Enzomenib Earns FDA Breakthrough Status in KMT2A-Rearranged Leukemia

The FDA has granted breakthrough therapy designation to enzomenib (DSP-5336), an investigational oral menin inhibitor developed by Sumitomo Pharma America, for patients with relapsed or refractory (R/R) acute leukemia harboring a KMT2A gene rearrangement. The designation is intended to expedite the development and review of treatments for serious conditions when preliminary clinical evidence suggests potential substantial improvement over available therapies.¹

Enzomenib is being evaluated as monotherapy in the registrational phase 2 Horizen-1 trial (NCT04988555), which includes patients with R/R KMT2A-rearranged acute leukemia and acute leukemia with NPM1 mutations. The agent is also being studied in combination with standard treatment regimens for patients with newly diagnosed or R/R acute myeloid leukemia (AML).

Enzomenib Targets Menin-Related Leukemia Biology

Enzomenib is an oral, small-molecule inhibitor designed to disrupt the interaction between KMT2A and menin, a protein interaction implicated in the development and progression of certain acute leukemias.

Menin plays a role in regulating gene expression and cellular processes involved in growth and hematopoiesis. In preclinical studies, enzomenib demonstrated selective growth inhibition in acute leukemia cell lines harboring KMT2A rearrangements or NPM1 mutations. The agent also reduced expression of the leukemia-associated genes HOXA9 and MEIS1 and increased expression of CD11b, a marker associated with cellular differentiation.¹

Patients with KMT2A-rearranged acute leukemia face an aggressive disease course and limited treatment options, particularly when their disease returns or fails to respond to standard therapy. Despite chemotherapy and hematopoietic stem cell transplantation, outcomes remain poor for many patients with this molecular subtype.

Clinical Development and Previous FDA Designations

The ongoing Horizen-1 program is evaluating enzomenib’s safety and efficacy in patients with acute leukemia, including those with KMT2A rearrangements or NPM1 mutations. The study builds on earlier phase 1/2 findings reported at the 2024 European Hematology Association Congress. Among 22 efficacy-evaluable patients treated in the dose-escalation study, the overall response rate was 45%, and the rate of complete remission or complete remission with partial hematologic recovery was 23%.²

The FDA previously granted fast track designation to enzomenib in July 2024 for patients with R/R AML harboring KMT2A rearrangements or NPM1 mutations. In early clinical findings, 12 of 21 patients with either molecular alteration responded to treatment.³ These preliminary findings supported continued investigation of enzomenib but do not establish its efficacy in the specific population covered by the new breakthrough therapy designation.

The FDA also granted orphan drug designation to enzomenib for AML in 2022 and in acute lymphoblastic leukemia in July 2026.¹

In a statement, Tsutomu Nakagawa, president and CEO of Sumitomo Pharma America, said patients with R/R KMT2A-rearranged acute leukemia continue to face poor outcomes. “FDA’s decision to grant breakthrough therapy designation underscores enzomenib’s potential and enables expedited FDA review that may potentially provide the opportunity to bring this investigational treatment to patients more quickly,” Nakagawa said. “We look forward to continued engagement with the FDA to advance clinical research of enzomenib with the goal of bringing it to patients as efficiently as possible.”

REFERENCES

1. Sumitomo Pharma america announces enzomenib (DSP-5336) receives FDA breakthrough therapy designation for treatment of R/R KMT2A-rearranged acute leukemia. News release. Sumitomo Pharma. October 26, 2026. Accessed October 26, 2026. https://tinyurl.com/3bk96e5r

2. Daver N, Erba H, Watts J, et al. First-in-human phase 1/2 study of the menin-MLL inhibitor DSP-5336 in patients with relapsed or refractory acute leukemia: Updated results from dose escalation. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract S132.

3. Sumitomo Pharma announces that DSP-5336 has received FDA fast track designation for the treatment of relapsed or refractory acute myeloid leukemia. News release. Sumitomo Pharma. July 15, 2024. Accessed July 15, 2024. https://tinyurl.com/y667azve