PXL065

PXL065

Clinical data
Other names	DRX-065; d-R-pioglitazone
Identifiers
IUPAC name (5R)-5-Deuterio-5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
CAS Number	1259828-75-5
PubChem CID	49835993
UNII	RQ8IV9N7OT
Chemical and physical data
Formula	C19H20N2O3S
Molar mass	356.44 g·mol^−1
3D model (JSmol)	Interactive image
SMILES [2H] [C@]1(C(=O)NC(=O)S1)CC2=CC=C(C=C2)OCCC3=NC=C(C=C3)CC
InChI InChI=1S/C19H20N2O3S/c1-2-13-3-6-15(20-12-13)9-10-24-16-7-4-14(5-8-16)11-17-18(22)21-19(23)25-17/h3-8,12,17H,2,9-11H2,1H3,(H,21,22,23)/t17-/m1/s1/i17D Key:HYAFETHFCAUJAY-VHLRUQIKSA-N

PXL065 (d-R-pioglitazone) is a drug candidate for the treatment of nonalcoholic steatohepatitis (NASH).[a] 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 C₁₉H₁₉^2HN₂O₃S (IUPAC recommends that the chemical symbol for deuterium should be ^2H, rather than D).

References

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.; DeWitt, Sheila (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. PMC 8369945. PMID 34430785.
2. Monternier, Pierre-Axel; Singh, Jaspreet; Parasar, Parveen; Theurey, Pierre; Dewitt, Sheila; Jacques, Vincent; Klett, Eric; Kaur, Navtej; Nagaraja, Tavarekere N.; Moller, David E.; Hallakou-Bozec, Sophie (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. PMC 9545763. PMID 35510808.
3. Harrison, Stephen A.; Thang, Carole; Bolze, Sébastien; DeWitt, Sheila; Hallakou-Bozec, Sophie; Dubourg, Julie; Bedossa, Pierre; Cusi, Kenneth; Ratziu, Vlad; Grouin, Jean-Marie; Moller, David E.; Fouqueray, Pascale (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. S2CID 257034807.
4. "Poxel Announces Positive Results from Phase 2 NASH Trial (DESTINY-1) for PXL065, A Novel, Proprietary Deuterium-Stabilized R-Stereoisomer of Pioglitazone". Poxel SA. 2022-08-30. Retrieved 2024-03-02.
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.
6. DeWitt, Sheila; Czarnik, Anthony W.; Jacques, Vincent (2020-10-08). "Deuterium-Enabled Chiral Switching (DECS) Yields Chirally Pure Drugs from Chemically Interconverting Racemates". ACS Medicinal Chemistry Letters. 11 (10): 1789–1792. doi:10.1021/acsmedchemlett.0c00052. ISSN 1948-5875. PMC 7549104. 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". Poxel SA. 2018-08-30. Retrieved 2024-03-02.