Biomea Fusion: Poster presentation entitled “Preclinical activity of the irreversible menin inhibitor, BMF-219, in chronic lymphocytic leukemia”. – Form 8-K







Preclinical Activity of the Irreversible Menin Inhibitor, BMF-219, in Chronic Lymphocytic Leukemia Priyanka Somanath, PhD1, Daniel Lu, MS 1 Brian Law, BS 1, Lekha Kumar, MS1, Tenley Archer, PhD, Tripta Rughwani, MS, Taisei Kinoshita, PhD1, Mini Balakrishnan, PhD1 and Thomas Butler, MSc MBA1,1Biomea Fusion, Inc. Redwood City, CAIntroduction Menin is a scaffolding protein that drives oncogene function through transcriptional modulation directed by its various cofactors. A previous report demonstrated that menin regulates a distinct set of genetic targets independent of its function with 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 malignant disease of B lymphocytes, for which reference agents are generally well tolerated; however, CLL patients with certain genetic backgrounds show poorer outcomes with these treatment regimens. / Large pre-B Immature Mature Pre-Bpre-B BBBB Memory cell B-cellALL MCL DLBCL MMFL CLLBL MZL WMMenin-dependent functionConfirmed BMF-219 activityA major hallmark of CLL is the overexpression of the anti-apoptotic marker, BCL2. We previously reported the ability of BMF-219, a selective and covalent inhibitor of menin, to downregulate BCL2 expression in acute leukemia cells. destruction of preclinical models of diffuse large B-cell lymphoma (DLBCL), prompting our exploration of BMF-219 activity in CLL. Here, we provide the first preclinical evidence for menin as a therapeutic target in CLL, demonstrating the high potency of BMF-219 against a diverse collection of CLL patient samples. Methods A comprehensive panel of CLL samples isolated from patients with Rai stage 1-3 disease, including relapsed or refractory disease, were cultured ex vivo in the presence of BMF-219 or a clinically reversible menin inhibitor to assess the antileukemic activity of the compounds.ResultsRelative Gene Expression – BMF-2191.2BCL2 MYC HOXA91.0 Figure 1. BMF-219 causes >90% reduction in BCL2 transcript at 24 Control 0.8 expression)hours post-treatment in MOLM-13DMSO 0 cells, 6 AMLs. HOXA9 gene and MYC (language mRNA expression was also significantly reduced by 0.4-Cha Relative by >90%). The ply change was calculated as 0.2 from the control vehicle. achieved >98% cell lethality against various CLL models ex vivoBMF-219 (1.1 uM)A Clinical reversible inhibitor of menin B100 (1.1 uM) 1 0 0 on Venetoclax (0.8 uM) *ti 80 7 5 hib i60 Inhibitionn 5 0I hth40t ow 2 520 G rGrow% 0% 0-20-2 5Stage 1 Stage 2 Stage 2 Relapse Stage 3al al al 1 el SM 1 1 3 3 mm m1D ATCHT TM 5 5 rrryq RA TWATPTP ooo om 3 , K 1 , ON NN est 1 2 HNT r1 C y T Rai Stage Binet m O iso NT rCytogenetic historyClinical samples with progression after prior treatment with bendamustine or ibrutinibD EC BM-301BM-302BM-303125 125 125 n 100 onno 100 io 100 ti ib i 7575 hibit 75 nh 50 nhibiti II In25 50 50 with th0 25 ow 25 ro G -25 Growth Gr% 0 0% -50 % -75-25-250.001 0.01 0.1 1 10 0.001 0.01 0.1 1 10 0.001 0.1 0.01 0.01 10Compound Concentration (mM) Compound Concentration (mM) Compound Concentration (mM)BMF-219 Clinical Reversible ibrutinib BMF-219 Clinical Reversible BMF-219 Clinical Reversible ibrutinib Inhibitor Menin Inhibitor Menin Inhibitor Menin Inhibitor reversible inhibitor of menin after 6 days of treatment. Percent growth inhibition at 1.1 mM BMF-219, 0.8 mM venetoclax, and 1.1 mM clinical inhibitor of menin is plotted for PDX samples, grouped by genetic background (A) or Rai-Binet stage where data are available (B). Representative dose-response curves for BMF-219 or the clinically reversible inhibitor of menin are shown for PDX samples from CLL patients with clinical profiles of progression after prior treatment with bendamustine (C) or ibrutinib (D), or pre-treated ibrutinib and then progressed to ibrutinib and venetoclax (E). IC50 values ​​are summarized in Table 1. Each data point represents the mean of at least two replicate values. (*Concentration of venetoclax set as standard for the positive control). Ibrutinib IC50 determined as a stand-alone experiment. 2 (relapsed) 0.373 98.7 progressed) BM-302 NOTCH1 Normal Ibrutinib (responded, then progressed) Stage 2 (relapsed) 0.332 99.7 Ibrutinib (responded), (post-collection: BM-303 TP53 N/A ibrutinib and venetoclax – responded, Stage 1 0.285 99.8 then progressed) 44, XX, add(3)(q21), -5, add(6)(p12), +11, der(11; 13)(q10;q10), -13,t( 15;18)(q15;q21),BM-304 None or N/A Ibrutinib (answered) Stage 1 0.104 99.9 add(16)(p13.3) , add(17)(p11.2) [cp15]/46.XX [6] BM-305 WT1 Normal Rituximab/Ibrutinib (responded) Stage 2 0.384 100BM-306 TP53 Normal Ibrutinib (responded, no progression) Stage 3 0.380 10047, XY, +12, t(14;19)(q32;q13.3) , Rituximab/MethylprednisoloneBM-307 KRAS, KMT2A, TET2 N/A 0.145 99.5 t(16;20)(p13.3;q13.1) [13]/46,XY [7] (answered), ibrutinib46~47, XY, del(6)(q13q25),Rituximab/Ibrutinib (answered,BM-308 None or N/A dic(7;21)(q31;p13), add(11)(q13 ), Stage 2 0.359 99 continued) del(13)(q12q14), +2mar, inc [cp4]/46,XY [3]BM-309 None or N/A Normal Ibrutinib (responded) Stage 3 0.331 100BM-310 None or N/A Normal Ibrutinib (responded) N/A 0.357 99 BM-311 NOTCH1, ATM N/AN/A Stage 2 (Relapse) 0.359 100 BM-312 None or N/NA/NA/NA/A 0.384 100BMF-219 exhibits higher ex vivo potency than standard of care agentsBMF 219 %BMF 219 Max Ibrutinib Bendamustine Idelasib Sample Mutation IC (mM) Inhibition IC ( mM ) IC (mM) IC (mM)50 50 50 50BM-301 ATM 0.373 98.7 14.8 15.6 8.91BM-302 NOTCH1 0.332 99.7 N/AN/AN/ABM-303 TP53 0.285 99, 8 29.1 31.9 37.2 BM-304 None or N/A 0.104 99.9 N/NA/NA/A BM-305 WT1 0.384 100 34.8 17.1 35.7 BM-306 TP53 0, 38 100 24.1 6.65 2.21KRAS, KMT2A,BM-307 TET2 0.145 99.5 18.3 16.1 0.28 None 26.7 15.7 22.7 BM-309 None or N/A 0.331 100 29.0 25.2 38.1 BM-310 None or N/A 0.357 99 12.4 6.84 1.67BM-311 NOTCH1, ATM 0.359 100 29.1 32.2 35.7 or N/A 380 None N/NA/NA/ATable 2. Potency of BMF-219 determined by IC50 values ​​compared to reference agents for CLL. Ex vivo CLL patient samples were cultured with BMF-219 for 6 days to determine IC50 values. IC50 values ​​for ibrutinib (BTK inhibitor), bendamustine (alkylating agent), and idelasib (PI3K inhibitor) were determined experimentally as stand-alone experiments in these patient models. exposure in all CLL patient samples tested, with IC50 values ​​ranging from 0.1 to 0.38 mM, similar to the potency of BMF-219 in ex vivo AML and DLBCL models.â-ª Samples isolated from patients with clinical profiles containing a high-risk genetic history associated with substandard therapy outcomes, such as mutations in TP53 and NOTCH1, and chromosomal aberrations such as del(13q), trisomy 12, and complex karyotype, showed a high sensitivity to BMF-219 treatment.â-ª BMF-219 was also highly effective against patient samples with clinical patterns of resistance to bendamustine or ibrutinib.â-ª A clinically reversible menin inhibitor does not demonstrated no significant activity in all patient samples tested, with incalculable IC50 values ​​and

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Biomea Fusion Inc. published this content on June 06, 2022 and is solely responsible for the information contained therein. Distributed by Audienceunedited and unmodified, on Jun 06, 2022 20:21:01 UTC.

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