YTX-7739 Works to Block SCD Enzyme at Well-Tolerated Doses, Yumanity Says

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by Steve Bryson PhD |

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YTX-7739 trial update

Dose-dependent decreases in targeted fatty acids were seen with YTX-7739, an investigational therapy for Parkinson’s disease, suggesting the medicine engages its therapeutic target, according to the results of a Phase 1a multiple-ascending dose study in healthy volunteers.

YTX-7739 is a small molecule designed to enter the brain and block the stearoyl-CoA desaturase (SCD) enzyme, which produces certain fatty molecules thought to mediate the effects of alpha-synuclein — the protein that builds inside nerve cells to toxic levels, causing cell death and Parkinson’s symptoms

Yumanity Therapeutics, the medicine’s developer, recently reported YTX-7739 was generally well-tolerated and had a favorable pharmacological profile at tested doses. 

Study data will be presented at the company’s upcoming R&D Day on May 17, and at a future medical conference.

“We are very pleased that repeated dosing with YTX-7739 was observed to be generally well-tolerated in these healthy volunteers,” said Brigitte Robertson, MD, the company’s chief medical officer, in a press release. “Additionally, the biomarker analysis revealed decreased levels of the enzyme’s product. 

“This finding supports that YTX-7739 inhibits [blocks] SCD and achieved target engagement,” she added.

The Phase 1a study included 16 healthy male and female volunteers given one of two YTX-7739 oral doses (15 mg and 25 mg) once daily for 14 to 28 days. For each dose, six people were randomly assigned to YTX-7739, while two received a placebo. 

No serious adverse events were reported, and all treatment-related adverse events were either mild or moderate in severity. Plasma profiles supported once-a-day dosing, and relevant YTX-7739 concentrations were measured in the cerebrospinal fluid, the clear fluid that surrounds the brain and spinal cord.

Binding to the SCD enzyme was demonstrated by dose-dependent decreases in the fatty acid desaturation index (FA-DI), a potential Parkinson’s biomarker that measures the ratio of SCD’s product to its precursor molecule (substrate) in blood plasma. 

Previous preclinical work supporting human trials showed that blocking SCD with YTX-7739 reduced FA-DI in a Parkinson’s mouse model and overcame alpha-synuclein’s toxicity, enhanced the survival of brain cells, and improved motor function. 

The plasma FA-DI achieved in this Phase 1a study was within the range associated with restoration of motor function in the Parkinson’s animal models.

“The pharmacology of YTX-7739 observed preclinically has translated nicely to the clinical experience observed in this part of the study,” Robertson said. “Most importantly, we know from preclinical work that a response in the plasma is associated with response in the brain.”

She added: “Furthermore, the potential to correlate changes in the plasma FA-DI with drug exposures support the use of FA-DI as a biomarker to help assess clinical response to YTX-7739 and potentially identify patients most likely to benefit, for inclusion in later phase trials.” 

Yumanity is also conducting a Phase 1b trial evaluating the safety and pharmacological properties of multiple increasing doses of YTX-7739 in about 30 people with Parkinson’s. Researchers will analyze the plasma FA-DI and YTX-7739′s concentration in the CSF, blood, and other fluids or tissues. Dosing has begun, and preliminary data is expected mid-year.

“We look forward to the results of our ongoing Phase 1b safety and biomarker study to assess the effect of chronic dosing in patients with Parkinson’s disease,” Robertson said. “Topline results from the Phase 1b part of the study are expected in mid-2021.”