P1024: MYLOX-1: A PHASE II STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL LOXL2 INHIBITOR GB2064 (WITH FOCUS ON BONE MARROW COLLAGEN) IN PATIENTS WITH MYELOFIBROSIS

• DOI: 10.1097/01.hs9.0000970996.87048.d4
• Publication Date: 2023-08-08T16:15:08Z
• Authors: Claire Harrison; John Mascarenhas; Daniela Cilloni; Richard Schlenk; Brian Jacoby; Robert J Slack; Vassilios Aslanis; Bhupinder Singh; Bertil Lindmark; Srdan Verstovsek; Raajit K Rampal
• Keywords: Tolerability; Pharmacodynamics

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Myelofibrosis (MF) treatment (Tx) with Janus kinase (JAK) inhibitors is limited by modest effects on bone marrow (BM) fibrosis & driver mutation allele burden. A high proportion of patients (pts) discontinue Tx due to cytopenias. GB2064, a LOXL2 inhibitor, being developed as potential disease-modifying for MF. Aims: To evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) clinical effects, specifically BM collagen fibrosis, oral GB2064 in pts primary or secondary MF (PMF/SMF). Methods: MYLOX-1 (NCT04679870) phase II trial (1000 mg BID) administered PMF/SMF 9 months, follow-up 1 month after their last dose. Eligible were not allowed JAK inhibitors, had laboratory parameters within protocol-defined limits an ECOG performance status 0–2. Primary endpoints: Safety tolerability. visits occurred at protocol-specified timepoints: safety PK, PD appropriate MF-specific assessments all except Day (D) 7, D15 Month (M) 4, when only tolerability assessed. biopsies MRI the spleen performed baseline M3, M6 M9. Pts who showed benefit entered extension may continue additional 3 years, during which are Results: As early February 2023, 17 have been enrolled started (59% PMF); 10 JAK2 positive (3 co-existing ASXL1 mutations, MPL mutations), 2 positive, 4 CALR (1 EZH2 mutation) positive. inhibitor status: refractory, 8 intolerant, ineligible, naïve. Dynamic International Prognostic Scoring System plus risk distribution: High pts, Intermediate-2 8, Intermediate-1 5 Low 2. Overall, 6 completed (2 phase), discontinued (6 adverse events [AEs], disease progression) continuing Tx. At data cut-off October 2022), received experienced Tx-emergent AEs. Most gastrointestinal nature (11/16 pts), including nausea (6/16 pts) vomiting (3/16 either self-limiting responded anti-emetics. Serious AEs 7 was related (fall). Of evaluable >6 months complete biopsy data, (20%) improved ≥1-grade reticulin (80%) 1- grade reduction (Figure). Spleen volume hematological remained stable from response; none required transfusion. After assessments, 2/4 progressed seen total symptom score >50% other Anemia response). penetration demonstrated through spatial distribution M3 using matrix-assisted laser desorption/ionization mass spectrometry imaging. good target engagement plasma, 49.5% decrease free hours post-dosing. Summary/Conclusion: acceptable profile improvements that indicated activity. thus be valid option combination agent ineligible intolerant novel therapies. Figure:Keywords: trial, Bone Marrow Fibrosis, Myelofibrosis, Kinase