icovamenib (BMF-219)

P1/2, N=414, Active, not recruiting, Biomea Fusion Inc. | Suspended --> Active, not recruiting | Trial primary completion date: Jul 2024 --> Nov 2024

P2, N=190, Active, not recruiting, Biomea Fusion Inc. | Suspended --> Active, not recruiting

P2, N=190, Suspended, Biomea Fusion Inc. | Recruiting --> Suspended

P1/2, N=414, Suspended, Biomea Fusion Inc. | Recruiting --> Suspended

P1, N=177, Recruiting, Biomea Fusion Inc. | Trial completion date: Jan 2024 --> Mar 2025 | Trial primary completion date: Jan 2024 --> Dec 2024

P2, N=150, Recruiting, Biomea Fusion Inc. | Not yet recruiting --> Recruiting

P1, N=90, Recruiting, Biomea Fusion Inc.

Eligible patients include those with any KRAS mutation and (Cohort 1) stage IIIB/IV NSCLC with 2-4 prior lines of therapy including immune checkpoint inhibitors (ICI) &/or platinum-based chemo ± bevacizumab with ECOG 0-2; (Cohort 2) stage III/IV PDAC with ≥ 1 prior line of therapy including either FOLFIRINOX or gemcitabine/nab-paclitaxel, ECOG 0-1; or (Cohort 3) stage III/IV CRC with ≥ 1 prior line of therapy including FOLFOX or FOLFIRI ± bevacizumab (prior ICI if MSI-H/dMMR), ECOG 0-2...Accrual began in January 2023 and is ongoing. Clinical trial information: NCT05631574.

P2, N=150, Not yet recruiting, Biomea Fusion Inc.

P1/2, N=430, Recruiting, Biomea Fusion Inc. | N=188 --> 430 | Trial completion date: Feb 2024 --> May 2025 | Trial primary completion date: Oct 2023 --> Jul 2024

Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups.

Enrollment commenced in January 2022 in the United States and in May 2023 in Europe.

P1 | "Preclinical data from BMF-219, an investigational, highly selective, orally bioavailable, small-molecule covalent inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling...Main Outcome Measures: Primary: Incidence of DLTs, treatment-emergent adverse events, and serious adverse events. Secondary: Best overall response rate, duration of response, progression-free survival, and time to progression per disease-specific response criteria."

Furthermore, we provide new data demonstrating the superior potency of BMF-219 and ability to achieve >98% growth inhibition in ex vivo cultured CLL patient specimens when compared to new investigational drugs currently in clinical development and established standard-of-care agents for CLL. Collectively, these data demonstrate the mechanistic impact of BMF-219 on key gene targets and molecular pathways modulated by covalent menin inhibition, further highlighting its potential as a novel therapeutic agent in CLL.

Enrollment commenced in January 2022 in the United States and in May 2023 in Europe.

Subsequently, each indication will enroll independently patients in parallel expansion cohorts to obtain further safety and efficacy data.Eligible patients include those with any KRAS mutation and stage IIIB/IV NSCLC with 2-4 prior lines of therapy including checkpoint inhibitors (CPI) and/or platinum-based chemo bevacizumab; stage III/IV PDAC with 1 prior line of therapy including either FOLFIRINOX or gemcitabine/nab-paclitaxel ( platinum-based chemo); or stage III/IV CRC with 1 prior line of therapy including FOLFOX or FOLFIRI bevacizumab (prior ICI if MSI-H/dMMR)...Secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and efficacy based on the duration of response (DOR) & disease control rate (DCR). Assessment of progression-free survival (PFS), overall survival (OS) & time to response (TTR) are part of the exploratory endpoints.

To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.

Repeated experiments revealed patterns of increased cell killing is achieved when trametinib, MEK inhibitor, and venetoclax, BCL2 inhibitor, are combined with BMF-219 treatment.Collectively, our studies demonstrate the utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of menin and FLT3 covalent inhibitors. Collectively, our studies demonstrate the utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of menin and FLT3 covalent inhibitors. Additionally, we show benefit of combinatorial approaches of menin and FLT3 covalent inhibitors with MEK and BCL2 blockade. These data provide initial pre-clinical evidence for combining pathway specific inhibitors as a promising therapeutic strategy for further investigation in acute leukemia.

Furthermore, we provide new data demonstrating the superior potency of BMF-219 and ability to achieve >98% growth inhibition in ex vivo cultured CLL patient specimens when compared to new investigational drugs currently in clinical development and established standard-of-care agents for CLL. Collectively, these data demonstrate the mechanistic impact of BMF-219 on key gene targets and molecular pathways modulated by covalent menin inhibition, further highlighting its potential as a novel therapeutic agent in CLL.

P1, N=90, Recruiting, Biomea Fusion Inc. | Initiation date: Jan 2022 --> Jan 2023

P1, N=90, Recruiting, Biomea Fusion Inc. | Initiation date: Dec 2022 --> Jan 2022

P1, N=90, Recruiting, Biomea Fusion Inc. | Not yet recruiting --> Recruiting

P1, N=90, Not yet recruiting, Biomea Fusion Inc.

Enrollment in COVALENT-101 commenced in January 2022.

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 (IC50 = 0.15 μM and 0.2 μM, respectively) and demonstrated complete growth inhibition at 1 μM exposure. 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.

Results The study is ongoing. Conclusion The enrollment commenced in January 2022.

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. 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.

Standard R-CHOP therapy is inadequate and results in poor patient outcomes. Collectively, our study demonstrates the unique ability of BMF-219's irreversible menin inhibition, which leads to marked killing of DHL cells. BMF-219, as a single agent, substantially reduces MYC and BCL2 gene expression in liquid tumor cells, providing a molecular basis for targeting DLBCL and other tumors with these aberrations. Additionally, BMF-219 offers single agent as well as treatment synergy when combined with ABT-199 in DHL cells.