A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis
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 c...
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Ferrata Storti Foundation
2025-04-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/12032 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Pankit Vachhani |
| collection | DOAJ |
| description |
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.
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| format | Article |
| id | doaj-art-fe053b40b57d433982b24e0088937fa0 |
| institution | OA Journals |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Ferrata Storti Foundation |
| record_format | Article |
| series | Haematologica |
| spelling | doaj-art-fe053b40b57d433982b24e0088937fa02025-08-20T02:27:39ZengFerrata Storti FoundationHaematologica0390-60781592-87212025-04-01999110.3324/haematol.2024.287231A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosisPankit Vachhani0Peter Tan1Anne-Marie Watson2Shang-Ju Wu3Ross Baker4Stanley Cheung5Sung-Eun Lee6Chih-Cheng Chen7Tsai-Yun Chen8Hui-Hua Hsiao9Jae Hoon Lee10Lucia Masarova11Shuh Ying Tan12Jana Baskar13Brett Charlton14Alison Findlay15Dieter Hamprecht16Wolfgang Jarolimek17Joanna Leadbetter18John Miller19Kristen Morgan20Amna Zahoor21Gabriela Hobbs22Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, BirminghamOne Clinical Research Pty Ltd, NedlandsLiverpool Hospital SW Area Pathology Service, LiverpoolNational Taiwan University Hospital and National Taiwan University College of MedicinePerth Blood Institute, Murdoch University, PerthICON Cancer Care, Kurralta ParkThe Catholic University of Korea, College of Medicine, SeoulChang-Gung Memorial Hospital, ChiayiCollege of Medicine, National Cheng Kung University, TainanKaohsiung Medical University, KaohsiungGachon University Gil Hospital, IncheonDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, HoustonDepartment of Haematology, St Vincent's Hospital, MelbourneSyntara Limited, Frenchs ForestSyntara Limited, Frenchs ForestSyntara Limited, Frenchs ForestSyntara Limited, Frenchs ForestSyntara Limited, Frenchs ForestSyntara Limited, Frenchs ForestSyntara Limited, Frenchs ForestSyntara Limited, Frenchs ForestSyntara Limited, Frenchs ForestMassachusetts General Hospital, Boston 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. https://haematologica.org/article/view/12032 |
| spellingShingle | 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 A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis Haematologica |
| title | A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis |
| title_full | A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis |
| title_fullStr | A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis |
| title_full_unstemmed | A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis |
| title_short | A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis |
| title_sort | phase i iia trial of pxs 5505 a novel pan lysyl oxidase inhibitor in advanced myelofibrosis |
| url | https://haematologica.org/article/view/12032 |
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