bomedemstat (MK-3543)

P3, N=300, Not yet recruiting, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Union Hospital, Tongji Medical College, Huazhong University of

P1, N=16, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P1/2, N=3, Terminated, University of Washington | Trial completion date: Jan 2026 --> Apr 2024 | Active, not recruiting --> Terminated; Closed per SRC Low Accrual Policy

P1, N=16, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=81, Completed, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Active, not recruiting --> Completed

P3, N=300, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P2, N=9, Active, not recruiting, The University of Texas Health Science Center at San Antonio | Recruiting --> Active, not recruiting | N=20 --> 9

P2, N=4, Active, not recruiting, Terrence J Bradley, MD | Recruiting --> Active, not recruiting | N=24 --> 4

P3, N=300, Not yet recruiting, Merck Sharp & Dohme LLC

P3, N=400, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P1/2, N=3, Active, not recruiting, University of Washington | Suspended --> Active, not recruiting | N=34 --> 3 | Trial primary completion date: Jan 2025 --> Aug 2023

P1, N=20, Completed, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc. | Recruiting --> Completed

P1/2, N=34, Suspended, University of Washington | Recruiting --> Suspended

P3, N=400, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=20, Active, not recruiting, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Recruiting --> Active, not recruiting | Trial primary completion date: Apr 2025 --> Jan 2025

P2, N=80, Active, not recruiting, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Trial completion date: Dec 2024 --> Aug 2024 | Trial primary completion date: Dec 2024 --> Aug 2024

P2, N=20, Recruiting, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Trial completion date: Aug 2025 --> Apr 2025 | Trial primary completion date: Aug 2025 --> Apr 2025

P1/2, N=90, Completed, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Phase classification: P2 --> P1/2

P3, N=300, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

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.

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 lethal with other somatic mutations that result in genome instability and, hence, protect against progression to AML.

P2, N=20, Recruiting, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Trial completion date: Feb 2025 --> Aug 2025 | Trial primary completion date: Feb 2025 --> Aug 2025

P3, N=300, Not yet recruiting, Merck Sharp & Dohme LLC | Trial primary completion date: Aug 2028 --> Aug 2026

P2, N=24, Recruiting, Terrence J Bradley, MD | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2023 --> Oct 2024

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.

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.

The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat)...For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors.

P3, N=300, Not yet recruiting, Merck Sharp & Dohme LLC

P1, N=16, Completed, Avance Clinical | Recruiting --> Completed

Prior treatment with ruxolitinib was reported in 82%, 70% had also received ≥1 other treatments. Further, bomedemstat selects against clones with ASXL1 mutations. The impact of the P6 haplotype on disease course and response to bomedemstat is under study.

In conclusion, treatment with IMG-7289 results in decreased viability, as demonstrated by induction of apoptosis and cell cycle arrest, as well as differentiation induction in pediatric AML cell lines. The in vitro and in vivo activity observed in pediatric AML is also observed in models with high-risk phenotypes (KMT2A-r AML and AMKL). Activity of LSD1 inhibition on the LIC population may represent a promising strategy to mitigate relapse or refractory disease.

LSD1 inhibition increased MHC-I expression and enhanced responses to PD1 inhibition in vivo, supporting a new clinical trial to combine bomedemstat with standard of care PD1 axis inhibition in SCLC.

Median age was 68 (42-92) yrs; of the patients most recently treated with hydroxyurea, 88% met ELN criteria for resistance/ intolerance. For those patients treated for at least 24 weeks, 79% achieved a durable reduction in platelet count to ≤400x10 9 /L without thromboembolic events. A Phase 3 study of bomedemstat for the treatment of ET is being planned.

Prior treatment with ruxolitinib was reported in 83% (74/89); 46% had also received at least 1 additional treatment. There have been no safety signals, DLTs, or deaths related to drug. Conclusion In patients with advanced MF, bomedemstat alone had an acceptable tolerability profile, relieved symptoms, reduced spleen volume and mutation burden while improving fibrosis and anemia without safety signals.

Prior treatment with ruxolitinib was reported in 81% (72/89), 43% (38/89) had also received up to 3 different treatments. Additionally, reductions in the allele frequency of both driver and high molecular risk mutations were observed and correlated with improved efficacy metrics. The study is now fully enrolled and additional data will be presented.

All but 6 patients were previously treated with ruxolitinib; 47% had received up to 3 additional treatments. Additionally, improvements in fibrosis scores, anemia and MAF have been observed. The study is active and is enrolling in the US, UK, EU and Hong Kong.

All but 1 patient were previously treated with ruxolitinib; 65% had received up to 4 additional treatments including fedratinib and CPI-0610. 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.

Although not included yet in formal risk stratification models, a number of studies have shown leukocytosis to be a risk factor for thrombosis in ET.18, 19, 20, 21 Young patients with ET without high risk features for thrombosis or bleeding (e.g., platelets > 1.5×109/L) do not need cytoreductive therapy and should be managed with low-dose aspirin alone.22 Acquired von Willebrand's disease (AVWD) can occur, particularly at high platelet counts, and aspirin should be stopped and cytoreductive therapy started if AVWD is found.23 Twice daily aspirin has been proposed for low-risk patients with cardiovascular risk factors, as well as for intermediate-risk patients, as an alternative to cytoreductive therapy,17 but the evidence for this is limited.24, 25 Twice daily aspirin can be useful to control the microvascular/vasomotor symptoms not adequately addressed by once daily aspirin.23 Young patients with CALR-mutated ET and no history of thrombosis should likely be observed, as their bleeding risk from aspirin may outweigh any benefit in terms of thrombotic risk reduction.26 Evidence from phase 3, randomized controlled trials supports the use of either hydroxyurea (HU) or pegylated interferon alfa as frontline cytoreductive therapy27, 28; HU is, by far, the more commonly used drug...Although no benefits for ruxolitinib in any parameters other than symptoms were observed in the UK MAJIC-ET trial,33 in which ruxolitinib was compared with best available therapy (BAT) in HU-resistant/intolerant patients with ET, ruxolitinib continues to be developed for this indication (NCT03123588), based on long-term, phase 2 evidence of efficacy in terms of count and symptom control from other studies.34 Like ruxolitinib, ropeginterferon alfa-2b, a novel, monopegylated interferon formulation administered every 2 weeks, is also being compared against anagrelide for HU-resistant/intolerant ET (NCT04285086)...A clinical trial of bomedemstat, a small-molecule inhibitor of lysine-specific demethylase 1 (LSD1), has also been announced (NCT04254978)...If cytoreductive therapy is required, interferon alfa, usually pegylated interferon alfa, is the drug of choice. There is no experience with the use of ruxolitinib or other JAK inhibitors in pregnancy.

Murine HSC-derived MLL-AF9 leukemias exhibited markedly reduced sensitivity to the LSD1 inhibitor, IMG-7289, when compared to GMP-derived MLL-AF9 leukemias, in vitro and in vivo...We found that modulation of Evi1 expression resulted in altered p53 protein stability: specifically, (1) shRNA-mediated knockdown of Evi1 in HSC-derived leukemias increased p53 protein stability and (2) overexpression of Evi1 blunted doxorubicin-induced p53 protein stability...By contrast, Evi1high HSC-derived leukemias exposed to the BCL2 inhibitor venetoclax in vivo were sensitized to LSD1 inhibition, resulting in enhanced apoptosis and greater reductions in disease burden, observations that we observed in patients with Evi1high AML treated with venetoclax. Our findings describe how the cell of origin of p53 wild-type cancers can differentially modulate p53 function and therapeutic response and provide a mechanistic rationale for therapies aimed to circumvent this resistance mechanism.