A Phase 2 Study of the LSD1 Inhibitor IMG7289 (bomedemstat) for the Treatment of Advanced Myelofibrosis

Virtually all patients with myelofibrosis (MF) exhaust the clinical benefits of approved therapies baring the need for therapies with distinct modes of action that can improve outcomes and the patient experience. Lysine-specific demethylase-1 (LSD1) is a histone H3K4 demethylase critical for self-renewal of malignant myeloid cells and for the differentiation of myeloid progenitors, e.g., LSD1 bound to the transcription factor GFI1b licenses maturation of megakaryocytes. IMG-7289 is an orally active LSD1 inhibitor that in mouse models of MPNs reduced peripheral cell counts, splenomegaly, inflmmatory cytokines, marrow fibrosis and mutant cell burdens (Jutzi et al. 2018).

IMG-7289-CTP-102 is an ongoing, multi-national, open-label study that has transitioned from a 12 week PK and dose-range finding Phase 1/2a study to a 24 week Phase 2b study of IMG-7289 taken once daily in patients with MF resistant to approved therapies. Key objectives are safety and reduction of spleen volume (SVR) by MRI/CT and total symptoms scores (TSS) using the self-administered MPN SAF TSS instrument. A platelet count ≥100k/μL is a key inclusion criterion. Periodic bone marrow (BM) biopsies and imaging studies are read centrally. Dosing is individually tailored using platelet count as a biomarker of IMG-7289 activity on megakaryocyte function, targeting a range between 50-100 k/μL and titrating as needed. 40 patients have enrolled: 45% PMF, 38% PET-MF, 17% PPV-MF. Median age is 68 (34-88) with 58% males. All but 1 patient were previously treated with ruxolitinib; 65% had received up to 4 additional treatments including fedratinib and CPI-0610. 37% of patients were transfusion-dependent at baseline. 62% were IPSS high-risk, the remainder, intermediate risk-2. 75% had ≥2 mutation among the 264 genes recurrently mutated in AML/MPN of which 43% were in ASXL1 or U2AF1. When tested, 60% (N=15) had abnormal karyotypes.

PK data in Phase 1/2a study (N=18) supported once-daily dosing. All patients required up-titration, hence, the dosing rules were amended to increase the starting dose 100%.

The median duration of treatment was 110 days (21-561) at the censoring point (8Jul2020). Of all enrolled patients evaluable at 24 weeks for TSS (N=14), 86% recorded a reduction in TSS (mean change -31%; -81% to 21%) with ~30% reporting >50% reduction. Of the Phase 2b patients evaluable for SVR after 12 weeks (N=10), 100% had a reduction in spleen volume from baseline (mean SVR: -19%; -2% to -41%) with 20% showing >35% SVR. 70% of evaluable patients (N=30) had stable or improved hemoglobin (>1 g/dL). In those whom IL-8, S100A9 or RANTES (CCL5) were elevated, all were significantly reduced. Serially tracking 49 distinct variant allele frequencies (VAF) among 22 patients, VAFs were reduced in 45% and stable in 41%. Cells with JAK2 mutations were more sensitive to treatment compared to CALR and MPL; clones with ASXL1 mutations showing the greatest sensitivity to IMG-7289. No new mutations were identified in any patients. Among germline variants, 7 of 40 patients had extremely rare but highly deleterious variants of BOD1L1 coding for an activity participating in histone H3K4 methylation, the substrate of LSD1.

38 patients (95%) reported 771 AEs of which 33 were SAEs. Four SAEs all Grade 3, each occurring once, were deemed possibly related to IMG-7289: painful splenomegaly, rectal bleeding, heart failure, and headache. There have been no safety signals, DLTs, deaths related to drug, or progression to AML.

22 Phase 2b patients have enrolled to date; 4 withdrew, 1 due to limited clinical benefit (D34), 2 due to adverse events of myalgia (unrelated, D51) and fatigue, (possibly related; D21), 1 due to death (unrelated complication of a fall, D62); of the 18 remaining, 14 have completed 12 weeks.

All 22 Phase 2b patients required up-titration from the starting dose to achieve the target platelet range, hence, the dosing rules have again been modified to increase drug exposure and further enhance efficacy.

This is the first clinical study of an LSD1 inhibitor in patients with MF. Once-daily IMG-7289 as monotherapy was well-tolerated among patients with advanced MF with limited treatment options. With dose optimization, IMG-7289 improved symptom burdens and reduced spleen volume without safety signals. Additionally, improvements in IL-8 levels, fibrosis scores, anemia and VAF have been observed.

The study is active and remains open for enrollment in the US, UK, EU and Asia.