Biomea Fusion to Present New Preclinical Data Showing BMF-219’s Strong Activity in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Tumor Models at ASCO 2022

• BMF-219 is the first investigational menin inhibitor in clinical development to show potential as a therapeutic agent for CLL
• BMF-219, a covalent menin inhibitor, demonstrated potency across ex vivo CLL tumor models with varying cytogenetic risk profiles and Rai stages, indicating broad activity with over 98% cell lethality in these models
• High- and intermediate-risk cytogenetic profile (TP53 alterations and NOTCH1 mutations, respectively) CLL patient samples, which represent a significant unmet clinical need, were highly sensitive to BMF-219 treatment
• BMF-219 was also highly active against samples taken from CLL patients with profiles of resistance to standard-of-care agents, including bendamustine and ibrutinib
• BMF-219 is currently in a Phase I clinical trial (COVALENT-101) in patients with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM).

REDWOOD CITY, Calif., May 26, 2022 (GLOBE NEWSWIRE) -- Biomea Fusion, Inc. (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, today announced it will present new data at the American Society of Clinical Oncology (ASCO) Annual Meeting demonstrating BMF-219’s activity in ex vivo preclinical models of CLL. In addition, the company will present a Trial In Progress (TIP) poster presentation detailing the design of COVALENT-101. Once released at the ASCO Annual Meeting, the preclinical and TIP presentations can be viewed on Biomea’s website at https://biomeafusion.com/publications.

“Given our leadership team’s involvement with the discovery and development of ibrutinib and, thus, its demonstrated efficacy in CLL, we were highly encouraged to see BMF-219 demonstrate greater activity than ibrutinib ex vivo, especially in patient samples with TP53 alterations and NOTCH1 mutations,” said Thomas Butler, Biomea’s Chief Executive Officer and Chairman of the Board. “BMF-219’s powerful cell-killing activity across ex vivo CLL models as a single agent, at similar concentrations as our prior experiments of BMF-219 in ex vivo models of other cancer types, is a very important finding. We are eager and very excited to fully explore the clinical potential of a covalent menin inhibitor across multiple liquid and solid tumor types.”

BMF-219 demonstrated potency across ex vivo CLL tumor models with varying cytogenetic risk profiles and Rai stages, indicating broad activity with over 98% cell lethality in all of these models. Additionally, BMF-219 showed consistently strong activity compared to venetoclax (used as a positive control) and significantly greater activity than a clinical non-covalent (reversible) menin inhibitor. Additionally, BMF-219 exhibited robust growth inhibition in patient samples that were less responsive to bendamustine and ibrutinib.

Poster Presentation Details:

Preclinical activity of irreversible Menin inhibitor, BMF-219, in chronic lymphocytic leukemia. (Abstract #7541) Session Title:  Hematologic Malignancies—Lymphoma and Chronic Lymphocytic LeukemiaSession Date and Time:  Saturday, June 4, 2022, 8:00 AM-11:00 AM CDTFull Text:Background: Menin is a scaffold protein that drives oncogenic function through transcriptional modulation directed by its various cofactors. A previous report demonstrated that menin regulates a distinct set of gene targets independent of its function with the MLL proteins in hematopoiesis and is essential for B-cell maturation (Li et al.Blood.2013;122(12):2039-46.). Chronic Lymphocytic Leukemia (CLL) is a disease of malignant B lymphocytes, for which standard-of-care agents are generally well tolerated; however, CLL patients with certain genetic backgrounds demonstrate inferior outcomes to these regimens. A major driving feature of CLL is overexpression of the anti-apoptotic marker, BCL2. We previously reported the ability of BMF-219, a selective, irreversible menin inhibitor, to downregulate the expression of BCL2 in acute leukemia cells. Additionally, we have reported the synergy of BCL2-targeted agent, venetoclax, with BMF-219 in potent cell killing of diffuse large B-cell lymphoma (DLBCL) preclinical models, prompting our exploration of BMF-219 activity in CLL. Here, we provide the first preclinical evidence for menin as a therapeutic target in CLL, by demonstrating high potency of BMF-219 against a diverse collection of CLL patient specimens.

Methods: A comprehensive panel of CLL samples isolated from patients with Rai Stages 1 to 3 disease, including relapsed or refractory disease, were cultured ex vivo in the presence of BMF-219 or clinical reversible menin inhibitors to assess the antileukemic activity of the compounds. Samples were analyzed for differential gene expression of select targets in response to treatment.

Results: BMF-219 demonstrated high potency, achieving >98% cell lethality at 1 μM exposure in all patient samples tested, with IC50 values in the range of 0.1 to 0.38 μM. Specimens isolated from patients with clinical profiles of high-risk genetic backgrounds associated with inferior outcomes to standard therapy, such as mutations in TP53 and NOTCH1, and chromosomal aberrations such as del(13q), trisomy 12 and complex karyotype, exhibited high sensitivity to BMF-219 treatment. BMF-219 was also highly effective against patient samples with clinical profiles of resistance to bendamustine, ibrutinib and venetoclax therapy. In comparison, clinical reversible menin inhibitors demonstrated no significant activity across all patient samples tested, with incalculable IC50 values and