YTX-7739 demonstrates pharmacological, physiological, and behavioral pre-clinical proof of concept in in vivo model
Study presented at AD/PD™ 2021
BOSTON, March 09, 2021 (GLOBE NEWSWIRE) -- 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 Disease
Poster #: P499 / #1463
Topic: Theme C: α-Synucleinopathies / C2.a. Therapeutic Targets, Mechanisms for Treatment: Αlpha-synuclein
Authors: D. Tardiff, M. Lucas, I. Wrona, B. Chang, C. Chung, B. Le Bourdonnec, K. Rhodes, R. Scannevin
Summary: 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 Disease
Poster #: P497 / #942
Topic: Theme C: α-Synucleinopathies / C2.a. Therapeutic Targets, Mechanisms for Treatment: Αlpha-synuclein
Authors: W. Raja, E. Neves, C. Burke, X. Jiang, P. Xu, V. Khurana, C. Chung, R. Scannevin
Summary: 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.
About YTX-7739
YTX-7739 is Yumanity Therapeutics’ proprietary lead small molecule investigational therapy designed to penetrate the blood-brain barrier and inhibit the activity of a novel target, stearoyl-CoA desaturase (SCD), that plays an important and previously unrecognized role in modulating neurotoxicity arising from the alpha-synuclein protein, a major driver of Parkinson’s disease and related neurodegenerative disorders. Misfolding and aggregation of alpha-synuclein triggers a cascade of events, ultimately resulting in neurotoxicity and the subsequent impairment of movement and cognition that afflicts patients living with this disease. Through inhibition of SCD, YTX-7739 modulates an upstream process in the alpha-synuclein pathological cascade and has been shown to rescue or prevent toxicity in preclinical models. The company is assessing the potential utility of YTX-7739 in Parkinson’s disease.
About SCD
SCD is an enzyme that catalyzes fatty acid desaturation, the products of which are incorporated into phospholipids, triglycerides, or cholesterol esters. These lipid-related molecules regulate multiple diverse cellular properties and processes, including membrane structure and function, vesicle trafficking, intracellular signaling and inflammation. SCD expression is regulated by a transcription factor known as SREBF1, which has been identified in human genome-wide association studies as a risk factor for Parkinson’s disease. In preclinical models, SCD inhibition appears to normalize the dynamic interaction of pathological alpha-synuclein with membranes, which improves neuronal function and reduces toxicity, leading to enhanced neuronal survival. Alpha-synuclein-dependent disruption of membrane-related biological pathways, such as vesicle trafficking, is closely linked to the formation of Lewy body protein/membrane aggregations, a hallmark pathological feature of Parkinson’s disease.
About Yumanity Therapeutics
Yumanity Therapeutics is a clinical-stage biopharmaceutical company dedicated to accelerating the revolution in the treatment of neurodegenerative diseases through its scientific foundation and drug discovery platform. The Company’s most advanced product candidate, YTX-7739, is currently in Phase 1 clinical development for Parkinson’s disease. Yumanity’s drug discovery platform is designed to enable the Company to rapidly screen for potential disease-modifying therapies by overcoming toxicity of misfolded proteins in neurogenerative diseases. Yumanity’s pipeline consists of additional programs focused on Lewy body dementia, multi- system atrophy, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), frontotemporal lobar dementia (FTLD), and Alzheimer’s disease. For more information, please visit www.yumanity.com.
Forward-Looking Statements
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