AUTHORS
Cristina Papayannidis, MD, PhD, Joshua F. Zeidner, MD2, Harry Erba, MD, PhD3, Kentaro Fukushima, MD, PhD4, Takahiro Shima, MD, PhD5, Thomas Cluzeau, MD, PhD6, Emmanuel Raffoux, MD7, Susana Vives, MD8, Shang-Ju Wu, MD, PHD9, Aravind Ramakrishnan, MD10, Justin M Watts, MD11, Dimitri Breems, MD, PhD12, Joseph Brandwein, MD13, Adolfo De la Fuente Burguera, MD14, Teresa Bernal Del Castillo, MD, PhD15, Juan M. Bergua-Burgués, MD16, Sylvain Garciaz, MD17, Benedetto Bruno, MD, PhD18, Takanori Teshima, MD, PhD19, Yasushi Miyazaki, MD20, Koichi Onodera, MD, PhD21, Jun Ho Jang, MD, PhD22, Melissa Ooi23, Andrew M Brunner, MD24, Emma Searle, MBChB, PhD25, Mark J. Levis I, MD PhD26, Bo Xu, PhD27, Nitika Fnu28, Priya Robson, BSN29, Mariko Takahara, MS30, Matthew Hitron, MD31, Stephen A. Strickland, MD32, Uma Borate, MBBS, MSc33, Naval Daver, MD34, Pau Montesinos, MD35
AFFILIATIONS
1 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy
2 University of North Carolina, Chapel Hill, North Carolina, United States
3 Duke University School of Medicine, Durham, North Carolina, United States
4 The University of Osaka Hospital, Osaka, Japan
5 Fukuoka University Faculty of Medicine, Fukuoka, Japan
6 Hôpital l'Archet, Nice, France
7 Hopital St Louis, Institut de la Leucemie, Universite Paris Cité, Paris, France
8 Institut Català d'Oncologia, Barcelona, Spain
9 National Taiwan University Hospital, Taipei, Taiwan
10 St. David's South Austin Medical Center, Austin, Texas, United States
11 University of Miami Miller School of Medicine, Miami, Florida, United States
12 ZNA Cadix, Antwerpen, Belgium
13 University of Alberta, Alberta, Canada
14 MD Anderson Cancer Center, Madrid, Spain
15 Instituto Universitario de Oncología del Principado de Asturias, Asturias, Spain
16 Hospital San Pedro de Alcántara, Cáceres?, Spain
17 Institut Paoli-Calmettes, Aix-Marseille Université; Centre National de la Recherche Scientifique; Centre de Recherche en Cancérologie de Marseille, Marseille, France
18 University of Torino, Torino, Italy
19 Hokkaido University, Sapporo, Japan
20 Nagasaki University Hospital, Nagasaki, Japan
21 Tohoku University Hospital, Sendai, Japan
22 Samsung Medical Center, Seoul, Korea, Rep. of South
23 National University Cancer Institute, National University Health System, Lower Kent Ridge Road, Singapore
24 Harvard Medical School, Boston, United States
25 University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom
26 Johns Hopkins University, Baltimore, Maryland, United States
27 Sumitomo Pharma America, Inc., Marlborough, Massachusetts, United States
28 Sumitomo Pharma America, Inc., Marlborough, Massachusetts, United States
29 Sumitomo Pharma America, Inc., Marlborough, Massachusetts, United States
30 Sumitomo Pharma America, Inc., Marlborough, Massachusetts, United States
31 Sumitomo Pharma America, Inc., Marlborough, Massachusetts, United States
32 TriStar Centennial Medical Center, Nashville, United States
33 The Ohio State University Comprehensive Cancer Center, Columbus, United States
34 MD Anderson Cancer Center, Houston, United States
35 Hospital Universitari I Politécnic La Fe, Valencia, Spain
ABSTRACT
Introduction: Menin inhibitors disrupt the menin-KMT2A protein interaction, suppressing downstream leukemogenic pathways in patients with NPM1 mutations (NPM1m), KMT2A rearrangements (KMT2Ar), and other genetic subsets. There are multiple menin inhibitors currently in development with promising results. However, there remains a high unmet medical need for a targeted therapy that yields robust response rates, is well-tolerated with manageable differentiation syndrome, and does not elevate the risk of clinically significant QT-interval prolongation. Enzomenib (ENZO, DSP-5336) is an investigational oral small-molecule menin inhibitor, intentionally engineered with specific physiochemical properties including a short half-life (2-5 hours), low lipophilicity, and high clearance, intended to optimize the therapeutic window, efficacy, and safety. We previously reported on the Phase 1 dose escalation study, where patients with R/R NPM1m AML treated with ENZO 200-400 mg BID had an overall response rate (ORR) and CR/CRh rate of 52% and 44%, respectively.
Here, we present the completed dose optimization that informed the recommended phase 2 dose (RP2D) in pts with R/R NPM1m AML for the ongoing pivotal, global, phase 2 Horizen-1 clinical trial.
Methods: Pts with R/R NPM1m AML received ENZO 200 mg or 300 mg BID in 28-day cycles. Eligibility criteria included age ≥12 yrs, ≥5% blasts in bone marrow by morphologic assessment, no prior use of a menin inhibitor, ECOG performance status ≤ 2, corrected QT-interval ≤ 480 msec, adequate hepatic and renal function, and no active CNS leukemia. The primary endpoints were safety and tolerability. Secondary endpoints were clinical activity and PK.
Results: As of May 15, 2026, 56 pts with R/R NPM1m AML received ENZO 200 mg BID (n = 26) or 300 mg BID (n = 30). The median age was 69 yrs vs 64 years at 200 vs 300 mg, respectively, with an equal distribution of male and female pts (50% each) in both dose groups. The median number of prior treatments was 2 and 1.5 at 200 and 300 mg, respectively. Overall, 15 pts (27%) had a prior allogeneic stem cell transplant (alloSCT n=7 at 200 mg; n=8 at 300 mg) and most pts had prior venetoclax (63%; n=18 at 200 mg; n=17 at 300 mg). Other baseline characteristics were similar in both dose groups.
The safety profile was similar between the two dose groups, with generally comparable treatment exposure. The proportion of pts with any serious adverse event, regardless of causality, was lower for pts receiving 300 mg BID (56.7%) than for 200 mg BID (69.2%). Dose reduction due to AE (300 mg: 13.3% vs 200 mg 11.5%) and AE leading to ENZO discontinuation (300 mg: 13% vs 200 mg: 15%) were similar between the dose levels, as was differentiation syndrome (DS) (overall DS all Grades n=5 (8.9%); 300 mg: n=2 vs 200 mg: n=3). There was only 1 Grade 3 event (reported at 200 mg BID) and no permanent discontinuation due to DS.
QTc prolongation of any grade and any cause was reported in 1 pt in the 200 mg BID cohort and 4 pts in the 300 mg BID cohort. All events recovered/resolved. Hematologic toxicities were generally similar between cohorts and febrile neutropenia was reported in 30.8% vs. 20.0% of patients at 200 mg vs. 300 mg, respectively.
The ORRs were 54% and 57% in pts receiving 200 and 300 mg, respectively, while the CR/CRh rates were 35% at 200 mg and 43% at 300 mg. The median time to ORR and CR/CRh was 1.7 and 3.2 months, respectively, at 200 mg and 1.0 and 1.9 months, respectively, at 300 mg. More patients proceeded to allo SCT at 300 mg vs. 200 mg (23.3% [7/30] versus 7.7% [2/26], respectively). The proportion to convert to transfusion independence was comparable at the two dose levels (200 mg: 74% vs 300 mg: 65%), the duration of transfusion independence was longer at 300 mg (190 days) than at 200 mg (137 days). Updated data will be presented.
Conclusions: Dose optimization demonstrated that ENZO 200 mg BID and 300 mg BID are generally well tolerated and demonstrated clinical activity in pts with R/R NPM1m AML. ENZO 300 mg BID was associated with a higher CR/CRh rate and faster time to achieve CR/CRh compared to 200 mg BID without an increase in toxicity. These findings support the use of ENZO 300 mg BID in pts with R/R NPM1m in the ongoing global Horizen-1 study.
DISCLOSURES
Cristina Papayannidis, MD, PhD: Istituto Gentili - Honoraria; AbbVie - Honoraria; Pfizer - Honoraria; Astellas - Honoraria; BluePrint - Honoraria; GlaxoSmithKline (GSK) - Honoraria; Servier - Honoraria; Menarini Stem Cell - Honoraria