A phase I/IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis

Abstract

Myelofibrosis is a progressive disease characterized by accumulation of extracellular matrix in the bone marrow (BM), which impairs normal hematopoiesis. While Janus kinase inhibitors reduce spleen volume and provide symptomatic improvement, they do not resolve BM fibrosis and may cause or exacerbate anemia and thrombocytopenia. An antifibrotic therapy capable of normalizing the BM microenvironment and function remains a significant gap in the current treatment landscape. Myelofibrosis is associated with elevated expression of lysyl oxidases, enzymes responsible for maturation of the most abundant extracellular matrix proteins: collagen and elastin. PXS-5505 is a novel pan-lysyl oxidase inhibitor designed to exert an antifibrotic effect by preventing the cross-linking of collagen and elastin. PXS5505-MF-101 is a multicenter phase I/IIa study of PXS-5505 in myelofibrosis patients which included a dose escalation phase (DEP) and a cohort expansion phase (CEP). Primary objectives of the study 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. Twenty-four patients (median age 72 years) with relapsed or refractory myelofibrosis 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. (ClinicalTrials.gov identifier: NCT04676529).

Figure 1.

Mode of action of PXS-5505 in myelofibrosis. Oxidation of platelet-derived growth factor receptor by lysyl oxidases in a graphical representation of work by Lucero et al. LOX: lysyl oxidases; PDGFR: platelet-derived growth factor receptor; EPOR: erythropoietin receptor; JAK: Janus kinase; Akt: protein kinase B; STAT: signal transducer and activator of transcription; MK: megakaryocyte; SC: stem cell; ECM: extracellular matrix.

Figure 2.

Patients’ disposition in the dose escalation and cohort expansion phases. NA: not applicable; AML: acute myeloid leukemia; BID: twice daily.

Figure 3.

Elevated LOX and LOXL2 concentrations and activities in myelofibrosis patients compared to those in healthy subjects. (A) LOX and (B) LOXL2 concentrations in healthy (reasonably age-matched) controls and patients with myelofibrosis (Disease) and (C) LOX and (D) LOXL2 activity in healthy (reasonably age-matched controls) and myelofibrosis patients. Subjects assessed at baseline (i.e. pre-dose at day 0). Unpaired t test, *P<0.01, ****P<0.0001. For further details see Online Supplementary Table S12.

Figure 4.

Pharmacokinetics and pharmacodynamics of PXS-5505 in the dose escalation phase. (A) Mean plasma concentration-time profiles (mean ± standard error of mean [SEM]) for PXS-5505 at days 0, 7 and 28 (pre-dose, 1 hour and 4 hours post-dose) after oral administration of 100, 150 or 200 mg BID for 28 days (N=3 except 100 mg BID day 28 data [N=2]). (B, C) Mean LOX (B) and LOXL2 (C) activity-time profiles depicted as activity normalized to day 0 pre-dose level (mean ± SEM) (LOX: N=3 except 100 mg BID day 28 data [N=2]; LOXL2: N=2 except 100 mg BID day 0 and 7 data [N=3]).

Figure 5.

Pharmacokinetics and pharmacodynamics of PXS-5505 in the cohort expansion phase. (A) Mean plasma concentration-time profiles (mean ± standard error of mean [SEM]) for PXS-5505 after oral administration of 200 mg BID for 24 weeks. (B, C) Mean LOX (B) and LOXL2 (C) activity-time profiles (mean ± SEM) depicted as activity normalized to day 0 pre-dose level. Results affected by compliance issues or sample analysis issues were excluded from the analysis, refer to Online Supplementary Table S13 for details.

Figure 6.

Platelet count and hemoglobin concentration by patient and study week in the cohort expansion phase. (A) Platelet counts and (B) hemoglobin levels for all patients (N=24) enrolled in the cohort expansion phase, by study week.