Physics:PXL065

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PXL065 (d-R-pioglitazone) is a drug candidate for the treatment of nonalcoholic steatohepatitis (NASH).[lower-alpha 1] It is the deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonist activity and the associated side effects of weight gain and edema.[1] PXL065 (formerly known as DRX-065) has demonstrated preclinical efficacy for both NASH[1] and X-linked adrenoleukodystrophy (X-ALD).[2] In 2022, it successfully completed a 9 month Phase 2 trial in biopsy-proven NASH patients where it met the primary endpoint for reduction in liver fat without weight gain or edema.[3][4][5]

PXL065 was discovered and advanced to Phase 1 by DeuteRx, LLC using the strategy of deuterium-enabled chiral switching (DECS).[6] In August 2018, PXL065 and a portfolio of deuterated thiazolidinediones (TZDs) was acquired by Poxel SA.[7]

Notes

  1. ↑ About the chemical formula: One of the hydrogens is deuterium, so a more precise formula is C19H192HN2O3S (IUPAC recommends that the chemical symbol for deuterium should be 2H, rather than D).

References

  1. ↑ 1.0 1.1 Jacques, Vincent; Bolze, Sébastien; Hallakou-Bozec, Sophie; Czarnik, Anthony W.; Divakaruni, Ajit S.; Fouqueray, Pascale; Murphy, Anne N.; Van der Ploeg, Lex H.T. et al. (2021-04-10). "Deuterium-Stabilized (R)-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity". Hepatology Communications 5 (8): 1412–1425. doi:10.1002/hep4.1723. ISSN 2471-254X. PMID 34430785. 
  2. ↑ Monternier, Pierre-Axel; Singh, Jaspreet; Parasar, Parveen; Theurey, Pierre; Dewitt, Sheila; Jacques, Vincent; Klett, Eric; Kaur, Navtej et al. (2022). "Therapeutic potential of deuterium-stabilized ('R')-pioglitazone - PXL065 for X-linked adrenoleukodystrophy". Journal of Inherited Metabolic Disease 45 (4): 832–847. doi:10.1002/jimd.12510. PMID 35510808. 
  3. ↑ Harrison, Stephen A.; Thang, Carole; Bolze, Sébastien; DeWitt, Sheila; Hallakou-Bozec, Sophie; Dubourg, Julie; Bedossa, Pierre; Cusi, Kenneth et al. (2023). "Evaluation of PXL065 – deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1)". Journal of Hepatology 78 (5): 914–925. doi:10.1016/j.jhep.2023.02.004. PMID 36804402. 
  4. ↑ "Poxel Announces Positive Results from Phase 2 NASH Trial (DESTINY-1) for PXL065, A Novel, Proprietary Deuterium-Stabilized R-Stereoisomer of Pioglitazone" (in en-US). 2022-08-30. https://www.poxelpharma.com/en_us/news-media/press-releases/detail/221/poxel-announces-positive-results-from-phase-2-nash-trial. 
  5. ↑ Fyfe, Ian (2023). "Safer pioglitazone alternative is effective". Nature Reviews Gastroenterology & Hepatology 20 (4): 201. doi:10.1038/s41575-023-00764-5. ISSN 1759-5053. PMID 36882559. https://www.nature.com/articles/s41575-023-00764-5. 
  6. ↑ DeWitt, Sheila; Czarnik, Anthony W.; Jacques, Vincent (2020-10-08). "Deuterium-Enabled Chiral Switching (DECS) Yields Chirally Pure Drugs from Chemically Interconverting Racemates" (in en). ACS Medicinal Chemistry Letters 11 (10): 1789–1792. doi:10.1021/acsmedchemlett.0c00052. ISSN 1948-5875. PMID 33062153. 
  7. ↑ "Poxel Expands Metabolic Pipeline Through Strategic Acquisition Agreement with DeuteRx for DRX-065, a Novel Clinical Stage Drug Candidate for NASH, and Other Programs" (in en-US). 2018-08-30. https://www.poxelpharma.com/en_us/investors/news-events/press-releases/detail/99/poxel-expands-metabolic-pipeline-through-strategic. 



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