December 11, 2023
By Catlin Nalley
New findings showed that PXS-5505, a pan-LOX inhibitor, is well-tolerated among patients with primary, post-polycythemia vera or post-essential thrombocythemia myelofibrosis with no dose-limited toxicity or serious treatment-related adverse events. This data was recently presented during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9-12 in San Diego (Abstract 625).
“JAK inhibitors provide major clinical benefits, but they can be significantly myelosuppressive and demonstrate modest effects on bone marrow fibrosis (BMF),” according to study author Pankit Vachhani, MD, Associate Professor of Medicine, University of Alabama at Birmingham. “High discontinuation rates are observed due to loss of therapeutic effect or drug-induced toxicity.
“Once ruxolitinib is discontinued, the survival outcomes are quite poor,” he continued. “Reducing bone marrow fibrosis may normalize the hematopoietic environment, resulting in stable or improved blood counts and may also improve symptoms of myelofibrosis.”
Study Design & Findings
Recognizing the need for novel, effective therapies for myelofibrosis, Vachhani and colleagues initiated the ongoing, multi-center, Phase I/IIa PXS5505-MF-101 study of PXS-5505 among patients with primary, post-polycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis. The objective of this analysis is to determine the safety and tolerability of PXS-5505 in this patient population. Other objectives include pharmacokinetics (PK) and pharmacodynamics (PD), BMF changes, spleen volume, and MF symptoms.
The study started with two phases—dose escalation (DEP) and cohort expansion (CEP). The DEP has been completed and established a monotherapy dose of 200 mg BID for the Cohort Expansion Phase. During this phase, up to 24 patients will undergo treatment for 6 months. Preliminary data from the CEP is discussed below.
Overall, 23 patients—seven female and 16 male—have been enrolled in the Cohort Expansion Phase of the study. Of these, eight had post-ET myelofibrosis, five had post-PV myelofibrosis, and 10 had PMF. Twenty-one of these 23 patients have completed at least 1 month of PXS-5505 therapy. Eleven patients have completed 24 weeks of treatment.
“Overall, PXS-5505 was very well tolerated and there were no serious treatment-related adverse events reported,” Vachhani said. “The vast majority of adverse events were mild, and 92 percent of adverse events were unrelated to the drug.”
Treatment-related adverse events were rare, he noted. Eleven patients have withdrawn from the CEP for the following reasons: death (n=1), transformation to AML (n=1), thrombocytosis (n=1), investigator decision (n=4), and withdrawal by subject (n=4).
“Preliminary CEP PK data are consistent with the DEP with steady state reached by Day 28 with no accumulation observed past this point,” the study authors reported. “The PD data from the DEP demonstrated excellent inhibition of LOX as measured by LOX and LOXL2 target engagement (data previously presented) and this level of inhibition continues to be observed in CEP.”
Seven of the 11 patients who have completed the 24-week CEP had stable/improved hemoglobin counts, including one patient who had an anemia response at Week 18 with no RBC transfusions, Vachhani highlighted during his presentation.
“Eight out of 11 patients had stable or improved platelet counts over 24 weeks, which included three patients who started with Grade 4 thrombocytopenia and they improved without platelet transfusions,” he said. “There were no reductions seen in spleen volume.”
Additionally, a reduction in collagen fibrosis was observed in five out of 10 patients at either week 12 and/or week 24. There were no changes in reticulin fibrosis.
“In conclusion, PXS-5505 is a pan-LOX inhibitor that prevents cross-linking of collagen and elastin and, consequently, exhibits anti-fibrotic activities,” Vachhani noted. “The study demonstrated excellent targeted LOX inhibition at a dose of 200 mg twice daily.
“Preliminary indications of disease modification were seen with stable/improved blood counts and an improvement in collagen fibrosis,” he continued. “PXS-5505 is well-tolerated and the clinical responses observed support the continued investigation of PXS-5505 in an earlier treatment setting.”
Based on this preliminary data, an additional cohort is planned to use PXS-5505 as an add-on to ruxolitinib, according to the investigators.
Catlin Nalley is a contributing writer.