FDA Grants Breakthrough Therapy Designation to Enzomenib in R/R KMT2A-Rearranged Acute Leukemia

The FDA has granted breakthrough therapy designation to enzomenib (DSP-5336) for the treatment of patients with relapsed/refractory acute leukemia harboring a KMT2A rearrangement.¹

Enzomenib is being evaluated as monotherapy in the registrational phase 2 portion of the phase 1/2 Horizen-1 trial (NCT04988555), which includes patients with relapsed/refractory KMT2A-rearranged acute leukemia and patients with relapsed/refractory NPM1-mutated acute myeloid leukemia (AML).^1,2

"Patients with relapsed/refractory KMT2A-rearranged acute leukemia continue to face poor outcomes," Tsutomu Nakagawa, president and chief executive officer of Sumitomo Pharma America, stated in a news release. "[The] 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."

The FDA previously granted fast track designation to enzomenib for relapsed/refractory AML with a KMT2A rearrangement or NPM1 mutation in June 2024. The agent also holds FDA orphan drug designations for AML, granted in June 2022, and for acute lymphoblastic leukemia (ALL), granted in July 2026. Japan's Ministry of Health, Labour and Welfare granted orphan drug designation to enzomenib for R/R AML with a KMT2A rearrangement or NPM1 mutation in September 2024.

What is the mechanism of action of enzomenib?

Enzomenib is an investigational, oral, small molecule inhibitor of the protein interaction between menin and lysine KMT2A, an interaction implicated in leukemic cell proliferation and growth. Menin is a scaffold nuclear protein involved in gene expression and in pathways governing cell growth, the cell cycle, genomic stability, and hematopoiesis.

In preclinical studies, enzomenib selectively inhibited the growth of human acute leukemia cell lines with KMT2A rearrangements or NPM1 mutations. In those cell lines, the agent reduced expression of the leukemia-associated genes HOXA9 and MEIS1 and increased expression of the differentiation marker CD11b.

How is the phase 1/2 Horizen-1 trial designed?

The open-label, multicenter Horizen-1 trial comprises a phase 1 dose-escalation and dose-expansion portion and a phase 2 portion, with an estimated enrollment of 606 patients at sites in North America, Europe, and Asia.²

Phase 1 is including patients with relapsed/refractory AML, ALL, or acute leukemia of ambiguous lineage, as well as, at selected sites, patients with high-risk relapsed/refractory myelodysplastic syndromes or relapsed multiple myeloma.

Enzomenib monotherapy is being evaluated with and without CYP3A4-inhibiting azole antifungals. Combination cohorts are evaluating enzomenib plus venetoclax (Venclexta) and azacitidine in Rrelapsed/refractory AML with an NPM1 mutation or KMT2A rearrangement; enzomenib plus gilteritinib (Xospata) in relapsed/refractory AML with a co-occurring FLT3 mutation; and enzomenib plus venetoclax/azacitidine or intensive 7+3 induction chemotherapy in newly diagnosed KMT2A-rearranged or NPM1-mutated AML.

The primary end points of phase 1 include safety and determination of the recommended phase 2 dose for each regimen.

The registrational phase 2 portion is evaluating enzomenib monotherapy in cohorts of patients with relapsed/refractory KMT2A-rearranged AML, relapsed/refractory KMT2A-rearranged ALL, and relapsed/refractory NPM1-mutated AML, with and without concomitant azoles. Eligible patients must have at least 5% bone marrow blasts, no prior exposure to a menin inhibitor, an ECOG performance status of 2 or lower, and a white blood cell count below 30,000/μL at enrollment. Patients in the KMT2A-rearranged cohorts must have a KMT2A fusion documented at relapse or before the determination of refractory status; other KMT2A alterations, such as partial tandem duplications, are not permitted. Where approved, patients aged 12 years or older who weigh at least 40 kg may enroll in monotherapy cohorts.

The primary end point of phase 2 is the rate of complete remission (CR) or CR with partial hematologic recovery. Secondary end points include composite CR rate, overall response rate, event-free survival, overall survival, safety, and pharmacokinetics. Primary completion is anticipated in June 2027.

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 America. October 26, 2026. Accessed October 26, 2026. https://www.businesswire.com/news/home/20261026951054/en/Sumitomo-Pharma-America-Announces-Enzomenib-DSP-5336-Receives-FDA-Breakthrough-Therapy-Designation-for-Treatment-of-RR-KMT2A-Rearranged-Acute-Leukemia
2. A phase 1/2 study of enzomenib (DSP-5336) in patients with acute leukemia (Horizen-1). ClinicalTrials.gov. Updated March 24, 2026. Accessed October 26, 2026. https://clinicaltrials.gov/study/NCT04988555