お知らせ • Nov 04
Biomea Fusion Announces Two Poster Presentations At Upcoming Ash Annual Meeting 2023
Biomea Fusion, Inc. announced that abstracts related to BMF-219, a novel, investigational covalent menin inhibitor, currently in Phase 1 clinical study across multiple liquid and KRAS-mutated solid tumors, and BMF-500, a novel, investigational covalent FMS-like tyrosine kinase 3 (FLT3) inhibitor currently in Phase 1 clinical study in FLT3-mutated acute leukemias, have been accepted for presentation at the upcoming American Society of Hematology (ASH) Annual Meeting, to be held in San Diego from December 9-12, 2023. Both BMF-219 and BMF-500 were originated in-house with Biomea’s proprietary FUSION™ system platform, which discovers and designs next-generation covalent binding small molecule product candidates. Details for the abstracts are listed below and can be viewed online at the ASH conference website. BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design. Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted. Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D. Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (=10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade =3 TRAE (=5%) was DS 13% (3). The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment. Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival. BMF-500 is a novel orally bioavailable, highly potent and selective covalent inhibitor of FLT3 including wildtype (WT), ITD, TKD, as well as a variety of additional resistance-conferring mutations such as the gatekeeper F691. BMF-500 has demonstrated high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing capacity despite drug washout (Law et al., ASH 2022 Abstract 2756). BMF-500 has shown sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Study Design: COVALENT-103 (NCT05918692) is an open-label, non-randomized, multicenter, first-in-human Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of twice daily oral BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3 mutations. The trial has 2 arms that will undergo dose escalation in parallel: Arm A (without) and Arm B (with) concomitant use of a moderate or strong CYP3A4 inhibitor. Utilizing an accelerated titration design (ATD), doses of BMF-500 will be escalated in single-subject cohorts until 1 subject experience either a Grade 2 or higher related-adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may be enrolled, up to a limit of 33% per arm. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or must have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care therapies, including HSCT. Participants with FLT3-mutant AML must have received treatment with a FLT3 inhibitor approved for treatment of relapsed or refractory FLT3-mutant AML. Key inclusion criteria include ECOG PS = 2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease involvement, clinically significant cardiovascular disease, and WBC count >50,000/µL (uncontrollable with cytoreductive therapy). Objectives: The primary objective of the study is to evaluate safety and tolerability and to determine the optimal biological dose (OBD)/recommended Phase 2 dose (RP2D) of BMF-500 oral monotherapy based on evaluation of available PK/PD, safety and efficacy data. Secondary objectives include characterization of the pharmacodynamics and pharmacokinetics of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or the NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. Endpoints include best overall response rate (ORR), complete remission (CRc), duration of response (DOR), relapse-free survival (RFS) and overall survival (OS).
