Benzinga | Nov 4, 2021 10:50AM EDT

Biomea Fusion Publishes Abstract For BMF-219 At American Society Of Hematology

* BMF-219 displays global disruption of menin, highlighting '219's novel mechanism of action

* Molecule elicits broad impact on the complexes surrounding menin, resulting in strong modulation of MYC expression, highlighting potential in multiple cancer types

* BMF-219 demonstrated potent preclinical efficacy in diffuse large B cell lymphoma (DLBCL) cell lines as a single agent

REDWOOD CITY, Calif., Nov. 04, 2021 (GLOBE NEWSWIRE) -- Biomea Fusion, Inc. ("Biomea") (NASDAQ:BMEA), a clinical-stage biopharmaceutical company dedicated to the discovery and development of novel irreversible small molecules to treat and improve the lives of patients with genetically defined cancers, today announced that an abstract containing preclinical data for BMF-219 has been published in Blood, the journal of the American Society of Hematology.

The study, as published in Blood, analyzed how Biomea's irreversible menin inhibitor, BMF-219, is impacting acute myeloid leukemia cells against the background of transcription factors in the GEO dataset. Menin is involved in many protein-protein interactions as part of a larger complex, with Menin and MLL/KMT2A being an example of one of those interactions. Here we investigated how '219 disrupts menin globally (selective disruption of global menin co-factors in addition to KMT2A).

Figure 1: Menin and various co-factors

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/210950de-0c6c-4204-9c99-a7ab3eb4a54c

The study demonstrates further the ability of BMF-219 to modulate MYC expression in leukemia cells, offering the foundation for exploring its activity in DLBCL cells. Transcription factor (TF) activity inference was calculated by analysis of TF-binding sites established by chromatin immunoprecipitation sequencing (ChIP-seq) GEO datasets that overlap with BMF-219 mediated differentially expressed genes in MOLM-13 cells using a published statistical framework and algorithm. This analysis revealed MYC, and its co-factor MAX, as top TFs regulating this subset of differentially expressed genes by BMF-219, as TF activity inference was highly enriched for both proteins. Established menin co-factors (KMT2A, JUND) also emerged as top candidates in this dataset. These results strongly point toward altered MYC-activity mediated by BMF-219 in leukemia cells, prompting additional exploration in MYC-dependent lymphoid malignancies.

Figure 2: Transcription factor (TF) activity inference using ChIP-seq of differentially expressed genes in MOLM-13 cells incubated with 500 nM BMF-219 at 24 hours. Each bar represents a study in the GEO repository using the specified TF antibody. TFs with more than one bar represent multiple study sets in GEO that overlap with BMF-219 mediated differentially expressed genes. MYC and MAX are top TFs regulating this subset of differentially expressed genes (p=10-49.5). Established menin co-factors (KMT2A, JUND) also emerged as top candidates in this dataset.

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/982b0dd0-91ce-482b-bd8a-fa06e9c01dd9

Using these results as the basis for further investigation, we explored BMF-219 and menin reversible inhibitors' impact on cell viability in two different DLBCL double hit lymphoma (DHL) cell lines (DB and Toledo). Single-agent BMF-219 reduced >90% of cell viability in DB and Toledo cells, at 1.0?M and 0.36 ?M, respectively. The IC50 values of BMF-219 were calculated near 0.3 mM for both DB and Toledo cells; however, the two reversible menin inhibitors tested were significantly less effective. One of the reversible inhibitors exhibited IC50 values at multi-fold higher drug concentrations than BMF-219 in both cell lines tested and the other reversible compound tested did not show sensitivity to either cell line.

"With this study, we gained valuable understanding and expanded our knowledge into the mechanism of action of our irreversible menin inhibitor, BMF-219. Besides its targeted selectivity profile, we also recognize the broad impact BMF-219 has on the complexes surrounding menin," said Alex Cacovean, M.D., Biomea Fusion's Executive Medical Director. "At low dosage levels, by targeting menin, we were able to inhibit MYC gene expression and demonstrated potent cell killing in two very aggressive cell lines, representative of underserved DLBCL subpopulations. We are very excited about these preclinical findings and we are hopeful to now clinically validate the effects of our irreversible menin inhibitor in MYC-positive, double expressor, and double hit DLBCL patients."

Abstract Details

Title: Novel Irreversible Menin Inhibitor, BMF-219, Shows Potent Single Agent Activity in Clinically Relevant DLBCL Cells

Abstract Number: 148045

About Diffuse Large B Cell Lymphoma (DLBCL)

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma. DLBCL starts in white blood cells called lymphocytes and grows in lymph nodes. Every year, there are ~18,000 people in the United States that are diagnosed with DLBCL. Following initial treatment with standard chemotherapy, ~70% of people have a complete response and ~50% of patients are cured. For patients with relapsed or refractory DLBCL, median overall survival is between 6-7 months. Double Hit Lymphomas (DHL) and Double Expressor Lymphomas (DEL) are high grade B cell lymphomas (HGBLs) that have high MYC and BCL2 dependency.