enzomenib (DSP-5336) / Sumitomo Pharma, Kyoto University - LARVOL DELTA

Monotherapy update from Phase 1 portion in Phase1/2 trial of the menin-MLL inhibitor enzomenib (DSP-5336) in patients with relapsed or refractory acute leukemia (ASH 2025) - P1/2 | "N=108 (93.1%) had AML and med prior regimen was 2 (1-9); 36 pts (31.0 %) had priorallogeneic stem cell transplant, 86 pts (74.1%) prior venetoclax...DSwas manageable with brief treatment interruption, corticosteroids and hydroxyurea as needed, with nodeaths, study discontinuations, or dose reductions due to DS... ENZO has been well tolerated with no DLTs in 116 pts. ENZO has low lipophilicity and highclearance, leading to a short half-life and has demonstrated a wide therapeutic window. This may allowdosing to be tailored to the specific biology of different AML subtypes."

Clinical • Monotherapy • P1/2 data • Central Nervous System Leukemia • Hematological Malignancies • Leukemia • HOXA9 • KMT2A • MEIS1 • NPM1 • NUP98 • TP53

GI Toxicity Profile of Menin Inhibitors in KMT2A-Rearranged and NPM1-Mutated Acute Leukemia: A Systematic Review and Meta-Analysis of 526 Patients (ACG 2026) - "Introduction: Menin inhibitors (revumenib, ziftomenib, bleximenib, enzomenib) block the menin-KMT2A interaction to reverse leukemogenesis in KMT2A-rearranged (KMT2Ar) and NPM1-mutated (NPM1m) acute leukemia. : DS of any grade was pooled across 9 arms (N=526, events=58): incidence 10.3% (95% CI 5.0-16.9%; prediction interval [PI] 0-33.9%; I²=73.1%). DS grade â¥3: 3.3% (95% CI 0.4-8.1%; PI 0-20.8%). QTc prolongation: 1.2% (95% CI 0-4.1%)."

Retrospective data • Review • Hematological Malignancies • Leukemia • KMT2A • NPM1

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 (EHA 2024) - "6% received prior venetoclax. DSP-5336 has been well tolerated with no DLTs in 58 pts. No Rx-related discontinuations or deaths wereobserved. Pharmacokinetic (PK) studies have not identified significant drug-drug interaction with azoles."

Clinical • P1/2 data • Anemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Septic Shock • Transplantation • HOXA9 • ITGAM • KMT2A • MEIS1 • NPM1 • PBX3

Preliminary data from the ongoing Phase 1 study of the menin-MLL inhibitor enzomenib (DSP-5336) in combination with venetoclax and azacitidine in patients with relapsed or refractory Acute Myeloid Leukemia (ASH 2025) - P1/2 | "Median age was 50 yrs (21-76), 56% were female andmedian prior regimens was 2 (1-4); 3 pts (16.7 %) had prior allogeneic stem cell transplant (SCT), 6 pts(33.3%) had prior VEN, and 5 pts (27.8%) received prior menin inhibitor (2 ziftomenib, 1 revumenib, 2enzomenib). Preliminary data show ENZO up to 300 mg BID to be well tolerated in combination withVEN/AZA with no DLTs in 18 pts with R/R KMT2Ar or NPM1m AML. No QT prolongation was reported andthere was 1 report of non-serious DS. Promising preliminary clinical activity has been observed,particularly in pts without prior VEN or menin exposure (100% ORR and 67% CRc rate)."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Central Nervous System Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Leukopenia • Neutropenia • Septic Shock • Thrombocytopenia • FLT3 • KMT2A • NPM1

Phase 1 Results: First-in-Human Phase 1/2 Study of the Menin-MLL Inhibitor Enzomenib (DSP-5336) in Patients with Relapsed or Refractory Acute Leukemia (ASH 2024) - P1/2 | "The median number of prior lines of therapy was 3 (range 1 to 9); 23 pts (28.4 %) had prior allogeneic stem cell transplant, 63 pts (77.8%) had prior venetoclax, and 6 pts (7.4%) had received a prior menin inhibitor. Dose optimization continues with the goal of identifying the RP2D for monotherapy. Updated clinical and translational data will be presented."

Clinical • First-in-human • P1/2 data • Central Nervous System Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • HOXA9 • ITGAM • KMT2A • MEIS1 • NPM1 • PBX3

Menin Inhibitors in Acute Myeloid Leukemia: Clinical Integration, Resistance, and the Path Beyond Monotherapy. (PubMed, Cancers (Basel)) - "We explore data from the landmark AUGMENT-101 and KOMET-001 trials, which have led to regulatory approval of revumenib and ziftomenib for select patients...We highlight resistance mechanisms that have emerged from the use of contemporary menin inhibitors and efforts aimed at addressing this resistance, with a focus on emerging clinical data on enzomenib and bleximenib. Finally, we discuss prospects on the putative role of menin inhibitors in the measurable residual disease (MRD)-positive and maintenance settings in AML. Menin inhibitors have successfully transitioned from biological proof-of-concept to approved targeted therapy, and future advances will depend on rational front line combination strategies, MRD-guided treatment, post-transplant maintenance strategies, and therapeutic sequencing informed by mechanisms of resistance."

Journal • Monotherapy • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • HOXA9 • KMT2A • NPM1

DISTINCT MEN1 MUTATIONAL SIGNATURES ARE ASSOCIATED WITH ACQUIRED RESISTANCE DURING MENIN-KMT2A INHIBITION IN A PHASE 1 ENZOMENIB TRIAL (EHA 2026) - P1/2 | "Results Of the 13 MI-naïve pts who subsequently relapsed, 6 (46%) acquired detectable MEN1 m. Mutations previously shown to drive drug resistance to revumenib (Perner, 2023) were undetected, and M327 was detected in only 2 pts (15%), both at low variant allele frequency (VAF < 0.3%). These findings are important and novel given that E368 mutations appear to only impact enzomenib in contrast to other mutations (i.e. M327) which are detrimental to all currently available MIs. Collectively, these findings support further investigation of rational sequential MI therapy to improve clinical outcomes."

P1 data • Preclinical • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEN1 • NPM1

Sumitomo Pharma America Announces Enzomenib (DSP-5336) Receives FDA Orphan Drug Designation for Treatment of Acute Lymphoblastic Leukemia (Businesswire) - "The safety and efficacy of enzomenib is currently being clinically evaluated in a Phase 1/2 dose-escalation/dose-expansion study in patients with relapsed or refractory acute leukemia (NCT04988555) and the registrational Phase 2 Horizen-1 R/R mono AML/ALL (KMT2Ar + NPM1m) study."

Orphan drug • Trial status • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia

Clinical research progress of menin inhibitors for acute myeloid leukemia: latest updates from the 2025 ASH Annual Meeting. (PubMed, Exp Hematol Oncol) - "Novel menin inhibitors, including revumenib, bleximenib, ziftomenib, and enzomenib, are currently under clinical evaluation, and selected updated clinical results were presented at the 2025 American Society of Hematology (ASH) Annual Meeting. This brief review summarizes the key findings and discusses the emerging clinical questions regarding combination strategies, treatment sequencing, and molecularly defined use of menin inhibitors."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

Translational research in leukemia and menin inhibition identifies E368K mutation as key resistance signature at relapse (Businesswire) - "Also, during the conference, translational research in leukemia and menin inhibition was shared by Jevon Cutler, PhD, Assistant Professor of Cell, Developmental and Cancer Biology at the Oregon Health Sciences University School of Medicine, that identified distinct MEN1 mutational signatures associated with acquired resistance to the menin inhibitor (MI) enzomenib in patients with acute leukemia. Serial molecular profiling revealed that the E368K mutation was the predominant resistance signature identified at relapse, appearing in 53% of patients who relapsed after an initial response. Preclinical work predicted the E368K mutation to be the primary resistance mutation and that this mutation may not affect the other menin inhibitors; these findings support the further exploration of rational, sequential MI therapy to improve clinical outcomes for patients with acute leukemia."

P1 data • Preclinical • Leukemia

Emerging drug profile: menin inhibitors in NPM1-mutated and KM2A-rearranged acute myeloid leukemia. (PubMed, Leuk Lymphoma) - "Currently, several small-molecule menin inhibitors are being tested in combination with conventional therapies. This publication reviews the recent progress in investigating the clinical evidence of menin inhibitors (revumenib, ziftomenib, bleximenib, enzomenib, BMF-219, emilumenib) toward aggressive leukemias, guides future study and optimal treatment for patients with this type of leukemia."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged acute myeloid leukemia (AACR 2026) - "In this study, we performed a combination drug screen using an epigenetic compound library in KMT2A-r AML cells to identify synergistic agents that could potentiate menin inhibitor activity.MV4-11 cells were treated with DSP-5336 (menin inhibitor) to optimize assay performance (Z′ > 0.5)...Follow-up studies used ORY-1001 (LSD1 inhibitor) and SNDX-5613 (menin inhibitor) across dose ranges...Ongoing in vivo studies aim to further elucidate the underlying mechanisms and therapeutic potential of this combination. Ultimately, this work may guide the development of innovative combination treatment strategies for KMT2A-r AML patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AFDN • ITGAM • KMT2A • PTPRC

How [14C]-DSP-5336 is Absorbed, Broken Down, and Removed From the Body After a Single Oral Dose in Patients With Advanced Blood Cancers (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: Sumitomo Pharma America, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

Combination drug screen identifies novel epigenetic therapies to enhance menin inhibitor efficacy in KMT2A rearranged and NPM1 mutant AML (AACR 2024) - "In this study, we performed a combination drug screen using an epigenetic drug library in KMT2A-rearranged (MV4; 11) and NPM1-mutant (OCI-AML3) AML cell lines to identify synergistic therapies that can be used in conjunction with menin inhibitors. During assay optimization, MV4; 11 and OCI-AML3 cells were treated with the menin inhibitor DSP-5336, and their viability was assessed... Our findings suggest combining menin inhibitors with other epigenetic drugs may improve AML treatment outcomes. The combination drug screen successfully identified four novel compounds that synergistically enhance menin inhibitor efficacy in both KMT2A-rearranged and NPM1-mutant AML cell lines. These compounds hold significant promise as potential therapeutic candidates for further investigation."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • KMT2A • NPM1

DSP-5336-101: A Phase 1/2 Study of Enzomenib (DSP-5336) in Patients With Acute Leukemia (Horizen-1) (clinicaltrials.gov) - P1/2 | N=606 | Recruiting | Sponsor: Sumitomo Pharma America, Inc. | N=362 ➔ 606

Enrollment change • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • IDH2 • KMT2A • NPM1

Differentiation Syndrome in Acute Myeloid Leukemia: Molecular Mechanisms, Clinical Spectrum, and Emerging Therapeutic Paradigms. (PubMed, Int J Mol Sci) - "While differentiation therapy revolutionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents...IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rates (ORRs) of 30-94% in AML with DS in 10-19%. Menin inhibitors (revumenib, ziftomenib, enzomenib, bleximenib) achieve ORRs of 33-88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10-25% and QT prolongation as key toxicities. FLT3 inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1-5%...Improved recognition of DS and rational combination approaches will be essential to maximize the therapeutic benefit. Future research should address mechanisms of resistance and biomarkers to achieve cures beyond APL."

Journal • Review • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • IDH2 • KMT2A • NPM1

Evolving Frontiers in Targeted Therapy: Menin Inhibition in AML (ICKSH 2026) - "Clinically, two menin inhibitors have been approved by the U.S. Food and Drug Administration for relapsed/refractory (R/R) disease in the United States: revumenib for KMT2Ar and NPM1- mutant acute leukemia, and ziftomenib for NPM1m acute leukemias. Additional menin inhibitors, including blexime nib, enzomenib, and BN104, are also being evaluated in clinical trials for R/R acute leukemia with KMT2Ar and NPM1m...Similarly, combining menin inhibitors with standard -of-care therapies, such as azacitidine/venetoclax or intensive chemotherapy, pa rticularly in newly diagnosed KMT2Ar and NPM1m AML, may help mitigate the resistance observed with single -agent therapy...A distinctive feature of menin inhibitor –associated DS is that, unlike DS induced by all -trans retin oic acid (ATRA), arsenic, or IDH inhibitors, corticosteroids are sometimes ineffective. This highlights the need to better understand the pathogenesis of menin inhibitor –associated DS, identify patients at..."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Respiratory Diseases • KMT2A • NPM1

How [14C]-DSP-5336 is Absorbed, Broken Down, and Removed From the Body After a Single Oral Dose in Patients With Advanced Blood Cancers (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Sumitomo Pharma America, Inc.

New P1 trial • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

Menin Inhibition in Acute Myeloid MLL Rearranged Leukemias: A New Target for Precision Care. (PubMed, Cancers (Basel)) - "Revumenib received approval in 2024-2025 for relapsed or refractory KMT2A-rearranged acute leukemia and NPM1-mutated AML...Several menin inhibitors, including ziftomenib, bleximenib, and enzomenib, are in clinical development...Combination therapies with azacitidine and venetoclax or intensive chemotherapy have achieved high response rates in newly diagnosed patients, supporting their potential use in frontline treatment...Approximately 30-40% of responders in relapsed or refractory trials proceeded to allogeneic transplantation, which remains a key pathway to potential cure. This review examines the molecular mechanisms of the menin-KMT2A interaction, and summarizes clinical trial data on the efficacy and safety of menin inhibitors as monotherapy and in combination."

Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • KMT2A • MEN1 • NPM1

ALLG BM15: A Double-blind, Phase I/II, Randomised Study to Compare the Efficacy of Enzomenib Versus Placebo as Maintenance after Allogeneic Haematopoietic Stem Cell Transplantation in Subjects with Acute Myeloid Leukaemia (AML). (ANZCTR) - P2 | N=53 | Not yet recruiting | Sponsor: Australasian Leukaemia and Lymphoma Group

New P2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Menin inhibitors for adult acute myeloid leukemia: 2025 update. (PubMed, Expert Opin Investig Drugs) - "Menin inhibitor approval/use is expanding into other HOX-driven subtypes (e.g. NPM1, NUP98r), as frontline option and in combination settings. Monitoring for differentiation syndrome, QT interval prolongation, recognizing pseudo-progression, and supportive care needs remains essential to maximize patient benefit."

Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • HOXA9 • KMT2A • MEIS1 • MEN1 • NPM1 • NUP98

A baseline transcriptomic signature predictive of clinical response to menin inhibitors in AML : The PRE-men retrosprospective Study (ASH 2025) - P1/2 | "In this study, we assessed thetranscriptomic profiles of R/R AML patients at baseline and during early MENi therapy to: (1) develop agene expression signature predictive of treatment response, and (2) gain insight into the molecularfeatures distinguishing sensitive from primary resistant patients.MethodsIn this monocentric retrosprospective study, patients treated with MENi monotherapy (revumenib (n=15),ziftomenib (n=3), bleximinib (n=1), enzomenib (n=1)) either in French revumenib compassionate useprogram or in dedicated clinical trials (2020-004104-34, 2023-510509-17, 2023-505584-36, 2022-502741-10-00) were included. Most of the DEG found were involved in immune signalingpathways. A transcriptomic signature predictive of response to MENi therapy is currently evaluated in anindependent external validation cohort and will be presented at the meeting."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ADNP • CD14 • HIF1A • HOXA9 • KMT2A • MEIS1 • NUP98

Preclinical activity of investigational menin inhibitor DSP-5336 (Enzomenib)-based combinations against MLL1-rearranged (MLL-r) or mutant-NPM1 AML models (ASH 2025) - "Previously reported preclinical data showed that treatment with Menin inhibitor (MI),e.g., SNDX-5613 (revumenib) or KO-539 (ziftomenib), disrupts binding of Menin to MLL1/2 and MLL1-FP,leading to reduced MLL1/2 and MLL1-FP target gene expression, as well as induction of differentiationand apoptosis in AML cells expressing MLL-FP or mtNPM1c...Notably, in the cell lines and PD AML cells with MLLr ormtNPM1c AML, in vitro treatment with DSP-5336 in combination with CDK9 inhibitor (CDK9i) AZD4573 orBAY1251152 for 48 to 96 hours induced synergistic apoptosis or loss of viability, as discovered by the ZIPmethod with SynergyFinder...In vivo co-treatment with DSP-5336 and BAY1251152 showedsignificantly greater reduction in AML burden than treatment with each agent alone (p< 0.05), withoutinducing weight loss or other toxicities. These preclinical findings underscore the anti-AML activity of DSP-5336 and its molecular correlates, aswell as demonstrate synergistic in vitro and..."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2 • CASP3 • CD123 • CD33 • CD99 • CDK6 • CLEC12A • FLT3 • HOXA9 • IFNG • IL3RA • ITGAM • KMT2A • MEF2C • MEIS1 • NPM1 • PBX3

Also presented were preliminary results of a Phase 1 study of enzomenib at dose levels of 140 mg, 200 mg, and 300 mg BID in combination with azacitidine and venetoclax (VEN/AZA) in patients with relapsed or refractory AML with KMT2Ar or NPM1m. (PRNewswire) - "A total of 40 patients were enrolled, of which 18 had KMT2Ar (45%) and 22 (55%) had NPM1m...There were no DLTs observed in the 40 patients enrolled...Promising preliminary clinical activity has been observed, particularly in patients without prior VEN or menin inhibitor exposure (N=13). The ORR is 85% (11/13) and the composite complete remission (CRc) rate is 62% (8/13). Local MRD assessments were available in 9 patients and 7/9 (78%) achieved MRD negativity as of the cut-off....Enrollment of newly diagnosed patients with KMT2Ar or NPM1m AML will begin in early 2026."

Enrollment status • P1 data • Acute Myelogenous Leukemia

Updated Data Shared with the Use of Enzomenib in Acute Myeloid Leukemia (PRNewswire) - "Enzomenib was escalated from 40 mg twice a day (BID) to 400 mg BID with no dose-limiting toxicities (DLTs)...In patients with KMT2Ar, dose optimization of 200, 300, and 400 mg BID is complete, and the RP2D has been determined as 300 mg BID. At RP2D, in patients with KMT2Ar who had not received prior treatment with a menin inhibitor (n = 15), the objective response rate (ORR) was 73.3% and CR+CRh was 40%. Across the optimization dose levels, the duration of CR+CRh (n = 11) was 12.5 months and in all optimization patients (n = 39) median overall survival (mOS) was 11.8 months....In the NPM1m dose optimization population (n=25, pts who received ≥ 200 mg BID), ORR is 52% and CR+CR is 44% with a duration of CR+CRh of 5.7 months. The mOS was 8.5 months."

P1/2 data • Acute Myelogenous Leukemia