A Phase 3, Randomized, Double-Blind, Active-Comparator-Controlled Study of Bomedemstat Versus Hydroxyurea in Patients with Essential Thrombocythemia Naïve to Cytoreductive Therapy

Background and Significance: Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by thrombocytosis, increased risk of thrombosis, and the potential to develop myelofibrosis (MF) and acute myeloid leukemia (AML). ET is driven by mutations in JAK2, CALR, and MPL. Clinical management is focused on reducing the incidence of thrombotic and bleeding events. Currently available treatments can normalize platelet counts (PC) but are not effective in all patients. There remains an unmet need for novel therapies that can alter the natural history of ET. Bomedemstat (MK-3543) is an irreversible inhibitor of lysine-specific demethylase 1, an enzyme that regulates hematopoietic stem and progenitor cell proliferation and maturation, including differentiation to megakaryocytes. Bomedemstat reduced PC, white cell counts (WCC), and serum levels of inflammatory cytokines in preclinical models of myeloproliferative neoplasms. In a phase 2 clinical study of patients with ET, bomedemstat improved symptoms, durably reduced PC and WCC, and reduced mutation burden. This randomized, double-blind, active-comparator-controlled, phase 3 study (NCT06456346) will investigate the efficacy and safety of bomedemstat versus hydroxyurea in patients with high-risk ET who are naive to cytoreductive therapy. Study Design and Methods: Eligible patients are aged ≥18 years and have cytoreductive therapy naive ET with an indication for cytoreductive therapy, a bone marrow fibrosis score of 0 or 1, a PC of >450 × 109/L, and an absolute neutrophil count of ≥0.75 × 109/L. Patients with documented increased bleeding risk or an active infection requiring systemic therapy are excluded. Approximately 300 patients will be enrolled and randomly assigned 1:1 to receive either bomedemstat at a starting dose of 50 mg/day by mouth (titrated to a target PC of ≥150× 109/L to ≤350 × 109/L) or hydroxyurea at a starting dose of 500 mg/day by mouth (titration per the approved product labeling allowed). Randomization will be stratified by mutation status (JAK2 V617F vs CALR/MPL vs others) and baseline Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) fatigue score (≥4 vs <4). Clinic visits will occur every 2 weeks through week 12 and every 4 weeks thereafter. Adverse events will be monitored up to 30 days after treatment end and graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria. The primary end point is durable clinicohematologic response, defined as confirmed PC reduction to ≤400 × 109/L; absence of WCC elevation to >10 × 109/L due to ET (local assessment); WCC reduction to ≤10 × 109/L confirmed at first subsequent measurement ≥2 weeks later (starting at week 24, maintained for ≥24 weeks) in patients with WCC >10 × 109/L at screening; and absence of any thrombotic or major hemorrhagic events or disease progression to MF or myelodysplastic syndrome (MDS)/AML by week 52. Secondary end points include change in fatigue and total symptom score from baseline per the MFSAF v4.0, change in total fatigue score from baseline per the PROMIS Fatigue SF-7a scale, duration of clinicohematologic response, duration of hematologic remission, incidence of thrombotic events, incidence of major hemorrhagic events, transformation to post-ET MF or MDS/AML, event-free survival, and safety. Exploratory end points include change from baseline in patient-reported outcome scores (Patient Global Impression of Severity [PGIS]-ET, Patient Global Impression of Change [PGIC]-ET, PGI-Fatigue, PGIC-Fatigue, EORTC QLQ-30, EuroQoL-5D-5L, and Work Productivity and Activity Impairment - ET), evaluation of bomedemstat pharmacokinetics, and molecular biomarker identification. Primary analysis and secondary patient-reported outcome analyses will be conducted with the intent-to-treat population (all randomly assigned patients). Safety analyses will be conducted with all randomly assigned patients who receive at least 1 dose of study intervention. The Stratified Miettinen-Nurminen method will be used to compare the end points of durable clinicohematologic response rate and incidence of disease progression between the 2 arms. Treatment difference in event-free survival will be assessed using a stratified log-rank test. Duration of clinicohematologic response and hematologic remission and an overall safety analysis will be summarized descriptively.

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