. Three-dimensional neurospheres were created and exhibited relevant PD phenotypes that responded to SCD inhibitors. These neurospheres have been used by Yumanity to evaluate the potential of small molecule therapeutics.
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