Therapeutics

YTX-7739

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Overview

Name: YTX-7739
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Yumanity Therapeutics

Background

This is a stearoyl-CoA desaturase inhibitor. SCD catalyzes the rate-limiting step in the production of monounsaturated fatty acids including oleic and palmitoleic acids from saturated fatty acid precursors. The drug is given orally, and was designed to cross the blood-brain barrier.

Oleic acid and SCD activity were found to promote α-synuclein neurotoxicity, and inhibitors of the enzyme to prevent it (Fanning et al., 2019; Imberdis et al., 2019; Vincent et al., 2018). In a mouse model of Parkinson’s disease, an SCD inhibitor calmed resting tremor and slowed progressive motor decline. Treated mice had less toxic insoluble α-synuclein in their brains, and smaller α-synuclein aggregates in dopaminergic nerve fibers than control mice (Oct 2020 news).

Several companies have identified SCD inhibitors for potential treatment of obesity, diabetes, and metabolic disorders, cancer, and acne (Uto 2016). Adverse events in early phase development included hair loss and dry eye.

Yumanity presented preclinical data at the 2021 AD/PD Conference (press release). Four months of oral YTX-7739 dosing in an α-synuclein mouse model reportedly inhibited SCD in brain, improved synuclein pathology, enhanced survival of dopaminergic neurons, and improved motor function. Published data indicate that seven days of dosing produced maximal inhibition of SCD in the brains of rats or monkeys (Tardiff et al., 2022).

Findings

At the 2021 CTAD conference, Yumanity reported results of a Phase 1, single- and multiple-ascending-dose study of YTX-7739 in healthy volunteers. Beginning in October 2019, the single-dose study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamic measures, and the effect of food in 72 men and women who received 5, 10, 30, 100, 250, or 400 mg YTX-7739, given by mouth. The company reported no serious or unexpected adverse events. The most frequent adverse event was headache. Pharmacokinetics were dose-proportional from 5 to 250 mg when the drug was given with food. The multiple-dose study tested 15 or 25 mg once daily for up to 28 days in two cohorts of eight volunteers each. Plasma and CSF pharmacokinetics were dose-proportional with food, and the drug was well tolerated. Target engagement was confirmed by dose-dependent decreases in blood fatty acid desaturation, a biomarker of SCD inhibition. The company is planning a multiple-dosing safety study in healthy volunteers, and a Phase 1b safety and biomarker study in people with Parkinson’s disease.

In November 2021, the company announced top-line results of a Phase 1b study in people with Parkinson’s disease (press release). The data included 20 patients with mild to moderate PD, who received 20 mg drug or placebo for 28 days. The company reported no serious safety events. Treatment with drug was associated with more procedural pain, muscle aches, dry eye, hyperbilirubinemia, pain sensitivity, lower back pain, and constipation than placebo. Target engagement was confirmed by a reduction in fatty acid desaturation in blood and CSF. The company also claimed the drug caused a significant change in quantitative EEG signals in a substudy of eight patients.

On January 19, 2022, Yumanity announced that the FDA had placed a partial hold on multidose trials of YTX-7739 (press release). The hold came in response to the company’s Investigational New Drug application submitted in December 2021, and suspends the initiation of multidose trials in the U.S. A planned single-dose trial will proceed, the company said. No further details were given.

As of January 2022, no clinical trials of YTX-7739 were registered in the U.S. For details, see The Netherlands trial registry.

Last Updated: 26 Jan 2022

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References

News Citations

  1. Curbing Fatty Acids Means No Parkinson’s—If You Are a Mouse

Paper Citations

  2. Imberdis T, Negri J, Ramalingam N, Terry-Kantor E, Ho GP, Fanning S, Stirtz G, Kim TE, Levy OA, Young-Pearse TL, Selkoe D, Dettmer U. Cell models of lipid-rich α-synuclein aggregation validate known modifiers of α-synuclein biology and identify stearoyl-CoA desaturase. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20760-20769. Epub 2019 Sep 23 PubMed.
  3. Vincent BM, Tardiff DF, Piotrowski JS, Aron R, Lucas MC, Chung CY, Bacherman H, Chen Y, Pires M, Subramaniam R, Doshi DB, Sadlish H, Raja WK, Solís EJ, Khurana V, Le Bourdonnec B, Scannevin RH, Rhodes KJ. Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity. Cell Rep. 2018 Dec 4;25(10):2742-2754.e31. PubMed.
  4. Uto Y. Recent progress in the discovery and development of stearoyl CoA desaturase inhibitors. Chem Phys Lipids. 2016 May;197:3-12. Epub 2015 Sep 3 PubMed.
  5. Tardiff DF, Lucas M, Wrona I, Chang B, Chung CY, Le Bourdonnec B, Rhodes KJ, Scannevin RH. Non-clinical Pharmacology of YTX-7739: a Clinical Stage Stearoyl-CoA Desaturase Inhibitor Being Developed for Parkinson's Disease. Mol Neurobiol. 2022 Apr;59(4):2171-2189. Epub 2022 Jan 20 PubMed.

External Citations

  1. press release
  2. press release
  3. The Netherlands trial registry
  4. press release

Further Reading

Papers

  1. Atkinson KA, Beretta EE, Brown JA, Castrodad M, Chen Y, Cosgrove JM, Du P, Litchfield J, Makowski M, Martin K, McLellan TJ, Neagu C, Perry DA, Piotrowski DW, Steppan CM, Trilles R. N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1621-5. Epub 2011 Jan 31 PubMed.
  2. Terry-Kantor E, Tripathi A, Imberdis T, LaVoie ZM, Ho GP, Selkoe D, Fanning S, Ramalingam N, Dettmer U. Rapid Alpha-Synuclein Toxicity in a Neural Cell Model and Its Rescue by a Stearoyl-CoA Desaturase Inhibitor. Int J Mol Sci. 2020 Jul 22;21(15) PubMed.
  3. Imberdis T, Negri J, Ramalingam N, Terry-Kantor E, Ho GP, Fanning S, Stirtz G, Kim TE, Levy OA, Young-Pearse TL, Selkoe D, Dettmer U. Cell models of lipid-rich α-synuclein aggregation validate known modifiers of α-synuclein biology and identify stearoyl-CoA desaturase. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20760-20769. Epub 2019 Sep 23 PubMed.
  4. Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak-Vance MA, Hulette C, Welsh-Bohmer KA. Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet. 2003 Dec 15;12(24):3259-67. PubMed.
  5. Niida Y, Masuda M, Adachi Y, Yoshizawa A, Ohminami H, Mori Y, Ohnishi K, Yamanaka-Okumura H, Uchida T, Nikawa T, Yamamoto H, Miyazaki M, Taketani Y. Reduction of stearoyl-CoA desaturase (SCD) contributes muscle atrophy through the excess endoplasmic reticulum stress in chronic kidney disease. J Clin Biochem Nutr. 2020 Sep;67(2):179-187. Epub 2020 Jun 9 PubMed.