Efficacy and safety of the LSD1 inhibitor bomedemstat in participants with polycythemia vera (PV) resistant or intolerant to cytoreductive therapy: The Phase 2 shorespan-004 study

Abstract

Abstract Introduction: PV is a JAK2-driven myeloproliferative neoplasm (MPN) characterized by an erythroid dominant trilineage proliferation of hematopoietic precursor cells. Current treatments target thrombosis and symptoms with little impact on the natural progression of PV. Bomedemstat is an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), which is an epigenetic modifier involved in regulating megakaryocyte and erythrocyte maturation. Bomedemstat has shown manageable safety and promising clinical activity in other MPNs, including myelofibrosis and essential thrombocythemia. Shorespan-004 (NCT05558696) is an open-label, phase 2 study designed to evaluate bomedemstat in participants (pts) with PV who are resistant or intolerant to ≥1 cytoreductive therapy. Methods: Pts were aged ≥18 y and had a confirmed diagnosis of PV resistant or intolerant to ≥1 standard cytoreductive therapy, a bone marrow fibrosis score of grade 0 or 1, an ECOG PS of 0 to 2, platelet counts of ≥250 x 109/L, and absolute neutrophil counts of ≥1.5 x 109/L. Pts received bomedemstat at a starting dose of 40 mg/d PO, with titration to a hematocrit target of <45%. Primary end points were safety and hematocrit reduction to <45% by wk 36 that lasted ≥12 wk without phlebotomy. Secondary end points included durability of hematocrit reduction; incidence and durability of platelet count reduction to ≤450 x 109/L and white blood cell (WBC) count reduction to <10 x 109/L; incidence of new thrombotic or major hemorrhagic events; and progression to post-PV myelofibrosis (PPV-MF) or myelodysplastic syndrome, or transformation to acute myeloid leukemia. Reduction in symptom burden was assessed using the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0 and the Patient Global Impression of Change (PGIC). Results: Twenty pts were treated. Median age was 67.5 y (range, 32.0-82.0), 15 pts (75%) were male, 15 (75%) had an ECOG PS of 1, and 5 (25%) had an ECOG PS of 2. Median time since diagnosis was 7.8 mo (range, 1.4-23.0), and median prior lines of therapy received was 1 (range, 1-5). Two pts (10%) had a history of bleeding and 7 (35%) had a history of thromboembolic events. Mean MFSAF total score at baseline was 17.9 (SD, 13.3). At data cutoff (March 25, 2025), 12 pts were ongoing and 8 had discontinued treatment (4 withdrawal by pt, 2 physician decision, 1 adverse event [AE], 1 progressive disease). Median time from treatment initiation to data cutoff was 14.1 mo (range, 12.0-17.7). Treatment-related AEs occurred in 19 pts (95%) and grade 3 or 4 events in 2 pts (10%; platelet count decreased, thrombocytopenia). No pts discontinued or died due to treatment-related AEs. One pt (5%) died due to a non–treatment-related hemorrhagic stroke. A sustained 12-wk reduction in hematocrit to <45% without phlebotomy occurred in 9 pts (45% [95% CI, 23-69]) by wk 36 and in 10 pts (50% [95% CI, 27-73]) by wk 52. Seventeen pts (85%) had a hematocrit reduction to <45% at any time; median duration of reduction was 6.5 mo (range, 0.3-16.8). A platelet reduction to ≤450 x 109/L occurred in 18 pts (90%) by wk 36 (no additional pts had a reduction at any time); median duration of reduction was 9.4 mo (range, 0-14.8). WBC reduction to <10 x 109/L occurred in 15 pts (75%) by wk 36 and in 17 pts (85%) by wk 52. Seventeen pts (85%) had a WBC reduction to <10 x 109/L at any time; median duration of reduction was 8.3 mo (range, 0.5-14.8). One pt (5%) had a new major hemorrhagic event (hemorrhagic stroke); no new thrombotic events occurred. One pt progressed to PPV-MF. The mean MFSAF total score for evaluable pts (n = 15) at wk 36 was 9.0 (SD, 8.1); least squares mean (LSM) change from baseline was -5.6 (95% CI, -8.8 to -2.5). The mean MFSAF total score at wk 52 was 11.6 (SD, 10.7); LSM change from baseline was -3.5 (95% CI, -6.7 to -0.3). Per the PGIC at wk 36, 5 evaluable pts (31%) reported their health status stayed the same, 4 (25%) a little better, 3 (19%) better, and 3 (19%) much better. Conclusion: Bomedemstat had manageable safety and clinically relevant activity in pts with previously treated PV. Half of all pts had a reduction in hematocrit to <45% by wk 52 that lasted ≥12 wk without phlebotomy; 85% had a hematocrit reduction to <45%, 90% had a platelet reduction to ≤450 x 109/L, and 85% had a WBC reduction to <10 x 109/L at any time. A clinically significant reduction in MFSAF total score was observed. These data suggest bomedemstat as a viable treatment option for PV.