HOXA9

– DSP-5336, an Investigational Menin and Mixed-lineage Leukemia Inhibitor, is Being Evaluated in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) with a mixed lineage leukemia rearrangement (MLLr) or nucleophosmin mutation (NPM1m) – MARLBOROUGH, Mass., July 15, 2024 /PRNewswire/ -- Sumitomo Pharma America, Inc. (SMPA) today 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). DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction, which plays key roles in gene expression and protein interactions involved in many biological pathways, including cell growth, cell cycle, genomic stability, and hematopoiesis.1,2,3 FDA Fast Track Designation is granted to investigational therapies being developed to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. "For patients and families facing a diagnosis of relapsed or refractory acute myeloid leukemia, significant unmet medical needs remain – and we share in their urgency to identify and advance new treatment pathways," said Tsutomu Nakagawa, Ph.D, President and Chief Executive Officer of SMPA. "We are encouraged by FDA's decision and look forward to working closely with the agency as we continue our clinical development of DSP-5336." Updated data from the ongoing open-label, dose escalation and optimization portion of the Phase 1/2 study for DSP-5336 were presented at the European Hematology Association (EHA) 2024 Hybrid Congress, building on preliminary data presented at the 2023 American Society of Hematology (ASH) Annual Meeting. Objective response was observed in 57% (12/21) of patients, which included responses in patients with both Nucleophosmin 1 (NPM1) mutation and KMT2A (MLL) rearrangement. The proportion with complete remission or complete remission with partial hematologic recovery (CR/CRh) was 24% (5/21 patients). To date, DSP-5336 remains well-tolerated with no dose limiting toxicity (DLT) observed and no significant cardiac signal nor treatment-related discontinuations or deaths. No significant drug-drug interactions with azoles have been identified and repeat dosing results in minimal to no pharmacokinetic accumulation. Importantly, no differentiation syndrome (DS) prophylaxis was needed, and the three cases of DS reported (5%) were manageable and did not result in intensive care unit (ICU) stays or discontinuation of DSP-5336. "Management of AML continues to be challenging with limited options for which there are currently no approved targeted therapies to treat AML with KMT2A (MLL) rearrangements or NPM1 mutations, leaving a serious unmet medical need," said Jatin Shah, M.D., Chief Medical Officer – Oncology at SMPA. "DSP-5336 has shown promising clinical activity, and menin inhibitors have tremendous potential to impact the outcomes of these types of acute leukemia. We are excited by these early results and FDA Fast Track Designation, and look forward to working closely with the agency and our collaborators to rapidly advance this program with the goal of providing a well-tolerated and effective targeted treatment option for patients with relapsed or refractory acute myeloid leukemia." Leukemia is a type of cancer that forms in blood-forming tissue, characterized by the uncontrolled growth of blood cells, usually white blood cells, in the bone marrow. Acute leukemia, a form of leukemia, requires immediate treatment as blood cells multiply rapidly leading to a sudden onset of symptoms.4 Approximately 30% of AML patients have NPM1 mutations6 and 5-10% of AML patients have KMT2A (MLL) rearrangements.5 About DSP-5336 DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction. Menin is a scaffold nuclear protein which plays key roles in gene expression and protein interactions involved in many biological pathways, including cell growth, cell cycle, genomic stability, and hematopoiesis.1,2 In preclinical studies, DSP-5336 has shown selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations.1,3 DSP-5336 reduced the expression of the leukemia-associated genes HOXA9 and MEIS1, and increased the expression of the differentiation gene CD11b in human acute leukemia cell lines with MLL rearrangements and NPM1 mutation.7,8 The safety and efficacy of DSP-5336 is currently being clinically evaluated in a Phase 1/2 dose escalation/dose expansion study in patients with relapsed or refractory acute leukemia (NCT04988555). The FDA granted Orphan Drug Designation for DSP-5336 for the indication of acute myeloid leukemia in June 2022. The FDA granted Fast Track Designation for DSP-5336 for the indication of relapsed or refractory acute myeloid leukemia with MLLr or NPM1m in June 2024. About Sumitomo Pharma Sumitomo Pharma Co., Ltd. is a global pharmaceutical company based in Japan with key operations in the U.S. (Sumitomo Pharma America, Inc.), Canada (Sumitomo Pharma Canada, Inc.) and Europe (Sumitomo Pharma Switzerland GmbH) focused on addressing patient needs in oncology, urology, women's health, rare diseases, psychiatry & neurology, and cell & gene therapies. With several marketed products in the U.S., Canada, and Europe, a diverse pipeline of early- to late-stage assets, and in-house advanced technology capabilities, we aim to accelerate discovery, research, and development to bring novel therapies to patients sooner. For more information on SMPA, visit our website or follow us on LinkedIn. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd. © 2024 Sumitomo Pharma America, Inc. All rights reserved. References Cierpicki T, Grembecka J. Challenges and opportunities in targeting the menin-MLL Interaction. Future Med Chem. 2014; 6(4):447-462. doi:10.4155/fmc.13.214. Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013; 38(8):394-402. doi:10.1016/j.tibs.2013.05.005. Kuhn MWM, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6(10):1166-1181. doi:10.1158/2159-8290.CD-16-0237. Chennamadhavuni A, Lyengar V, Mukkamalla SKR, et al. Leukemia. [Updated 2023 Jan 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: . Borkin D, Klossowski S, Pollock J, et al. Complexity of Blocking Bivalent Protein-Protein Interactions: Development of a Highly Potent Inhibitor of the Menin-Mixed-Lineage Leukemia Interaction. J Med Chem. 2018;61(11):4832-4850. doi:10.1021/acs.jmedchem.8b00071. Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev. 2021;42(2):133-170. doi:10.1210/endrev/bnaa031 Eguchi K, Shimizu T, Kato D, et al. Preclinical Evaluation of a Novel Orally Bioavailable Menin-MLL Interaction Inhibitor, DSP-5336, for the Treatment of Acute Leukemia Patients with MLL-Rearrangement or NPM1 Mutation. Blood 2021; 138 (Supplement 1): 3339. Available at: . Daver N, Zeidner JF, Yuda J, et al. Phase 1/2 First-in-Human Study of the Menin-MLL Inhibitor DSP-5336 in Patients with Relapsed or Refractory Acute Leukemia. Blood 2023; 142 (Supplement 1): 2911. Available at: . SOURCE Sumitomo Pharma America

– DSP-5336, an Investigational Menin and Mixed-lineage Leukemia Inhibitor, is Being Evaluated in Patients with Relapsed or Refractory Acute Leukemia – MARLBOROUGH, Mass., June 14, 2024 /PRNewswire/ -- Sumitomo Pharma America, Inc. (SMPA) today announced the oral presentation of data from the ongoing Phase 1/2 first-in-human study of DSP-5336 in patients with relapsed or refractory acute leukemia at the European Hematology Association (EHA) 2024 Hybrid Congress. DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction, which plays key roles in biological pathways, including cell growth regulation, cell cycle control, genomic stability, bone development, and hematopoiesis.1,2,3 Building on preliminary data presented at the 2023 American Society of Hematology (ASH) Annual Meeting, authors presented updated data from the open-label, ongoing dose escalation and optimization portion of the Phase 1/2 study. Patients received oral DSP-5336 in repeating 28-day cycles at doses ranging from 40 mg to 300 mg twice-daily. The oral presentation at EHA included the results of 57 patients. Responses were more consistently observed in patients who received 140 mg twice-daily or higher, particularly in the 21 patients with either Nucleophosmin 1 (NPM1) mutation or KMT2A (MLL) rearrangement documented by local testing. Objective response was observed in both patient populations with 57% of patients (12/21), with complete remission or complete remission with partial hematologic recovery (CR/CRh) observed in 24% (5/21 patients). To date, DSP-5336 remains well-tolerated with no dose limiting toxicity (DLT) observed and no significant cardiac signal nor treatment-related discontinuations or deaths. No significant drug-drug interactions with azoles have been identified and repeat dosing results in minimal to no pharmacokinetic accumulation. Importantly, no differentiation syndrome (DS) prophylaxis was needed, and the three cases of DS reported (5%) were manageable and did not result in intensive care unit (ICU) stays or discontinuation of DSP-5336. "The response in patients previously untreated with menin inhibitors is encouraging, and competitive with greater than 50% objective response rate alongside a favorable safety profile in patients with relapsed or refractory acute leukemia," said Naval Daver, M.D., Director, Leukemia Research Alliance Program and Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, and lead author on the DSP-5336 poster at EHA. "Menin inhibitors have tremendous potential to improve the outcomes of certain types of acute leukemia, as they reverse the leukemogenic activity of MLL fusion and mutated NPM1 proteins. In addition to promising clinical activity the safety profile of DSP-5336 has been especially encouraging and may differentiate it from other menin inhibitors with no severe DS, DLTs nor treatment-related discontinuations." Leukemia is a type of cancer that forms in blood-forming tissue, characterized by the uncontrolled growth of blood cells, usually white blood cells, in the bone marrow. Acute leukemia, a form of leukemia, requires immediate treatment as blood cells multiply rapidly leading to a sudden onset of symptoms.4 Approximately 30% of acute myeloid leukemia (AML) patients have NPM1 mutations7 and 5-10% of AML patients have KMT2A (MLL) rearrangements.5 "There remains a high unmet need in relapsed or refractory acute leukemia, as there are no approved targeted treatments for AML with KMT2A (MLL) rearrangements or NPM1 mutations," said Jatin Shah, M.D., Chief Medical Officer – Oncology at SMPA. "The biology of menin inhibition is clearly important and we are very early in the rapidly evolving field. We're excited by these early results and aim to provide a needed option that is both efficacious and well-tolerated. We look forward to continuing to progress the study of DSP-5336 in the hopes of improving outcomes in AML and advancing patient care." About DSP-5336 DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction. Menin is a scaffold nuclear protein that plays various key roles in biological pathways, including cell growth regulation, cell cycle control, genomic stability, bone development, and hematopoiesis.1,2 In preclinical studies, DSP-5336 has shown selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations.1,3 DSP-5336 reduced the expression of the leukemia-associated genes HOXA9 and MEIS1, and increased the expression of the differentiation gene CD11b in human acute leukemia cell lines with MLL rearrangements and NPM1 mutation.9,10 The safety and efficacy of DSP-5336 is currently being clinically evaluated in a Phase 1/2 dose escalation/dose expansion study in patients with relapsed or refractory acute leukemia (NCT04988555). The FDA granted Orphan Drug Designation for DSP-5336 for the indication of acute myeloid leukemia in June 2022. About Sumitomo Pharma Sumitomo Pharma Co., Ltd. is a global pharmaceutical company based in Japan with key operations in the U.S. (Sumitomo Pharma America, Inc.), Canada (Sumitomo Pharma Canada, Inc.) and Europe (Sumitomo Pharma Switzerland GmbH) focused on addressing patient needs in oncology, urology, women's health, rare diseases, psychiatry & neurology, and cell & gene therapies. With several marketed products in the U.S., Canada, and Europe, a diverse pipeline of early- to late-stage assets, and in-house advanced technology capabilities, we aim to accelerate discovery, research, and development to bring novel therapies to patients sooner. For more information on SMPA, visit our website or follow us on LinkedIn. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd. © 2024 Sumitomo Pharma America, Inc. All rights reserved. For a copy of this release, visit Sumitomo Pharma America's website at . References Cierpicki T, Grembecka J. Challenges and opportunities in targeting the menin-MLL Interaction. Future Med Chem. 2014; 6(4):447-462. doi:10.4155/fmc.13.214. Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013; 38(8):394-402. doi:10.1016/j.tibs.2013.05.005. Kuhn MWM, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6(10):1166-1181. doi:10.1158/2159-8290.CD-16-0237. Chennamadhavuni A, Lyengar V, Mukkamalla SKR, et al. Leukemia. [Updated 2023 Jan 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: . Borkin D, Klossowski S, Pollock J, et al. Complexity of Blocking Bivalent Protein-Protein Interactions: Development of a Highly Potent Inhibitor of the Menin-Mixed-Lineage Leukemia Interaction. J Med Chem. 2018;61(11):4832-4850. doi:10.1021/acs.jmedchem.8b00071. Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023;615(7954):920-924. doi:10.1038/s41586-023-05812-3 Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev. 2021;42(2):133-170. doi:10.1210/endrev/bnaa031 Borlenghi E, Cattaneo C, Bertoli D, et al. Prognostic Relevance of NPM1 and FLT3 Mutations in Acute Myeloid Leukaemia, Longterm Follow-Up-A Single Center Experience. Cancers (Basel). 2022;14(19):4716. Published 2022 Sep 28. doi:10.3390/cancers14194716 Eguchi K, Shimizu T, Kato D, et al. Preclinical Evaluation of a Novel Orally Bioavailable Menin-MLL Interaction Inhibitor, DSP-5336, for the Treatment of Acute Leukemia Patients with MLL-Rearrangement or NPM1 Mutation. Blood 2021; 138 (Supplement 1): 3339. Available at: . Daver N, Zeidner JF, Yuda J, et al. Phase 1/2 First-in-Human Study of the Menin-MLL Inhibitor DSP-5336 in Patients with Relapsed or Refractory Acute Leukemia. Blood 2023; 142 (Supplement 1): 2911. Available at: . SOURCE Sumitomo Pharma America

Using CRISPR/Cas9, scientists identified RBM5 as a vital component of leukemia cell fitness, making it a promising target for drug development. The protein HOXA9 is overexpressed in most acute myeloid leukemia (AML) cases and is associated with poor patient outcomes. However, HOXA9 is a difficult protein to target therapeutically, so researchers at St. Jude Children's Research Hospital looked for ways to extinguish it indirectly. Using CRISPR/Cas9 screening, the researchers identified RBM5, demonstrating a causative link between RBM5 expression and leukemia cell proliferation. This link is driven by a novel dual function of RBM5 as both a DNA and RNA handler in gene expression. The research was published today in Genome Biology. Overexpression of the protein HOXA9 is a hallmark of AML, present in over 70% of cases, often with poor prognosis. While this would implicate it as a useful drug target, the protein's role as a transcription factor has left it "undruggable" because a drug that interferes with HOXA9 would likely have numerous other off-target effects. This inspired researchers to approach the problem from a different angle by investigating the proteins HOXA9 works alongside and relies on to function. Chunliang Li, PhD, St. Jude Department of Tumor Cell Biology, co-corresponding author on this paper, is one such researcher. Through his recent work devising an unbiased CRISPR screening strategy to identify targets of HOXA9, he uncovered a network of opportunities. "This has been a continued effort since my lab was established in 2017," said Li, "We built up this unique reporter system in early 2019, which is the first reporter authentically representing HOXA9 expression in these leukemia systems." The CRISPR/Cas9 screening approach is elegantly simple in design but incredibly effective. It involves attaching a fluorescent tag to the HOXA9 gene and inserting it into leukemia cell lines. This enables researchers to track differences in expression levels by looking at fluorescence in cells. "We wanted to identify a more targetable or novel regulator. So, we conducted an unbiased whole genome CRISPR screening to target all the genes expressed in cells," Li stated. This allowed the researchers to examine different pathways where HOXA9 left its fluorescent fingerprint. To the researchers' surprise, splicing factors appeared to be the most represented pathway. "This was quite surprising to us because splicing factors regulate different combinations of the transcript, but not usually the level. Our data suggested these proteins control the HOXA9 expression level," said Li. "So, we hypothesized maybe the splicing factors have another function, like a dual function." The protein that stood out was the RNA-binding protein RBM5. The researchers found that RBM5 is highly expressed in leukemia cells as opposed to other cell types and that both the DNA- and RNA-binding sites are vital to its oncogenic functions. While the RBM family comprises vital RNA splicing factors, their function in DNA transcription was unknown. To address the direct transcriptional regulation of RBM5/HOXA9, the researchers generated a system to allow the acute degradation of RBM5. "Immediately after RBM5 protein was removed from cells, HOXA9 mRNA levels were significantly reduced," Li explained, "This reduction happened as early as two hours later but did not impact splicing events of HOXA9." Additionally, leukemia cells stripped of their ability to produce RBM5 were rescued through overexpression of HOXA9, further demonstrating the link between the two proteins. These results have Li looking to explore the protein as a drug target to treat AML. "We think RBM5 is a very good dependency gene, which should be a good target based on our functional assays," he said. "If we can specifically target the DNA binding affinity of these proteins, we should be able to combine with other existing therapies in synergy to target HOXA9-driven leukemia." Authors and funding The study's first author is Mengli Zhang, Soochow University. The co-corresponding author is Peng Xu, Soochow University. Other authors include Judith Hyle, Shaela Wright, Zhenling Liu, Wojciech Rosikiewicz, Beisi Xu and Liusheng He of St. Jude; Xiaowen Chen of Shenzhen Children's Hospital; Ye Xin, Yingcai Jin, Jianxiang Zhang, Xue Yang and Xinfeng Chen of Soochow University; Hong Liu, Nana Ping and Depei Wu of The First Affiliated Hospital of Soochow University; and Feiqiu Wen of Shenzhen Children's Hospital. The study was initially supported by grants from ALSAC, the fundraising and awareness organization of St. Jude.