Mylox-1: An Open-Label, Phase IIa Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral LOXL2 Inhibitor, GB2064, in Myelofibrosis

Background: GB2064 is a high-affinity, selective, pseudo‑irreversible, small-molecule inhibitor of LOXL2, a secreted glycoprotein that crosslinks extracellular matrix collagens and elastin which contributes to stiffness and loss of function of fibrotic organs. GB2064 is being developed as an oral treatment for myelofibrosis (MF), a rare myeloproliferative disease with high morbidity and mortality. Janus kinase (JAK) inhibitor therapy has brought significant advancements in the treatment of MF, but a significant proportion of patients would eventually discontinue treatment, predominantly due to the development of cytopenias (Kyukendall et al., Ann Hematol. 2018). Thus, a substantial unmet need to develop well-tolerated disease-modifying treatments that reduce bone marrow fibrosis to improve haematological parameters, splenomegaly, symptom burden and quality of life remains.

Aims: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical effects of oral GB2064 (1000 mg twice daily [BID]), which was administered to participants with primary or secondary myelofibrosis (PMF/SMF) for 9 months.

Methods: Open-label study in 16 adult participants diagnosed with PMF or SMF in accordance with World Health Organization diagnostic criteria (Barbui et al., Blood Cancer 2018; Cruz et al., Expert Rev Hematol. 2020), who are not taking a JAK inhibitor and therefore are likely to be refractory, intolerant or ineligible for such inhibitors; participants had Eastern Cooperative Oncology Group performance status 0-2, and the clinical laboratory parameters were within appropriate limits per protocol. Primary endpoint is safety and tolerability. Safety and tolerability, PK, PD and appropriate MF-specific assessments will take place at all visits except Day 7, Day 15 and Month 4 when only safety and tolerability will be assessed (Fig A). Bone marrow biopsies, magnetic resonance imaging of spleen and quality of life measures, MPN-10 and EQ-5D-5L are performed at prespecified timepoints within the protocol. Exploratory endpoints include LOXL2 binding assay in the circulation, relationships between PK plasma exposure, PD markers, and markers of clinical activity, fibrosis and inflammation biomarkers (YKL-40, PAI-1, PDGF, CCN2, collagen formation and degradation neoepitopes). The study is not formally powered. Participants who derive benefit may continue therapy for an additional 3 years (Fig B).

Results: At least half of the intended participants have been enrolled and are on GB2064 treatment as of June 2022. One participant successfully completed the study in May 2022 and moved to the extension phase. GB2064 was detected in bone marrow biopsies at concentrations close to those in the plasma and demonstrated LOXL2 target engagement in the systemic compartment using a LOXL2 binding assay in plasma. No significant safety concerns were observed at a dose of 1000 mg BID to date.

Conclusions: MYLOX-1 is designed to explore the safety and clinical effects of GB2064, a novel small-molecule LOXL-2 inhibitor, addressing bone marrow fibrosis as a main element of MF, with the aim to decrease extramedullary haematopoiesis and improve haematological parameters, symptom burden and the quality of life for patients with MF.