{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:39:39Z","timestamp":1790962779942,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T00:00:00Z","timestamp":1618012800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:p>The antidiabetic drug pioglitazone is, to date, the most efficacious oral drug recommended off\u2010label for the treatment of nondiabetic or diabetic patients with biopsy\u2010proven nonalcoholic steatohepatitis (NASH). However, weight gain and edema side effects have limited its use for NASH. Pioglitazone is a mixture of two stereoisomers ((<jats:italic toggle=\"yes\">R<\/jats:italic>)\u2010pioglitazone and (<jats:italic toggle=\"yes\">S<\/jats:italic>)\u2010pioglitazone) that interconvert <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. We aimed to characterize their individual pharmacology to develop a safer and potentially more potent drug for NASH. We stabilized the stereoisomers of pioglitazone with deuterium at the chiral center. Preclinical studies with deuterium\u2010stabilized (<jats:italic toggle=\"yes\">R<\/jats:italic>)\u2010pioglitazone (PXL065) and (<jats:italic toggle=\"yes\">S<\/jats:italic>)\u2010pioglitazone demonstrated that (<jats:italic toggle=\"yes\">R<\/jats:italic>)\u2010pioglitazone retains the efficacy of pioglitazone in NASH, including reduced hepatic triglycerides, free fatty acids, cholesterol, steatosis, inflammation, hepatocyte enlargement, and fibrosis. Although both stereoisomers inhibit the mitochondrial pyruvate carrier, PXL065 shows limited to no peroxisome proliferator\u2013activated receptor gamma (PPAR\u03b3) activity, whereas (<jats:italic toggle=\"yes\">S<\/jats:italic>)\u2010pioglitazone appears responsible for the PPAR\u03b3 activity and associated weight gain. Nonetheless, in preclinical models, both stereoisomers reduce plasma glucose and hepatic fibrosis to the same extent as pioglitazone, suggesting that these benefits may also be mediated by altered mitochondrial metabolism. In a phase 1a clinical study, we demonstrated safety and tolerability of single 7.5\u2010mg, 22.5\u2010mg, and 30\u2010mg doses of PXL065 as well as preferential exposure to the (<jats:italic toggle=\"yes\">R<\/jats:italic>)\u2010stereoisomer in comparison to 45\u2010mg pioglitazone. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: PXL065 at a dose lower than 22.5\u00a0mg is predicted to exhibit efficacy for NASH equal to, or greater than, 45\u2010mg pioglitazone without the potentially detrimental weight gain and edema. The development of PXL065 for NASH represents a unique opportunity to leverage the therapeutic benefits of pioglitazone, while reducing or eliminating PPAR\u03b3\u2010related side effects.<\/jats:p>","DOI":"10.1002\/hep4.1723","type":"journal-article","created":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T15:00:45Z","timestamp":1618066845000},"page":"1412-1425","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":49,"title":["Deuterium\u2010Stabilized (R)\u2010Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPAR\u03b3 Activity"],"prefix":"10.1097","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2607-8805","authenticated-orcid":false,"given":"Vincent","family":"Jacques","sequence":"first","affiliation":[{"name":"DeuteRx, LLC,Andover,MA,USA"},{"name":"Poxel SA,Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Bolze","sequence":"additional","affiliation":[{"name":"Poxel SA,Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Hallakou\u2010Bozec","sequence":"additional","affiliation":[{"name":"Poxel SA,Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony W.","family":"Czarnik","sequence":"additional","affiliation":[{"name":"DeuteRx, LLC,Andover,MA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit S.","family":"Divakaruni","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,University of California, San Diego,La Jolla,CA,USA"},{"name":"Department of Molecular and Medical Pharmacology,University of California, Los Angeles,Los Angeles,CA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Fouqueray","sequence":"additional","affiliation":[{"name":"Poxel SA,Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne N.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,University of California, San Diego,La Jolla,CA,USA"},{"name":"Cytokinetics Inc,South San Francisco,CA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lex H.T.","family":"Van der Ploeg","sequence":"additional","affiliation":[{"name":"DeuteRx, LLC,Andover,MA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"DeWitt","sequence":"additional","affiliation":[{"name":"DeuteRx, LLC,Andover,MA,USA"},{"name":"Poxel 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