Bomedemstat for Blood Disorders
Recruiting in Palo Alto (17 mi)
+14 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Merck Sharp & Dohme LLC
Must be taking: Bomedemstat
Disqualifiers: Other study, Noncompliance, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?The primary purpose of the study is to transition participants into an extension study to collect long-term safety and efficacy data. The study will include participants who are safely tolerating bomedemstat, receiving clinical benefit from its use in estimation of the investigator, and have shown the following criteria:
* Participants from the IMG-7289-202/MK-3543-005 (NCT05223920) study must have received at least 6 months of treatment with bomedemstat;
* Essential thrombocythemia (ET) and polycythemia vera (PV) participants from studies other than IMG-7289-202/MK-3543-005 must have achieved confirmed hematologic remission.
No hypothesis testing will be conducted in this study.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it mentions that participants should not have received prohibited concomitant medications. It's best to discuss your current medications with the trial team to see if they are allowed.
What makes the drug Bomedemstat unique for treating blood disorders?
Bomedemstat is unique because it targets LSD1, an enzyme involved in cell cycle regulation and differentiation, which is a promising approach for treating blood disorders. Unlike some other LSD1 inhibitors, Bomedemstat has been optimized for better stability and reduced side effects, making it a novel option in this therapeutic area.
12345Eligibility Criteria
This trial is for people with certain blood disorders like Polycythemia, Essential Thrombocythemia, or Myelofibrosis who have been part of previous bomedemstat studies. They must be able to take oral medication and have shown benefits from at least 6 months of prior treatment with bomedemstat.Inclusion Criteria
I can take pills and follow home dosing instructions.
I am part of a bomedemstat study by Imago Biosciences or MSD, approved for MK-3543-017.
I've been on bomedemstat for 6+ months, tolerated it well, and it's working for me.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Transition
Participants transition from a prior study to the extension study to continue receiving bomedemstat
Up to 10 years
Follow-up
Participants are monitored for safety and efficacy of long-term bomedemstat treatment
Up to 10 years
Participant Groups
The study tests the long-term safety and effectiveness of a drug called Bomedemstat in patients who've previously responded well to it. It's an extension study without hypothesis testing, meaning they're not trying to prove a specific theory but rather gather more data.
1Treatment groups
Experimental Treatment
Group I: BomedemstatExperimental Treatment1 Intervention
Participants will receive oral capsules of bomedemstat once daily for up to 10 years, with the starting dose as the same dose that the participant was on at the time of transition from the feeder study.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Michigan ( Site 6000)Ann Arbor, MI
UPMC Hillman Cancer Center ( Site 6004)Pittsburgh, PA
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Who Is Running the Clinical Trial?
Merck Sharp & Dohme LLCLead Sponsor
References
Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles. [2023]Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (trans-2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is S2157; however, this compound has a high hERG channel inhibitory activity and a low microsomal stability, making it unsuitable as a drug candidate. Here, using an in silico hERG inhibition prediction model, we designed, synthesized, and evaluated a novel series of S2157 derivatives characterized by modifications of the benzyloxy and piperazine groups. Among the synthesized derivatives, a compound possessing 2-fluoropyridine and 2,8-diaza-spiro[4.5]decane groups (compound 10) showed the most desirable activities, and its eutomer, S1427, was isolated by the optical resolution of 10. In addition to potent LSD1 inhibitory activity, S1427 exhibited desirable hERG channel inhibition and microsomal stability profiles.
Recent advances of LSD1/KDM1A inhibitors for disease therapy. [2023]Lysine-specific demethylase 1 (LSD1/KDM1A) dysregulation is closely associated with the pathological processes of various diseases, especially hematologic malignancies. Significant progresses have been made in the field of LSD1-targeted drug discovery. Nine LSD1 inhibitors including tranylcypromine, ORY-1001, ORY-2001, GSK-2879552, IMG-7289, INCB059872, TAK-418, CC-90011 and SP-2577 have entered clinical stage for disease treatment as either mono- or combinational therapy. This review updates LSD1 inhibitors reported during 2022. Design strategies, structure-activity relationship studies, binding model analysis and modes of action are highlighted. In particular, the unique multiple-copies binding mode of quinazoline derivatives paves new ways for the development of reversible LSD1 inhibitors by blocking the substrate entrance. The design strategy of clinical candidate TAK-418 also provides directions for further optimization of novel irreversible LSD1 inhibitors with low hematological side effects. The influence of the stereochemistry on the potency against LSD1 and its homolog LSD2 is briefly discussed. Finally, the challenges and prospects of LSD1-targeted drug discovery are also given.
Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology. [2022]Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.
First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia. [2021]Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML).
Viscosalactone B, a natural LSD1 inhibitor, inhibits proliferation in vitro and in vivo against prostate cancer cells. [2023]Lysine-specific demethylase 1 (LSD1) has been a promising target to treat prostate cancer, and discovery of novel LSD1 inhibitors would have great clinical significance. In this work, viscosalactone B was first identified as a novel LSD1 inhibitor. Viscosalactone B isolated from Withania Somnifera displayed antiproliferative activity against PC3, DU145, C42B, PC3/MDVR, DU145/MDVR, and C42B/MDVR cells with IC50 values of 1.17, 0.72, 3.86, 2.06, 0.96 and 1.15 μM, respectively. In comparison, it was a selective LSD1 inhibitor with an IC50 value of 970.27 nM and could induce a significant accumulation of LSD1 substrates H3K9me1, H3K9me2, and H3K4me1 in a concentration-dependent manner in DU145 cells. According to docking studies, it formed hydrogen bonds with the Thr11, Lys14, and Arg8 residues of LSD1. Importantly, while it displayed potent antitumor efficacy in vivo, it did not show obvious cytotoxicity on the major organs of nude mice. Therefore, viscosalactone B, as a novel LSD1 inhibitor, is a potential candidate that can be used for the treatment of prostate cancer in clinics.