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

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

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

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

The promise of menin inhibitors: from approval to triplet regimens. (PubMed, Hematology Am Soc Hematol Educ Program) - "Next-generation agents (ziftomenib, bleximenib, enzomenib, BMF-219) have displayed similar composite complete remission rates (20-35%) and overall response rates (45-65%) in heavily pretreated KMT2Ar and NPM1m acute myeloid leukemia (AML) with measurable residual disease (MRD) negativity and prolonged overall survival (5-7 months)...Acquired mutations in the menin gene described in 39% of post-revumenib relapses have not been identified following other inhibitors (ziftomenib, bleximenib), prompting new questions about resistance mechanisms. These promising results swiftly led to the launch of multiple trials of menin inhibitors combined with intensive (cytarabine and anthracycline) and nonintensive (venetoclax and hypomethylating) chemotherapy backbones...Ongoing/pending phase 3 trials will clarify whether menin blockade should be incorporated into frontline and maintenance regimens for all patients with KMT2A rearranged or NPM1 mutant disease. In the current era, menin..."

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

Phase 1/2 First-in-Human Study of the Menin-MLL Inhibitor DSP-5336 in Patients with Relapsed or Refractory Acute Leukemia (ASH 2023) - "Of these 4 pts, all had received prior intensive induction chemotherapy as well as a venetoclax-based regimen, and 3 had received prior allo-transplant. DSP-5336 has been well tolerated with no DLTs to date in heavily pretreated R/R AML patients with NPM1c and MLLr AML. Importantly, no cardiac signals (including no QTcF prolongation) have been observed. PK studies have not identified a significant drug-drug interaction with azoles."

Clinical • First-in-human • P1/2 data • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Pneumonia • Respiratory Diseases • Septic Shock • HOXA9 • ITGAM • KMT2A • MEIS1 • NPM1 • PBX3 • TP53

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

ASH 2025 tip sheet: Sylvester researchers contribute to more than 35 oral presentations at ASH Annual Meeting (Eurekalert)

Clinical data • Acute Myelogenous Leukemia • Large B Cell Lymphoma • Multiple Myeloma

Discerning the Landscape of Menin Inhibitor Resistance (ASH 2024) - "With higher dose MI therapy, only 1 of 5 mice developed a MEN1 mutation and in the remaining mice MEN1 WT cells persisted and slowly expanded over the course of ≥6 months of therapy despite on-target gene expression changes : decreased MEIS1 and HOXA cluster genes, increased CD11b, CD13, CD14.Given that CRISPR-Cas9 base editing previously predicted some of the MEN1 mutations that arose with revumenib, we utilized improved base editing technology to help discern the landscape of MEN1 acquired mutations for four additional MIs currently in clinical trials (DS-1594, DSP-5336, JNJ-75276617, ziftomenib). An in vitro technique leveraging large starting cell numbers validates this base editor screening approach, which resulted in rapid development of resistant MEN1 mutant clones in less than 4 weeks of treatment. Identifying MEN1 mutations in patients receiving MIs is important because there may be opportunities for patients with select MEN1 mutations to derive benefit from an..."

Hematological Malignancies • Leukemia • Oncology • ANPEP • CD14 • ITGAM • KMT2A • MEIS1 • MEN1 • NPM1

Sumitomo Pharma America to Present New Investigational Data at the 2025 American Society of Hematology Annual Meeting (PRNewswire) - "In this dose-escalation study of enzomenib monotherapy, enzomenib was escalated from 40 mg twice a day (BID) to 400 mg BID with no dose-limiting toxicities (DLTs) in 116 patients with sustained complete remission (CR) and complete remission with partial hematologic recovery (CRh) seen at doses of 200, 300 and 400 mg BID...Additionally, preliminary findings from a Phase 1 study of enzomenib in combination with VEN/AZA in patients with relapsed or refractory AML with KMT2Ar or NPM1m subtypes show enzomenib with VEN/AZA to be well-tolerated to up to 300 mg BID with no DLTs and no evidence of significant drug-drug interaction between enzomenib and VEN."

P1/2 data • Acute Myelogenous Leukemia

Sumitomo Pharma Presents Latest Clinical Data on Investigational Anti-Cancer Agent Enzomenib (DSP-5336) at the 2025 Annual Meeting of the Japanese Society of Hematology (JSH) (Sumitomo Pharma Press Release) - "The safety analysis set of the study included 84 patients with acute leukemia, of whom 94% (79/84) had acute myeloid leukemia (AML)....Preliminary efficacy data from the dose optimization cohort (200 mg and 300 mg twice daily) were also presented. This included patients with KMT2A rearrangements or nucleophosmin 1 (NPM1) mutations who had received at least one dose of enzomenib and had not previously been treated with menin inhibitors. Among these, the overall population (n=40) showed an objective response rate (ORR) of 62.5% (25/40) and a complete remission plus complete remission with partial hematologic recovery (CR+CRh) rate of 37.5% (15/40). In the Japanese population (n=12), ORR was 75.0% (9/12) and CR+CRh was 41.7% (5/12)...At JSH2025, Sumitomo Pharma also presented clinical data from a Phase 1/2 study of nuvisertib....targeting relapsed or refractory myelofibrosis."

P1/2 data • Acute Myelogenous Leukemia • Myelofibrosis

Menin Inhibitors in KMT2A-Rearranged and NPM1-Mutated Acute Leukemia: A Scoping Review of Safety and Efficacy (SOHO 2025) - " Thirteen clinical trials evaluating six menin inhibitors—revumenib (SNDX-5613), ziftomenib (KO-539), bleximenib (KO-2806), enzomenib (DS-1594), BMF-219, and JNJ-75276617—were analyzed. These findings demonstrate the potent efficacy of menin inhibitors in genetically defined subsets of leukemia. However, their clinical application requires careful management of toxicity profiles, including QTc prolongation and differentiation syndrome. Additionally, menin inhibitors exhibit synergistic effects with agents like venetoclax and FLT3 inhibitors, enhancing therapeutic efficacy and potentially improving outcomes in KMT2A-rearranged and NPM1-mutated AML."

Clinical • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • KMT2A • NPM1

The role of menin inhibitors in acute myeloid leukemia. (PubMed, Curr Opin Oncol) - "These findings justify the integration of menin inhibitors into the AML therapeutic landscape, and support ongoing randomized trials to confirm their benefit in both frontline and relapse or refractory settings."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEIS1 • MEN1 • NPM1

Therapeutic Implications of Menin Inhibitors in the Treatment of Acute Leukemia: A Critical Review. (PubMed, Diseases) - "Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options."

Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • KMT2A • MEIS1 • NPM1

Menin inhibitors from monotherapies to combination therapies: clinical trial updates from 2024 ASH annual meeting. (PubMed, J Hematol Oncol) - "Following the promising outcomes of the two pioneering menin inhibitors, revumenib and ziftomenib, other menin inhibitors, including bleximenib, enzomenib, BN-104 and HMPL-506 are currently under investigation in clinical trials. Several trials presented their initial outcomes at the 2024 ASH Annual Meeting. This review highlights the key outcomes of these pivotal clinical trials."

Journal • Review • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEIS1 • NPM1 • NUP98

Menin Inhibitors in KMT2A-Rearranged and NPM1-Mutated Acute Leukemia: A Scoping Review of Safety and Efficacy. (PubMed, Crit Rev Oncol Hematol) - "Menin inhibitors demonstrate promising clinical activity in molecularly defined leukemias, with Revumenib establishing proof-of-concept for this therapeutic approach. However, challenges remain, including resistance development, optimal timing of therapy initiation, and determination of effective combination strategies. Larger randomized trials with extended follow-up are needed to establish long-term efficacy and safety profiles. The rapid clinical development of multiple agents in this class suggests an expanding role for Menin inhibitors in leukemia treatment paradigms."

Journal • Review • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEN1 • NPM1

MENIN inhibitor-based therapy in acute leukemia: latest updates from the 2024 ASH annual meeting. (PubMed, Exp Hematol Oncol) - "At the 2024 ASH annual meeting, updated clinical data regarding monotherapy with MENINis in AL, including revumenib, bleximenib, enzomenib and BN104, were presented. Furthermore, the therapeutic effects of venetoclax plus azacitidine or "3 + 7" regimens were further enhanced by the addition of MENINis in KMT2Ar- and NPM1m-AML patients. Therefore, MENINis offer new therapeutic prospects for AML patients, particularly for those with high-risky and poor-prognostic on-target subtypes."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HOXA9 • KMT2A • MEIS1 • NPM1

Sumitomo Pharma America enters into a Cooperative Research and Development Agreement with the National Cancer Institute to Advance Clinical Understanding of Enzomenib (Businesswire) - "Sumitomo Pharma America, Inc...announced it has entered into a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH), to evaluate enzomenib, an investigational, oral, small molecule designed to inhibit the menin and KMT2A protein interaction present in certain difficult to treat cancers...As part of the collaboration, enzomenib will be explored in MyeloMATCH (Myeloid Malignancies Molecular Analysis for Therapy Choice), an NCI precision medicine clinical trial designed to improve treatment outcomes for individuals diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Enzomenib will also be explored with other important NCI programs."

Commercial • Acute Myelogenous Leukemia • Leukemia • Myelodysplastic Syndrome

DSP-5336-101: A Study of DSP-5336 in Relapsed/Refractory AML/ ALL With or Without MLL Rearrangement or NPM1 Mutation (clinicaltrials.gov) - P1/2 | N=362 | Recruiting | Sponsor: Sumitomo Pharma America, Inc. | N=70 ➔ 362 | Trial completion date: Feb 2025 ➔ Oct 2027 | Trial primary completion date: Jan 2025 ➔ Apr 2027

Enrollment change • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • IDH2 • KMT2A • NPM1

Foundation Medicine Collaborates with Sumitomo Pharma America to Advance Investigational Treatment for Patients with Acute Leukemia with NPM1 Mutations or KMT2A Rearrangements Using the FoundationOne Heme Platform (Businesswire) - "Foundation Medicine, Inc...announced a collaboration with Sumitomo Pharma America, Inc. (SMPA) to develop the FoundationOne Heme platform as a companion diagnostic to identify patients with acute leukemia with a KMT2A rearrangement, also known as mixed lineage leukemia (MLL) rearrangement, or NPM1 mutations for potential treatment with SMPA’s enzomenib (DSP-5336), an investigational menin inhibitor."

Diagnostic • Licensing / partnership • Acute Myelogenous Leukemia • Oncology

Sumitomo Pharma America Presents New Data...Enzomenib at the 2024 American Society of Hematology Annual Meeting (PRNewswire) - P1/2 | N=70 | NCT04988555 | Sponsor: Sumitomo Pharma America, Inc. | "New preliminary clinical and translational data from the enzomenib Phase 1/2 study were also presented at the conference by Dr. Joshua Zeidner from the University of North Carolina. The safety population included 84 total patients with acute leukemia, most of whom (94%, 79/84) had acute myeloid leukemia (AML)....In these patients, enzomenib was administered twice daily in continuous 28-day study cycles at dose levels from 40 mg BID up to 300 mg BID. Enzomenib was well tolerated with low overall rates of drug-related adverse events and no dose limiting toxicity (DLT) reported. Differentiation syndrome was reported in 10.7% of patients but did not result in patient deaths nor did it require permanent discontinuations of enzomenib."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Clinical Data for Investigational Cancer Agents Nuvisertib (TP-3654) and Enzomenib (DSP-5336) to be Presented at ASH 2024 [Google translation] (Dainippon Sumitomo Press Release) - "Results from a Phase 1/2 study of nuvisertib in patients with relapsed or refractory myelofibrosis showed that nuvisertib was well tolerated as a single agent with no dose-limiting toxicities (DLTs) and demonstrated promising early clinical activity...Results from a Phase 1/2 study of enzomenib in patients with relapsed or refractory acute leukemia showed that the drug was well tolerated across a range of doses, with no DLTs or discontinuations due to enzomenib-related adverse events, and demonstrated promising early clinical activity."

P1/2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Myelofibrosis

Sumitomo Pharma Announces that DSP-5336 Has Received FDA Fast Track Designation for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia (PRNewswire) - "Sumitomo Pharma America...announced that the U.S. Food and Drug Administration (FDA) granted Fast Track designation to DSP-5336 for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with a KMT2A rearrangement, also known as, mixed lineage leukemia rearrangement (MLLr) or nucleophosmin mutation (NPM1m)."

Fast track • Acute Myelogenous Leukemia