Findings in a murine model of cholangiocarcinoma (CCA) showed that PXS-5505 might be a useful component in combination therapy. The results of the study were recently presented at The Liver Meeting 2021, hosted by the American Association for the Study of Liver Diseases (AASLD).
PXS-5505, an oral drug that was developed by Pharmaxis, inhibits all members of the lysyl oxidase (LOX) family of enzymes. It has been shown to have promising effects in the treatment of severe fibrosis and cancers with prominent stroma or fibrotic metastatic niches.
When used in combination with the chemotherapy drug gemcitabine, PXS-5505 decreased tumor growth and improved survival in a spontaneous murine model of CCA. After 28 days of treatment with PXS-5505 and retroorbital gemcitabine, the authors observed a significant elevation of the intratumoral concentration of gemcitabine.
Moreover, the combination of PXS-5505 with 5-fluorouracil and oxaliplatin increased mean vessel area (P =.0002) and mean vessels per area (P =.0003) when compared to 5-fluorouracil and oxaliplatin alone.
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Results from the phase 1 clinical trial demonstrated that PXS-5505 was well-tolerated and that it effectively inhibited all LOX enzymes involved in fibrosis. In mid-2020, PXS-5505 was granted Orphan Drug Designation for the treatment of myelofibrosis by the US Food and Drug Administration (FDA).
LOX enzymes regulate collagen crosslinking, a reaction that is commonly dysregulated in CCA.
“CCA is highly desmoplastic featuring dense collagen matrices that stiffen the tumor matrix and decrease the efficacy of systemic therapy,” the authors explained. “Increased LOX expression is associated with increased stromal desmoplasia and correlates with poor prognosis in human patients with CCA.”
Burchard PR, Ruffolo LI, Ullman NA, et al. Gemcitabine with PXS-5505 slows tumor progression and increases mean vessel area in cholangiocarcinoma – a novel strategy to improve chemotherapeutic delivery. Presented at: The Liver Meeting 2021: November 12-15, 2021; Virtual.
Oral pan-LOX Inhibitor (PXS-5505). Pharmaxis. Accessed November 16, 2021.