Promising Tolerability and Symptom Reduction Using PXS-5505 in Myelofibrosis

Combining ruxolitinib with the first-in-class pan-lysyl oxidase (LOX) inhibitor PXS-5505 improved symptoms over time for participants with myelofibrosis (MF) in an open-label phase 1/2a study. The combination therapy was well tolerated, with no overlapping toxicity observed with ruxolitinib.

Bone marrow fibrosis and splenomegaly are key features of MF. Excess LOX activity causes excessive collagen-elastin cross-linkage in the extracellular matrix of the bone marrow, resulting in stiffening of the matrix. Preclinical data have shown that PXS-550 can effectively reduce bone marrow fibrosis and splenomegaly. Peter Tan, MBBS(Hons), MPhil, One Clinical Research, Perth, Western Australia, presented the results of the ongoing, open-label, phase 1/2a study (NCT04676529) investigating the safety and efficacy of PXS-5505 for participants with post-essential thrombocythemia, primary, or post-polycythemia vera MF.¹

After 12 weeks of treatment with ruxolitinib and at least 8 weeks of stable dosing, 16 participants received 200 mg of PXS-5505 twice daily for 52 weeks or until disease progression occurred. At the time of the presentation of results, not all participants had reached the 52-week treatment endpoint, and four participants had dropped out.

Symptom improvement was evident after 12 weeks of PXS-5505 combination therapy, with 46% of participants achieving a reduction in total symptom score of more than 50%. By week 38, the population achieving this symptom reduction increased to 62%. Spleen volume reduction or stabilization was seen in 82% of participants; however, only one of 11 met the threshold for spleen volume reduction of more than 35%.

Combined with the phase 1 data, 72% of observed adverse events were below grade 2, and the few instances of high-grade adverse events included anemia, thrombocytopenia, and infections. “During the trial, there were no changes in ruxolitinib dose, and thus there was likely no additional overlapping toxicity,” remarked Dr. Tan.

Thus far, results of this study support the exploration of PXS-5505 due to its safety and potential therapeutic benefit for participants with MF already treated with Janus kinase inhibitors. “Data from the entire cohort at 52 weeks will help inform clinical and regulatory discussions on further development,” concluded Dr. Tan.

1. Tan PT, Baker R, Lee S, et al. Multicenter, open-label phase 1/2a study of Pxs-5505 and ruxolitinib in patients with primary, post-polycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis. Abstract #1001. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.