BMF-219 Demonstrates Early Activity in Menin-Dependent AML

Steve Morris, MD

Oral treatment with BMF-219 led to 2 complete responses (CRs) of 5 patients with relapsed/refractory acute myeloid leukemia (AML) with menin-dependent mutations, both of which remain on treatment, according to topline data from the phase 1 COVALENT-101 trial (NCT05153330).¹

The CRs occurred within the first two 28-day treatment cycles in dose level 4: 500 mg once daily in the non-CYP3A4 inhibitor arm and 125 mg once daily in the CYP3A4 inhibitor arm, with comparable exposures. Represented menin-dependent mutations were as follows: NPM1 (n = 2), KMT2A/MLL1 rearranged (n = 1), MLL-PTD (n = 1), and NUP98 fusion (n = 1). These patients had received between 1 and 8 prior treatments, including standard-of-care and investigational therapies, such as allogeneic bone marrow transplant.

Additional data from the trial, including dose-escalation findings from the acute leukemia cohort, will be presented at an upcoming scientific conference.

“We are very excited to share these early findings confirming that our targeted, covalently binding menin inhibitor, BMF-219, can elicit profound and rapid responses in patients with menin inhibitor-sensitive acute leukemia even at this dose level, which we believe we can further build on,” Steve Morris, MD, chief medical officer of Biomea, stated in a news release. “Notably these complete remissions were achieved within the first two cycles of BMF-219 therapy in [patients with] relapsed/refractory AML who had limited therapeutic options and an overall poor prognosis. We are continuing to dose escalate and are looking forward to identifying the recommended phase 2 dose [RP2D] within the next several months.”

BMF-219 is a covalent inhibitor that suppresses the menin protein, which is involved in oncogenic signaling in genetically defined leukemias and diabetes. Preclinically, BMF-219 has shown robust downregulation of leukemogenic genes and menin in acute leukemia cell lines.

Additionally, BMF-219 has demonstrated antitumor activity in in vitro, in vivo, and ex vivo models of acute leukemia, multiple myeloma, diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).

COVALENT-101 is an open-label, multi-center, dose-escalation and -expansion study designed to evaluate BMF-219 in patients with relapsed/refractory acute leukemias, including those with MLL1/KMT2A gene rearrangements and NPM1 mutations, as well as relapsed/refractory multiple myeloma, DLBCL, and CLL. The study will also include a cohort of patients who are receiving a CYP3A4 inhibitor and those not receiving a CYP3A4 inhibitor.

To be eligible for enrollment, patients with acute leukemia or DLBCL, and multiple myeloma must have received between 2 and 5, or 3 or more prior lines of therapy, respectively, and failed or are ineligible for standard therapy.2 Patients must also have an ECOG performance status between 0 and 2 and adequate organ function. Known central nervous system disease involvement, prior menin inhibitor therapy, and clinically significant cardiovascular disease will prohibit patients from enrollment.

The primary objective of the study is to determine the optimal biological dose/RP2D of BMF-219 in each cohort and tumor type. Secondary end points include further study of safety and tolerability, pharmacodynamic and pharmacokinetic activity, and overall response rate, duration of response, progression-free survival, and time to progression.

Investigators will employ an accelerated titration design, where doses of BMF-219 will be escalated in single-subject cohorts independently for each indication until 1 patient experiences a grade 2 or greater related adverse effect or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical 3+3 design, where treatment will be administered in 28-day cycles until disease progression or intolerability.

In November 2022, Biomea announced that the first patient with CLL had been dosed in the trial.³

At the time of the acute leukemia analysis, 20 patients with AML had received BMF-219 during the dose-escalation portion of the study.1 Notably, dose level 4 became the first dose level enriched for patients with known menin-dependent mutations following a protocol amendment removing eligibility regardless of mutational status.

Regarding safety, BMF-219 has been generally well tolerated, with no documented cases of QTc prolongation. No DLTs were reported in dose level 4, allowing for the continuation of dose escalation.

Dose level 5 has begun enrollment, and completion of the dose-escalation portion for the acute leukemia cohort is expected by the end of 2023.

References

1. BMF-219 induces complete responses in target acute myeloid leukemia (AML) patient population. News release. Biomea Fusion, Inc. July 24, 2023. Accessed July 25, 2023. https://investors.biomeafusion.com/news-releases/news-release-details/bmf-219-induces-complete-responses-target-acute-myeloid-leukemia
2. Ravandi F, Kishtagari A, Carraway HE, et al. COVALENT-101: A phase 1 study of BMF-219, a novel oral irreversible menin inhibitor, in patients with relapsed/refractory (R/R) acute leukemia (AL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). J Clin Oncol. 2022;40(suppl 16):TPS7064 doi:10.1200/JCO.2022.40.16_suppl.TPS7064
3. Biomea Fusion announces first patient dosed with chronic lymphocytic leukemia (CLL) in COVALENT-101 trial. News release. Biomea Fusion Inc. October 27, 2022. Accessed July 25, 2023. https://investors.biomeafusion.com/news-releases/news-release-details/biomea-fusion-announces-first-patient-dosed-chronic-lymphocytic