BOSTON—Biopharmaceutical company Yumanity Therapeutics has reported that its lead program, YTX-7739, has demonstrated pharmacological, physiological, and behavioral preclinical proof of concept in a mouse model of Parkinson’s disease (PD). This work was conducted in collaboration with the laboratories of Drs. Silke Nuber and Dennis Selkoe at Brigham & Women’s Hospital.
YTX-7739 is a proprietary small-molecule investigational therapy designed to penetrate the blood-brain barrier and inhibit the activity of a novel target, stearoyl-CoA desaturase (SCD). According to Yumanity Therapeutics, by inhibiting 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 enzyme SCD catalyzes fatty acid desaturation, and it also plays a significant role in modulating neurotoxicity related to the alpha-synuclein protein, which is a driver of Parkinson’s disease and other neurodegenerative disorders. SCD expression is regulated by the transcription factor SREBF1, which is a risk factor for Parkinson’s. Preclinical work has shown that SCD inhibition may normalize how pathological alpha-synuclein interacts with membranes, thereby improving neuronal function, reducing toxicity, and improving neuronal survival.
“Evidence suggests that α-synuclein pathology is a strong risk factor for Parkinson’s disease,” said Dr. Dan Tardiff, 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.”
This work assessed YTX-7739 vs. control in a mouse model of Parkinson’s disease, looking at the effect of the inhibitor on motor function, lipid metabolism, neuronal survival, and associated biochemical features. The study showed that YTX-7739 prevented motor function deficits in mouse models after four months of oral dosing compared to placebo-treated mice, and YTX-7739 brain concentrations reached levels that inhibited SCD activity consistent with in-vitro studies. SCD inhibition was also found to decrease monounsaturated fatty acids—which may contribute to alpha-synuclein pathology—in both plasma and the brain. Several biochemical measures of alpha-synuclein pathology were significantly improved in the YTX-7739-treated mice compared to controls, including levels of pathological alpha-synuclein. In addition, YTX-7739-treated mice showed enhanced survival of dopaminergic neurons.
The company presented the data from this study at the 15th Annual International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2021) Virtual Conference, held March 9 to 14.
This follows on the heels of a February update of Yumanity's progress with its YTX-7739 program in humans. In a Phase 1, single-ascending dose study in healthy volunteers, no safety concerns were identified and YTX-7739 was found to be well tolerated. As noted in the press release, “The half-life of YTX-7739 combined with a favorable dose-proportional pharmacokinetic (PK) profile, in the fed state, supports that low daily doses administered with food will sustain the target range of exposure. Drug plasma concentrations in the study exceeded levels of exposure estimated to be sufficient for target engagement based on pharmacodynamic modeling. Consistent with preclinical data, YTX-7739 also demonstrated clinically relevant drug concentrations in the cerebral spinal fluid.”
In moving from single-ascending dose studies to multiple-ascending doses studies, the company reported that it had completed enrollment in its Phase 1 multiple-ascending dose study to evaluate the safety, tolerability, and pharmacokinetics of once-daily oral administration of two doses of YTX-7739 (15 mg and 25 mg) for 14 to 28 days in 16 healthy male and female volunteers. Yumanity also began dosing in a Phase 1b study of YTX-7739 in Parkinson’s disease patients to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic parameters, including potential biomarkers of SCD activity and target engagement in cerebral spinal fluid, plasma, and other fluids or tissues.