PXS-5505 May Close the Treatment Gap in Advanced Myelofibrosis

Myelofibrosis is marked by extracellular matrix (ECM) accumulation in the bone marrow, impairing hematopoiesis and leading to splenomegaly and leukemic progression. Janus kinase (JAK) inhibitors, such as ruxolitinib, alleviate symptoms but fail to resolve bone marrow fibrosis.

“Beyond effects on the ECM, lysyl oxidase (LOX) enzymes influence key intracellular signaling pathways, including platelet-derived growth factor receptor (PDGFR) signaling. LOX activity enhances PDGFR stability and downstream signaling, ultimately driving fibroblast activation and fibrosis. PDGFR signaling is a known bypass for JAK-STAT inhibition by ruxolitinib, which may contribute to persistent disease activity and limit the therapeutic efficacy of ruxolitinib,” corresponding author of a recent study published in Haematologica and Chief Medical Officer at Syntara Jana Baskar, MD, told Blood Cancers Today.

Within the limited treatment options for myelofibrosis, the “side effect profile (particularly the development of cytopenias) often leads to treatment discontinuation and suboptimal dosing,” the authors wrote. Their findings suggest that treatment with novel LOX inhibitor PXS-5505 led to symptom relief and collagen fibrosis improvement in patients with ruxolitinib-ineligible or refractory disease.

This multicenter, open-label phase 1/2a trial aimed to evaluate the safety and tolerability of PXS-5505 in addition to defining dosing. The study also examined pharmacokinetics (PK), pharmacodynamics (PD), bone marrow fibrosis reduction, spleen volume changes, and symptom improvement via Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.

Eligible patients were aged 18 years and older. They had WHO-confirmed myelofibrosis (≥grade 2 fibrosis), intermediate-2 or high-risk disease per the Dynamic International Prognostic Scoring System (DIPSS), and symptomatic disease (an MFSAF score ≥1 in ≥2 items). Patients with more than 10% blasts, recent splenectomy, or malignancies were excluded. Of the 27 enrolled patients, 59% were male, with a median age of 72 years. LOX/LOXL2 concentrations and activities were significantly elevated in patients with myelofibrosis versus healthy control participants.

No dose-limiting toxicity was observed during the dose escalation period of 100 to 200 mg bid for 28 days. For the cohort expansion phase, 200 mg bid was selected based on PK (C_max, 2,530 ng/mL) and PD (>90% LOX/LOXL2 inhibition at trough). Steady-state concentrations of PXS-5505 were reached by day 28, with a maximum plasma concentration of 1,517 ng/mL. The treatment provided consistent inhibition of LOX/LOXL2 enzymes, maintaining approximately 90% reduction in their activity throughout the dosing period.

Thirteen of 24 patients (54%) in the cohort expansion phase completed 24 weeks of treatment, with a median exposure of 169 days. Eight patients experienced serious adverse events (AEs), including pneumonia. No abnormal wound healing or osteosclerosis was noted on femur MRI.

The median change in total symptom score was a 26% decrease from baseline at the best observed point during treatment. Sixty-two percent of patients experienced at least a 20% reduction in their total symptom score, and 15% achieved at least a 50% reduction by week 24. Hemoglobin levels, platelet counts, and white blood cell counts remained generally stable over the course of the study, with 77% showing an improvement in platelet counts by week 24. The median change in spleen volume was an increase of 22%, which may be attributable to baseline measurements often occurring shortly after discontinuation of prior JAK inhibitor therapy. Collagen fibrosis improved by one grade in 42% of patients, remained stable in 25%, and worsened in 33%.

Ongoing research is focused on assessing the safety and efficacy of longer-term treatment with PXS-5505. “It is expected that the use of amsulostat (the recently granted INN [international nonproprietary name] for PXS-5505), in addition to ruxolitinib, may provide a complementary approach in which the reduction of ECM fibrosis and mechanical stress, as well as regulation of abnormal cell growth and division, giving rise to a more durable treatment response associated with improvements in symptoms and spleen volume and normalization of blood counts over time,” Dr. Baskar stated. “This approach is currently being explored in a 12-month study of myelofibrosis patients with an inadequate response to ruxolitinib where amsulostat is given on top of ruxolitinib. Promising interim safety and efficacy data were presented at EHA [European Hematology Association Congress] 2025.”