Menin-KMT2A Disruption

Revumenib is a potent, selective, small molecule inhibitor of the menin-KMT2A binding interaction that is being developed for the treatment of KMT2A-rearranged (KMT2Ar), also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and NPM1-mutant (NPM1m) AML. Revumenib is currently being evaluated in several clinical trials, including the Company’s pivotal AUGMENT-101 Phase 1/2 open-label clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias. Together, KMT2A rearrangements and NPM1 mutations represent up to 40% of AML cases.


Source: *KMT2A = KMT2A rearrangement or KMT2A wildtype; Adapted from: Uckelmann HJ, et al. Presented at ASH Annual Meeting, 2018.

Menin is a scaffold protein, and its binding to KMT2A leads to transcriptional activation of leukemogenic genes such as HOX and MEIS1. When revumenib is introduced, it fits into the binding pocket of menin and displaces KMT2A. In disrupting the binding interaction, the HOX and MEIS genes are turned off and leukemic cell growth is halted.

Late-Stage Clinical Development

In October 2023, the Company announced positive topline data from the protocol-defined pooled analysis of the pivotal portion of the AUGMENT-101 trial in patients with R/R KMT2Ar acute leukemia. The trial met its primary endpoint with a complete remission (CR) or a CR with partial hematological recovery (CRh) rate of 23% at the interim analysis of the pooled KMT2A-rearranged AML and ALL cohorts (p-value = 0.0036). In the efficacy-evaluable patients, the overall response rate was 63% (36/57).  39% (14/36) of patients who achieved a CR/CRh underwent hematopoietic stem cell transplant (HSCT); eight of whom went to transplant prior to achieving CR/CRh and therefore, were not included in the reported CR/CRh rate.  Half (7/14) of the patients who had an HSCT received post-transplant maintenance as of the July 2023 data cut-off.

The CR/CRh responses in both the overall population and the AML subset were durable with a 6.4-month (95% CI: 3.4, NR) median duration as of the data cut-off, with 46% (6/13) remaining in response. Minimal residual disease (MRD) status was assessed in 10 of the 13 patients who achieved a CR/CRh, 70% (7/10) of whom were MRD negative.

Revumenib was well tolerated, and the overall safety profile was consistent with the Company’s previously reported data. Treatment-related adverse events leading to dose reductions and treatment discontinuation were low. Based on the Independent Data Monitoring Committee recommendation, the Company stopped the AUGMENT-101 trial to further accrual in the KMT2Ar cohorts.

Revumenib was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and European Commission for the treatment of patients with AML, and Fast Track designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. Revumenib was also granted Breakthrough Therapy Designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.

To learn more about revumenib, check out our publications page, including the topline data from the pivotal Phase 2 trial of revumenib in relapsed/refractory KMT2Ar acute leukemia and the Phase 1 data for revumenib in relapsed/refractory acute leukemia published in Nature.