bomedemstat (MK-3543) / Merck (MSD) - LARVOL DELTA

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 (ASH 2025) - P2 | "Bomedemstat had manageable safety and clinically relevant activity in pts with previouslytreated PV. Half of all pts had a reduction in hematocrit to <45% by wk 52 that lasted ≥12 wk withoutphlebotomy; 85% had a hematocrit reduction to <45%, 90% had a platelet reduction to ≤450 x 109/L, and85% had a WBC reduction to <10 x 109/L at any time. A clinically significant reduction in MFSAF total scorewas observed."

Clinical • P2 data • Acute Myelogenous Leukemia • Cerebral Hemorrhage • Essential Thrombocythemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytopenia • Thrombocytosis • Thrombosis • JAK2

MK-3453-023: A Study of Bomedemstat (MK-3543) in Participants With Mild or Moderate Hepatic Impairment (MK-3543-023) (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatitis C • Hepatology • Liver Failure

Bomedemstat (IMG-7289), an LSD1 Inhibitor, Manages the Signs and Symptoms of Essential Thrombocythemia (ET) While Reducing the Burden of Cells Homozygous for Driver Mutations (ASH 2023) - P2 | "All current treatments - hydroxyurea, interferon, or anagrelide - have their limitations and do not substantially affect the natural history of ET. Furthermore, this study shows that sequencing germline+granulocyte DNA provides a reliable qualitative view of the impact of treatment on the genotypic distribution among CD34+ cells as revealed by scDNA genotyping. Finally, bomedemstat showed activity reducing stem/progenitor cells homozygous for mutations in JAK2, CALR, and MPL."

Cardiovascular • CNS Disorders • Constipation • Essential Thrombocythemia • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Infectious Disease • Musculoskeletal Pain • Myeloproliferative Neoplasm • Oncology • Pneumonia • Respiratory Diseases • Thrombocytopenia • Thrombocytosis • CALR • CD14 • CD34 • JAK2

VenBom: Venetoclax and Bomedemstat in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Terrence J Bradley, MD | Suspended ➔ Recruiting | Trial completion date: Nov 2025 ➔ Nov 2026 | Trial primary completion date: Nov 2025 ➔ Nov 2026

Enrollment open • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

IMG-7289 in Patients With Essential Thrombocythemia (ET) or Polycythemia Vera (PV) (clinicaltrials.gov) - P2 | N=4 | Active, not recruiting | Sponsor: Terrence J Bradley, MD | Trial completion date: Oct 2026 ➔ Oct 2027 | Trial primary completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • Essential Thrombocythemia • Hematological Disorders • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis

Combined inhibition of lysine-specific demethylase 1 and kinase signaling as a preclinical treatment strategy in glioblastoma. (PubMed, Neurooncol Adv) - "Glioblastoma stem cell (GSC) lines and normal human astrocytes (NHAs) were treated with catalytic LSD1 inhibitors, NCD38 and bomedemstat, and the LSD1 scaffolding inhibitor, seclidemstat alone and in combination with kinase inhibitors, including osimertinib, afatinib, and ulixertinib. Combined treatment with NCD38 and osimertinib in glioblastoma-bearing mice delayed tumor growth and improved survival outcomes. These findings provide a rationale for further investigation of combination therapies of catalytic inhibitors of LSD1 and EGFR and dual-targeted inhibitors to overcome resistance and improve outcomes."

Journal • Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • EGFR • KDM1A

Elucidating Stemness-Associated Regulatory Pathways to Guide Personalized Treatment for Ductal Carcinoma in Situ (SABCS 2025) - "To target FOXA1, we employed bomedemstat, an inhibitor of lysine-specific demethylase 1 (LSD1)... Cellular stemness may serve as a predictor of DCIS with a future risk for invasive progression. By targeting the key biological drivers of cellular stemness, our goal is to distinguish aggressive from indolent disease, ultimately reducing overtreatment and improving outcomes for patients with high-risk DCIS."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • CEACAM6 • EGFR • FOXA1 • HER-2

LSD1 inhibition enhances venetoclax efficacy in Acute Myeloid Leukemia via metabolic rewiring (ASH 2025) - "Supporting this, combiningbomedemstat with OxPhos inhibitors (IACS-010759, rotenone, antimycin, oligomycin) synergisticallyreduced cell proliferation, and Rho-zero MOLM-13 cells, lacking mitochondrial DNA, were more sensitiveto bomedemstat than wild-type cells.Consistent with its metabolic effects, bomedemstat increased expression (P = 0.0002) and activation (P =0.02) of the energy stress sensor AMPK, as shown by western blotting. Bomedemstat and venetoclax co-treatment showed synergistic anti-leukemic effects in AMLmodels in vitro and in vivo. Our findings suggest that LSD1 inhibition primes AML cells to venetoclax viadifferentiation-induced metabolic rewiring and activation of AMPK-mediated stress responses, providingthe basis for a planned clinical trial."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ANXA5 • DNMT3A • FLT3 • HOXA9 • IDH2 • MEIS1 • NPM1 • PTPRC • WT1

Shorespan-017: Phase 3 extension study for safety of bomedemstat in participants with essential thrombocythemia who received bomedemstat from a prior clinical study (ASH 2025) - P3 | "Bomedemstat had a manageable safety profile in participants with essentialthrombocythemia who were currently receiving bomedemstat for longer duration in this extension studyand achieved a clinical benefit."

Clinical • P3 data • Cardiovascular • Constipation • Essential Thrombocythemia • Gastroenterology • Gastrointestinal Disorder • Heart Failure • Hematological Disorders • Infectious Disease • Musculoskeletal Pain • Myelofibrosis • Myeloproliferative Neoplasm • Neutropenia • Respiratory Diseases • Thrombocytosis

Dec. 6, Merck presented the first data from a phase 2 study of bomedemstat, an oral lysine-specific demethylase 1 (LSD1) inhibitor… (FierceBiotech) - "In the Shorespan-004 trial, patients took bomedemstat daily for 36 weeks, with some patients continuing on for a total treatment period of 52 weeks. Of the 20 patients enrolled, nine achieved blood cell counts that were below 45% of their baselines by Week 36 without needing to have blood drawn, the trial’s primary endpoint. In all, 40% of patients experienced a serious adverse event, though none of the patients who discontinued treatment did so because of treatment-related adverse events."

P2 data • Polycythemia Vera

MK-3453-023: A Study of Bomedemstat (MK-3543) in Participants With Mild or Moderate Hepatic Impairment (MK-3543-023) (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial primary completion date: Nov 2025 ➔ Mar 2026

Trial primary completion date • Hepatitis C • Hepatology • Liver Failure

A Study of Bomedemstat (IMG-7289/MK-3543) Compared to Best Available Therapy (BAT) in Participants With Essential Thrombocythemia and an Inadequate Response or Intolerance of Hydroxyurea (MK-3543-006) (clinicaltrials.gov) - P3 | N=340 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial primary completion date: Sep 2026 ➔ Jul 2027

Trial primary completion date • Essential Thrombocythemia • Hematological Disorders • Myeloproliferative Neoplasm • Thrombocytosis

Merck…announced that new data across multiple hematologic malignancies will be presented at the American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Fla. from Dec. 6-9. (Merck (MSD) Press Release) - "Data presentations will feature Merck’s pipeline candidates, including: MK-1045, an investigational CD19xCD3 T-cell engager; bomedemstat (MK-3543), an investigational, orally available lysine-specific demethylase 1 (LSD1) inhibitor; and nemtabrutinib (MK-1026), an investigational, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. Additionally, Merck will present new and updated results highlighting zilovertamab vedotin (MK-2140), an investigational antibody-drug conjugate (ADC) that targets receptor tyrosine kinase-like orphan receptor 1 (ROR1)."

Clinical data • B Acute Lymphoblastic Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Essential Thrombocythemia • Follicular Lymphoma • Marginal Zone Lymphoma • Polycythemia Vera

The Randomized, Double-Blind, Phase 3 Shorespan-007 Study of Bomedemstat Versus Hydroxyurea in Cytoreductive Therapy–Naive Essential Thrombocythemia (MPN 2025) - No abstract available

Clinical • P3 data • Essential Thrombocythemia • Hematological Disorders • Myeloproliferative Neoplasm • Thrombocytosis

Phase 2 Study to Assess the Safety and Efficacy of Bomedemstat (MK3543) in Combination with Ruxolitinib in Patients with Myelofibrosis (ASH 2023) - "Conclusions These early results suggest that the addition of bomedemstat to a ruxolitinib regimen is well tolerated, improves splenomegaly and symptom scores, and stabilizes hemoglobin both in the frontline and second-line setting. Enrollment in ongoing."

Clinical • Combination therapy • P2 data • Myelofibrosis • Myeloproliferative Neoplasm • CALR • JAK2

Bomedemstat (MK3543) in Combination with Ruxolitinib in Patients with Advanced Myelofibrosis (ASH 2024) - P2 | "Conclusions These results suggest that the addition of bomedemstat to a ruxolitinib regimen is well tolerated, improves splenomegaly and symptom scores, and stabilizes hemoglobin both in the frontline and second-line setting. ClinicalTrials.gov Identifier : NCT05569538"

Clinical • Combination therapy • Metastases • Fibrosis • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • CALR • JAK2

LSD1 Inhibition Synergizes with Venetoclax in Acute Myeloid Leukemia By Targeting Cellular Metabolism (ASH 2023) - "The combination of bomedemstat and venetoclax had synergistic cytocidal effects on AML cell line and primary AML cells in vitro. It significantly reduced the leukemic burden in PDX AML models and synergistically downregulated cellular energy metabolism. These findings suggest that combining venetoclax with LSD1 inhibition holds promise as a combination treatment in AML and warrants further clinical investigation."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • HOXA9 • MEIS1 • NPM1 • PTPRC

Bomedemstat vs Hydroxyurea for Essential Thrombocythemia (MK-3543-007) (clinicaltrials.gov) - P3 | N=300 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Apr 2029 ➔ Mar 2028

Trial completion date • Essential Thrombocythemia • Hematological Disorders • Myeloproliferative Neoplasm • Thrombocytosis

LSD1 Inhibition Enhances Antigen Presentation and Co-Stimulation in AML to Promote T Cell-Mediated Anti-Leukemia Immune Responses (ASH 2023) - "In conclusion, we demonstrate both phenotypically and functionally that LSD1 inhibition by bomedemstat can enhance the immunogenicity of human and murine AML models. These findings point towards a potential role of LSD1 inhibition as a maintenance therapy after allo-HSCT."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Gene Therapies • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD4 • CD69 • CD86 • CIITA • CXCL10 • HOXA9 • IFNG • IL2RA • IRF8 • MEIS1

Phase 1/2a Trial of Bomedemstat with or without All- Trans Retinoic Acid (ATRA) in Advanced Myeloid Malignancies (ASH 2023) - "Pts could not have received immunotherapy within 30% of marrow within <2 weeks of treatment. Bomedemstat up to 6. 0 mg/kg alone or in combination with ATRA was well-tolerated in pts with high-risk AML or MDS. Change in blast count seen in treated pts could be due to differentiation to monocytes induced by bomedemstat rather than blast count reduction per se."

IO biomarker • Metastases • P1/2 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Respiratory Diseases • Thrombocytopenia

Mutational Analysis of the Genome Stability Factor BOD1L1 in Myeloproliferative Neoplasm (ASH 2023) - "To investigate the contribution that mutations might make to the pathogenesis or clinical course of MPNs, 261 genes recurrently mutated in myeloid malignancies were sequenced in DNA from germline and blood samples from patients with AML, ET and MF enrolled in studies of the LSD1 inhibitor bomedemstat...To investigate this prediction, we disrupted BOD1L1 using a doxycycline-inducible CRISPR-Cas9 system in HeLa cells and complemented them with gRNA-resistant wild-type BOD1L1,or one of six mutants distributed throughout the protein...The presence of BOD1L1 somatic mutations in megakaryocytes in MF patients may deregulate polyploidization, altering megakaryocyte function that may contribute to the development of bone marrow fibrosis. That no patients with BOD1L1 germline mutations progressed to AML in these clinical studies, coupled with the fact that these variants were not enriched in patients with AML, invites the possibility that BOD1L1 mutations may be synthetically..."

Biomarker • Acute Myelogenous Leukemia • Essential Thrombocythemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • CALR • ITGA2B • JAK2 • RIF1 • SETD1A

634. Myeloproliferative Syndromes: Clinical and Epidemiological: Treatment and Outcomes in MPNs (ASH 2023) - "Hydroxyurea and pegylated interferon are common first line treatments for MPN, each with potential advantages and disadvantages...Novel therapies include hepcidin mimetic rusfertide in PV and the LSD-1 inhibitor bomedemstat in ET. In mastocytosis, the KIT inhibitor bezuclastinib shows efficacy and safety in patients with indolent mastocytosis. In myeloid neoplasms with eosinophilia, a custom NGS panel is used to explore the molecular landscape in patients negative for tyrosine kinase fusion genes, identifying recurrent JAK/STAT mutations associated with response to JAK inhibitors."

Clinical • Cardiovascular • Eosinophilia • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • Thrombosis

The Histone Methyltransferase DOT1L Cooperates with LSD1 to Control Cell Division in Blast-Phase MPN (ASH 2024) - "To validate the synthetic lethal interaction between DOT1L and LSD1 we treated DOT1L-ko cells with Bomedemstat or GSK2879552 and discovered a 100-fold increase in drug sensitivity compared to WT cells (MTS-assay)...Consistent with this observation, treatment of the MPN blast-phase cell lines HEL or SET2 with LSD1-inhibitors in combination with the DOT1L-inhibitor EPZ5676 only showed a modest cooperative effect...This cooperation is caused by orchestrated binding of DOT1L and LSD1 at selected enhancer regions and is independent of DOT1L's enzymatic activity. This non-canonical function of DOT1L in blast-phase MPN provides a strong rationale for the development of targeted protein degraders (PROTACs) of DOT1L to exploit these findings therapeutically."

Epigenetic controller • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ANXA5 • CDK4 • CDK6 • DOT1L • DUSP6 • JAK1 • JAK2 • KMT2A • YBX1

A Phase 3, Randomized, Double-Blind, Active-Comparator-Controlled Study of Bomedemstat Versus Hydroxyurea in Patients with Essential Thrombocythemia Naïve to Cytoreductive Therapy (ASH 2024) - P3 | "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."

Clinical • P3 data • Tumor mutational burden • Acute Myelogenous Leukemia • Cardiovascular • Essential Thrombocythemia • Fatigue • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytosis • Thrombosis • CALR • JAK2 • TMB

The Transcription Factor IRF8 Regulates the Sensitivity of AML Cells to LSD1 Inhibition and All-Trans Retinoic Acid (ASH 2024) - "Methods : In murine retrovirally-induced AML cells (Hoxa9-Meis1, H9M; MN1) treated with LSD1 inhibitor (Bomedemstat) and ATRA, we assessed proliferation via the methoxynitrosulfophenyl-tetrazolium carboxanilide (XTT) assay, and the differentiation effect by flow cytometry...Conclusion : In summary, we found that IRF8 expression modulates the response of AML cells to both LSD1 inhibition and ATRA. These findings suggest IRF8 expression is a potential biomarker for selecting patients for treatment with an LSD1 inhibitor and ATRA."

Acute Myelogenous Leukemia • Brain Cancer • CNS Tumor • Hematological Malignancies • Leukemia • Meningioma • Oncology • Solid Tumor • GATA1 • GATA2 • GFI1 • HOXA9 • IRF8 • ITGAM • MEIS1 • SPI1 • TGM2