On March 8, 2022 Biomea Fusion, Inc. ("Biomea") (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to the discovery and development of novel irreversible covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported that two abstracts on BMF-219 have been accepted for poster presentation at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Biomea Fusion, MAR 8, 2022, View Source [SID1234609643]). The AACR (Free AACR Whitepaper) Annual Meeting will be held from April 8-13, 2022, at the Ernest N. Morial Convention Center in New Orleans, LA. BMF-219, Biomea’s lead program, is an irreversible covalent menin inhibitor, currently in a Phase I study for the treatment of patients with relapsed/refractory acute leukemias, including those with the MLL1/KMT2A gene rearrangements and NPM1 mutations. BMF-219 is the first and only irreversible covalent menin inhibitor in the clinic.
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"The preclinical data we will present at AACR (Free AACR Whitepaper) further validate our planned development of BMF-219 in KRAS- and MYC-dependent solid tumors and highlight the potential anti-cancer benefits of inhibiting menin, achieved via irreversible covalency," said Thomas Butler, Biomea’s CEO and Chairman of the Board. "In preclinical models, BMF-219 demonstrated near complete tumor growth inhibition in both MYC-dependent and pan-KRAS mutant cancers. These mutations are broadly manifested in numerous tumor types and are generally considered categories of very high unmet need. We are excited with the potential benefits BMF-219 may bring to patients across a spectrum of multiple liquid and solid cancers, and we look forward to seeing the results in the clinic."
Biomea plans to initiate enrollment of patients with MM and diffuse large B-cell lymphoma (DLBCL) in the ongoing Phase I clinical trial of BMF-219 in the first half of 2022. The company anticipates submitting an investigational new drug (IND) application for BMF-219 in KRAS-mutant solid tumors, including patients with NSCLC, CRC, and pancreatic cancer in the fourth quarter of 2022.
Poster Presentation Details
Biomea abstracts are now available on the AACR (Free AACR Whitepaper) website, www.aacr.org. Details for the upcoming presentations are as follows:
Anti-tumor activity of irreversible menin inhibitor, BMF-219, in high-grade B-cell lymphoma and multiple myeloma preclinical models (Abstract #1205)
Session Category: Experimental and Molecular Therapeutics
Session Title: Novel Targets and Pathways
Session Date and Time: Tuesday, April 12, 2022 9:00 AM – 12:30 PM
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 24
Poster Board Number: 23
Permanent Abstract Number: 2654
Full Text of Abstract:
Double/Triple Hit Lymphoma (DHL/THL) and Double Expressor Lymphoma (DEL) are high-grade B-cell lymphomas (HGBCL) that exhibit low responses to standard therapeutic regimens resulting in poor prognosis. DHL harbor translocations in MYC and BCL2 or BCL6, THL contain translocations in MYC/BCL2/BCL6, and DEL are characterized by high expression of MYC and BCL2. Menin is a scaffold protein that drives oncogenic function through its regulation of genes such as HOXA9, with distinct effects on transcription that are directed by various cofactors. A recent study reported that knockdown of HOXA9 resulted in marked growth inhibition of multiple myeloma (MM) cells (Chapman et al., 2017).
We previously reported the ability of irreversible menin inhibitor, BMF-219, to modulate MYC expression and exhibit high potency against DHL DLBCL preclinical models. Moreover, we demonstrated that MYC and its co-factor MAX, regulate differential gene expression in BMF-219-treated leukemia cells. Here, we demonstrate the anti-tumor activity of BMF-219 in HGBCL and MM preclinical models harboring various mutational backgrounds.
BMF-219 exhibited high potency against THL and DEL cell lines, with IC50 values of 0.27 μM and 0.37 μM, respectively. Both models achieved >90% growth inhibition with single-agent treatment. Notably, BMF-219 was multi-fold more potent and exerted dramatically greater growth inhibition compared to clinical reversible menin inhibitors in all DLBCL cell lines tested, including an expanded panel of DHL cell lines. In ex vivo studies, an R-CHOP refractory THL patient sample and an R-EPOCH refractory MYC-amplified DLBCL patient sample were highly sensitive to BMF-219 treatment, with IC50 values of 0.15 μM and 0.2 μM, respectively, and demonstrated complete growth inhibition at 1 μM exposure. In contrast, two clinical reversible menin inhibitors demonstrated much lower potency (IC50 = 0.96 μM and 6.3 μM in the MYC-amplified model, and IC50 = 5.63 μM and not calculable for the second reversible inhibitor in the THL model). MM cell lines harboring mutations in TP53, KRAS and NRAS were all sensitive to BMF-219 with IC50 values in the range of 0.25 μM to 0.5 μM and achieved 100% growth inhibition at 1 μM exposure. Combination treatments of BMF-219 with standard-of-care agents in MM cell lines were also tested. Notably, BMF-219 demonstrated single-agent efficacy (IC50 values between 0.1 μM and 0.3 μM) against a panel of newly diagnosed and R/R ex vivo MM samples, including a p53- deleted clinical profile.
Collectively, our data demonstrate the novel and robust anti-tumor activity of BMF-219 in HGBCL and MM preclinical models that represent categories of high unmet need. BMF-219 exhibits multi-fold higher potency and complete growth inhibition in these preclinical models compared to clinical reversible menin inhibitors, demonstrating its unique anti-tumor potential in these cancers.
Irreversible menin inhibitor, BMF-219, inhibits the growth of KRAS-mutated solid tumors (Abstract #1202)
Session Category: Experimental and Molecular Therapeutics
Session Title: Signaling Pathway Inhibitors
Session Date and Time: Tuesday, April 12, 2022 9:00 AM – 12:30 PM
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 25
Poster Board Number: 8
Permanent Abstract Number: 2665
Full Text of Abstract:
Introduction:
KRAS (Kirsten rat sarcoma virus) is the most frequently mutated isoform amongst RAS oncogenes in human solid tumors being present in a high percentage of colorectal cancers (CRC), non-small cell lung cancers (NSCLC), and pancreatic cancers. With only one approved KRAS G12C inhibitor for NSCLC, KRAS driven tumors continue to represent a significant unmet medical need where novel effective therapies are highly desired. Menin is a required co-factor of oncogenic transcriptional proteins with functional interactions that are critical for various malignancies including acute leukemia. We previously reported that BMF-219, a novel irreversible menin inhibitor, exhibits strong potency on acute leukemia (MOLM-13) and KRAS-mutant (MiaPaCa-2) cells. Results from MiaPaCa-2 cells prompted our exploration of the effects of BMF-219 in an expanded panel of KRAS-mutant solid tumors through in vitro and ex vivo preclinical models.
Methods:
BMF-219, clinical reversible menin inhibitors, or clinically approved KRAS G12C inhibitor, sotorasib, were cultured with CRC, NSCLC and pancreatic cancer cell lines for 4-days. Human ex vivo preclinical models harboring KRAS mutations were cultured with BMF-219 and reversible menin for 6-days. Cell viability was measured using CellTiter Glo and IC50 values were calculated. MiaPaCa-2 cells incubated with BMF-219 were analyzed by RNA-seq on the Illumina NextSeq 550 platform.
Results:
MiaPaCa-2, a KRAS G12C-mutant cell line, showed marked reduction of KRAS expression levels following 24 hours of BMF-219 treatment at 0.5 μM. An expanded panel of 14 CRC, NSCLC and pancreatic KRAS-mutant cell lines harboring G12C, G12D, G12V, and Q61L revealed single-agent BMF-219 activity after a 4-day treatment. Majority of the cell lines tested exhibited >90% inhibition of growth, independent of KRAS mutation type. Sotorasib reached a maximum of 90-93% growth inhibition in three of eight cell lines. By contrast, BMF-219 inhibited cell viability ≥ 90% in six of eight KRAS G12C lung cancer lines. Human CRC, NSCLC and pancreatic ex vivo preclinical models with G12C, G12D, and G12V KRAS mutations were all sensitive to BMF-219 after a 6-day treatment. Complete abrogation of growth was observed in all samples with IC50 values ranging between 0.2 μM – 0.6 μM.
Conclusion:
KRAS-mutant CRC, NSCLC, pancreatic cancer cell lines and ex vivo preclinical models are highly sensitive to irreversible menin inhibitor, BMF-219, where clinical reversible menin inhibitors displayed limited activity. High potency of BMF-219 was observed amongst various KRAS-mutant cell lines suggesting that BMF-219 broadly inhibits these tumors. As an irreversible menin inhibitor, BMF-219, manifests advantages over the KRAS-targeted inhibitor sotorasib in multiple cell lines tested, and displays unique potency compared with clinical reversible menin inhibitors in ex vivo preclinical models of CRC, NSCLC, and pancreatic cancer.