A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis
| Title: | A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis |
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| Authors: | Pankit Vachhani, Peter Tan, Anne-Marie Watson, Shang-Ju Wu, Ross Baker, Stanley Cheung, Sung-Eun Lee, Chih-Cheng Chen, Tsai-Yun Chen, Hui-Hua Hsiao, Jae Hoon Lee, Lucia Masarova, Shuh Ying Tan, Jana Baskar, Brett Charlton, Alison Findlay, Dieter Hamprecht, Wolfgang Jarolimek, Joanna Leadbetter, John Miller, Kristen Morgan, Amna Zahoor, Gabriela Hobbs |
| Source: | Haematologica, Vol 999, Iss 1 (2025) |
| Publisher Information: | Ferrata Storti Foundation, 2025. |
| Publication Year: | 2025 |
| Collection: | LCC:Diseases of the blood and blood-forming organs |
| Subject Terms: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| More Details: | Myelofibrosis (MF) is a progressive disease characterized by accumulation of extracellular matrix (ECM) in the bone marrow (BM) which impairs normal hematopoiesis. While Janus kinase (JAK) inhibitors reduce spleen volume and provide symptomatic improvement, they do not resolve BM fibrosis and may cause or exacerbate anemia and thrombocytopenia. An anti-fibrotic therapy capable of normalising BM microenvironment and function remains a significant gap in the current treatment landscape. MF is associated with elevated expression of lysyl oxidases; enzymes responsible for maturation of the most abundant ECM proteins, collagen and elastin. PXS-5505 is a novel pan-lysyl oxidase inhibitor designed to exert an anti-fibrotic mode of action by preventing the cross-linking of collagen and elastin. PXS5505-MF-101 is a multi-center phase 1/2a study of PXS-5505 in MF patients which included a dose escalation phase (DEP) and a cohort expansion phase (CEP). Primary objectives were to determine the safety and tolerability of PXS-5505 and to define dosing for future studies. The DEP demonstrated that the highest dose tested, 200 mg BID, was safe and achieved robust systemic reduction of lysyl oxidase activity; this dose was therefore selected for the CEP. Twentyfour patients (median age 72 years) with relapsed or refractory MF were recruited into the CEP and 54% (13/24) completed 24 weeks of treatment. PXS-5505 was well tolerated and reached steady state concentrations by Day 28. Over the 24-week treatment period preliminary indications of clinical efficacy, including a reduction in BM collagen, were evident. Overall, these data support continued investigation of PXS-5505. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 0390-6078 1592-8721 |
| Relation: | https://haematologica.org/article/view/12032; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721 |
| DOI: | 10.3324/haematol.2024.287231 |
| Access URL: | https://doaj.org/article/fe053b40b57d433982b24e0088937fa0 |
| Accession Number: | edsdoj.fe053b40b57d433982b24e0088937fa0 |
| Database: | Directory of Open Access Journals |
| ISSN: | 03906078 15928721 |
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| DOI: | 10.3324/haematol.2024.287231 |
| Published in: | Haematologica |
| Language: | English |