A Phase 1/2, Open-Label, Dose-Escalation, Dose-Expansion Study of DSP-5336 in Adult Patients with Acute Leukemia and Other Selected Hematologic Malignancies, with and Without Mixed Lineage Leukemia (MLL) Rearrangement or Nucleophosmin 1 (NPM1) Mutation

A Phase 1/2 dose escalation / dose expansion study of DSP 5336 in patients with relapsed or refractory AML.

Start Date28 Feb 2022

Sponsor / Collaborator

Sumitomo Pharma America, Inc.

100 Clinical Results associated with Enzomenib

100 Translational Medicine associated with Enzomenib

100 Patents (Medical) associated with Enzomenib

Literatures (Medical) associated with Enzomenib

01 Sep 2023·Journal of cancer research and clinical oncology

Targeting the undruggable: menin inhibitors ante portas

Review

Author: Desole, Maximilian ; Sica, Simona ; Dempke, Wolfram C M ; Chiusolo, Patrizia ; Schmidt-Hieber, Martin

Acute myeloid leukaemias harbouring a rearrangement of the mixed lineage leukaemia gene (MLL) are aggressive haematopoietic malignancies that relapse early and have a poor prognosis (event-free survival less than 50%). Menin is a tumour suppressor, however, in MLL-rearranged leukaemias it functions as a co-factor which is mandatory for the leukaemic transformation by interaction with the N-terminal part of MLL, which is maintained in all MLL-fusion proteins. Inhibition of menin blocks leukaemogenesis and leads to differentiation and, in turn, to apoptosis of leukaemic blasts. Furthermore, nucleophosmin 1 (NPM1) binds to specific chromatin targets, which are co-occupied by MLL, and menin inhibition has been shown to trigger degradation of mNPM1 resulting in a rapid decrease in gene expression and activating histone modifications. Therefore, disruption of the menin-MLL axis blocks leukaemias driven by NPM1 mutations for which the expression of menin-MLL target genes (e.g., MEIS1, HOX etc.) is essential. To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. In the revumenib phase I/II AUGMENT-101 trial (N = 68) with very heavily pretreated AML patients the ORR was 53% with a CR rate of 20%. The ORR in patients harbouring MLL rearrangement of mNPM1 was 59%. Patients who achieved a response had a mOS of 7 months. Similar results have been reported for ziftomenib in the phase I/II COMET-001 trial. ORR was 40% and CRc was 35% in AML patients with mNPM1. However, outcome was worse in AML patients with a MLL rearrangement (ORR 16.7%, CRc 11%). Differentiation syndrome was a notable adverse event. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.

01 Oct 2022·Clinical Lymphoma Myeloma & Leukemia

AML-391 Phase 1/2, Open-Label, Dose Escalation, Dose Expansion Study of Menin Inhibitor DSP-5336 in Adult Patients With Acute Leukemia With and Without Mixed-Lineage Leukemia (MLL)– Rearrangement or Nucleophosmin 1 (NPM1) Mutation

Article

Author: Daver, Naval ; Stoudemire, Jay ; Dobrowolska, Hanna ; Hitron, Matthew ; Affinito, John ; Eguchi, Ken ; Watanabe, Akinobu ; Cai, Hongliang

Patients who relapse after initial acute leukemia (AL) treatment have median survival <6 months for AML and <1 y for ALL, especially AML or ALL with MLL rearrangements (MLLr) or relapsed AML with NPM1 mutations. Translocations of the MLL gene (5% to 10% of adult patients) produce an aggressive subtype, with a median overall survival (OS) of approximately 9 months. The NPM1 mutation (NPM1m) occurs in 30%-35% of adult de novo AML and is associated with a favorable prognosis. However, 40%-50% of these patients have concurrent FLT3-internal tandem duplication mutations negating this favorability. DSP-5336, a novel oral small-molecule, was developed to prevent menin protein binding to MLL fusion proteins that drive leukemogenesis. Nonclinical DSP-5336 studies showed selective growth inhibition against human AL cell lines with MLLr or NPM1m. Evidence of antitumor activity and survival advantage was demonstrated in 3 AML xenograft models with MLLr and/or NPM1m. Treatment with DSP-5336 may reduce leukemic cells and benefit patients with relapsed or refractory (R/R) MLLr or NPM1m AML or patients with R/R MLLr ALL. An open-label, single-arm, phase 1/2 study (NCT04988555) will evaluate the safety and efficacy of DSP-5336 and determine the recommended phase 2 dose (RP2D) in adults aged ≥18 y with relapsed/refractory AML or ALL after at least one line of therapy. Key inclusion criteria are ECOG performance status 0-2 and adequate organ function. Patients will be dosed twice daily in 28-day cycles. In phase 1, 21-30 patients will be enrolled into multiple dose cohorts (1-6 patients per dose level), with dose escalation determined using a two-parameter Bayesian logistic regression model. The RP2D will be informed by the maximum biologic effect or maximum tolerated dose, whichever is lower. The phase 2 study will include two arms (R/R AML with MLLr and R/R AML with NPM1m). Patients will be treated at the RP2D to evaluate clinical activity and safety and monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses begins after the first 10 enrolled patients are evaluable for efficacy. This study is recruiting in the United States and Japan.

News (Medical) associated with Enzomenib

09 Dec 2024

·www.prnewswire.com

Sumitomo Pharma America Presents New Data on Nuvisertib and Enzomenib at the 2024 American Society of Hematology Annual Meeting

Latest results in Phase 1/2 studies show promise for two investigational treatments for patients with relapsed/refractory blood and bone marrow cancers Nuvisertib (TP-3654), an investigational oral small molecule highly selective PIM1 kinase inhibitor, is being evaluated in a Phase 1/2 study in patients with relapsed/refractory myelofibrosis Enzomenib (DSP-5336), an investigational, oral small molecule designed to inhibit the menin and KMT2A protein interaction, is being evaluated in a Phase 1/2 study in patients with relapsed/refractory acute leukemia MARLBOROUGH, Mass., Dec. 9, 2024 /PRNewswire/ -- Sumitomo Pharma America, Inc. (SMPA) today presented new clinical data supporting further development of nuvisertib, an investigational small molecule being researched for the treatment of relapsed/refractory myelofibrosis (MF), and enzomenib, an investigational oral small molecule being researched for relapsed/refractory acute leukemia, at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition. Preliminary data presented from the ongoing Phase 1/2 study of nuvisertib monotherapy (N=74) in patients with relapsed/refractory MF show nuvisertib was well tolerated with no dose-limiting toxicities (DLTs). Preliminary data in evaluable patients showed clinical activity including spleen volume reduction (SVR25 of 22.2%), symptom reduction (TSS50 of 44.4%), and bone marrow fibrosis (47.8% patients) and hemoglobin (25% patients) and platelet count (27.6% patients) improvement. Additional data presented show nuvisertib treatment led to significant cytokine modulation (e.g. EN-RAGE, IL-18, MIP-1β, and adiponectin) over time correlating with spleen and symptom responses. The global study has been expanded to evaluate nuvisertib add-on to ruxolitinib, the first approved Janus-associated kinase (JAK) inhibitor, and in combination with momelotinib, a recently approved JAK inhibitor for MF patients with anemia, to assess safety and potential clinical activity. 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). The study population was diverse, with 47.6% non-white (40/84), and also heavily pre-treated, with a median of 3 prior regimens. 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. Also presented were clinical activity results from the dose optimization cohorts at the dose levels of 200 mg BID and 300 mg BID. The data included results from all patients with KMT2A rearrangement (KMT2Ar) or NPM1 mutation (NPM1m) who had received at least one dose of enzomenib and who had not received a menin inhibitor previously. In 23 patients with KMT2Ar, the Objective Response Rate (ORR) using ELN 2017 criteria was 65.2% (15/23) and the proportion to achieve CR+CRh was 30.4% (7/23). In the subset of patients with KMT2Ar to receive 300 mg BID (n = 15), the ORR was 73.3% (11/15) and CR+CR was 40% (6/15). In the 17 total patients with NPM1 mutation (NPM1m) who received 200 mg BID or 300 mg BID, the ORR was 58.8% (10/17) and the proportion to achieve CR+CRh was 47.1% (8/17). The 400 mg BID dose optimization cohort is ongoing, with 21 patients enrolled as of the clinical cut-off and data planned for presentation at a future conference. These encouraging clinical activity results combined with an excellent safety profile suggest that enzomenib may play an important role in the treatment of patients with relapsed/refractory acute leukemia with KMT2A rearrangement or NPM1 mutation. "These data signal growing momentum in our oncological pipeline and an important milestone in our development of new treatments for relapsed/refractory MF and acute leukemia," said Tsutomu Nakagawa, Ph.D., President and Chief Executive Officer of SMPA. "With these promising results in hand, we remain committed to advancing nuvisertib and enzomenib as we believe our investigational therapies may have the potential to improve the lives of patients living with these critical cancers who do not respond to currently available therapeutics." MF is a rare type of blood cancer that is characterized by the buildup of fibrous tissue in the bone marrow, which can affect the production of blood cells. This buildup is caused by a dysregulation in the JAK signaling pathway. MF is a serious and rare disease with 0.7 new cases per 100,000 people worldwide each year.4 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.1 Approximately 30% of AML patients have NPM1 mutations2 and 5-10% of AML patients have KMT2A (MLL) rearrangements.3 "Patients and families living with incurable cancers of MF and AML are in need of new treatment options – and we are encouraged by the promising clinical activity for both nuvisertib and enzomenib," said Jatin Shah, M.D., Chief Medical Officer, Oncology, SMPA. "This additional preliminary data reinforces the strong potential for PIM1 inhibition in myelofibrosis, and for menin inhibitors in acute leukemia." About enzomenib (DSP-5336) Enzomenib (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.5,6 In preclinical studies, enzomenib has shown selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations.5,7 Enzomenib 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.8,9 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). The FDA granted Orphan Drug Designation for enzomenib for the indication of acute myeloid leukemia in June 2022. The FDA granted Fast Track Designation for enzomenib for the indication of relapsed or refractory acute myeloid leukemia with MLLr or NPM1m in June 2024. The PMDA granted Orphan Drug Designation for enzomenib for the indication of relapsed or refractory acute myeloid leukemia with MLLr or NPM1m in September 2024. About nuvisertib (TP-3654) Nuvisertib (TP-3654) is an oral investigational selective inhibitor of PIM1 kinase, which has shown potential antitumor and antifibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.10,11 Nuvisertib was observed to inhibit proliferation and induce apoptosis in murine and human hematopoietic cells expressing the clinically relevant JAK2V617F mutation.10 Nuvisertib alone and in combination with ruxolitinib showed white blood cell and neutrophil count normalization, and also reduced spleen size and bone marrow fibrosis in JAK2V617F and MPLW515L murine models of myelofibrosis.11 The safety and efficacy of nuvisertib is currently being clinically evaluated in a Phase 1/2 study in patients with intermediate and high-risk myelofibrosis (NCT04176198). The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for nuvisertib for the indication of myelofibrosis in May 2022. The PMDA granted Orphan Drug Designation for nuvisertib for the indication of myelofibrosis in November 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, 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 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: . 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 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. Hernández-Boluda J-C, Czerw T. Transplantation Algorithm for Myelofibrosis in 2022 and Beyond. Best Practice & Research Clinical Haematology. June 2022, 101369. doi: 10.1016/j.beha.2022.101369 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. 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: . Foulks JM, Carpenter KJ, Luo B, et al. A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. Neoplasia. 2014;16(5):403-412. Dutta A., Nath D, Yang Y, et al. Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models. Leukemia. 2022; 36 (3): 746-759. doi: 10.1038/s41375-021-01464-2. For a copy of this release, visit Sumitomo Pharma America's website at . SOURCE Sumitomo Pharma America WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Orphan DrugClinical ResultASHFast Track

17 Jul 2024

·www.pharmaceutical-technology.com

FDA issues CRL to Orexo’s NDA for opioid overdose medication

In September last year, the company submitted the NDA to the FDA seeking approval for the product. Credit: luchschenF / Shutterstock. The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) to Orexo regarding a new drug application (NDA) for its high-dose naloxone rescue medication, OX124, designed to counteract opioid overdoses. The company submitted the NDA to the FDA in September 2023. The US regulator is seeking an additional human factors (HF) study, consistent with prior communications. Further technical data on the final commercial product was also sought by the FDA, with no additional clinical or non-clinical studies needed. The company has already conducted a new HF study to comply with the FDA’s requirements. However, the request for additional technical data on commercial-scale manufacturing was not anticipated. See Also: Sumitomo Pharma’s DSP-5336 gains FDA fast track for AML AstraZeneca completes Amolyt Pharma acquisition Orexo will now work with the FDA to provide the necessary information and aims to resubmit the NDA promptly. The FDA’s review following resubmission could take up to six months. Orexo states that the technical data required by the FDA was generated during pilot-scale production and included in the initial NDA. However, the FDA has sought data from established commercial-scale manufacturing. Once approved, OX124 is expected to address the need for medications and higher naloxone dosages, especially due to the prevalence of synthetic opioids such as fentanyl, which are implicated in 92% of all fatal opioid overdoses. OX124’s formulation is designed for quick absorption and increased bioavailability, to reverse the effects of synthetic opioid overdose. Orexo president and CEO Nikolaj Sørensen stated: “I am impressed by the vigour and agility of the teams in Sweden and the US in addressing the FDA’s concerns from April regarding the instructions for use and our ability to complete a new human factors study shortly. However, I am surprised by the agency´s other requests with regard to additional technical data from the final commercial product, but confident we can address this efficiently. “We remain confident that our powerful life-saving medication, OX124, can contribute to reducing the steep number of Americans who die from overdoses caused by the increasingly prevalent synthetic opioids.”

NDAFast Track

17 Jul 2024

·www.pharmaceutical-technology.com

CatalYm secures $150m to advance GDF-15-targeting immune modulator

This $150m funding round builds on a $51m Series C round in November 2022. Credit: ma_Design via Shutterstock. German cancer biotech CatalYm has secured $150m in a Series D funding round following the recently announced data for its lead monoclonal antibody visugromab. The company has centred its pipeline on drugs targeting GDF-15 or growth differentiation factor-15, which acts as a key regulator of immune resistance to cancer therapies. The company was in the news earlier this year, when it shared follow-up data of its drug visugromab showing efficacy in heavily pretreated patients. The new funding, led by Canaan Partners and Bioqube Ventures, is set to fund the company’s planned Phase IIb trial of visugromab in select checkpoint-naïve front-line and second-line treatment settings. The drug has so far been studied in combination with Bristol Myers Squibb’s (BMS) anti-PD-1 drug Opdivo (nivolumab) in patients with non-squamous non-small cell lung cancer (NSCLC), hepatocellular cancer, and urothelial cancer. CatalYm presented data from the ongoing GDFATHER Phase I/IIa trial (NCT04725474) that is testing this combination at the American Society of Clinical Oncology (ASCO) meeting held in Chicago, on 2 June. Across all tumour types, patients who received visugromab showed an objective response rate of 16.7%. The average duration of response surpassed 15 months for NSCLC, and 14 months for urothelial cancer, with 77% of the patients’ responses still ongoing. These 90 patients were heavily pretreated and had experienced failed anti-PD-1 therapies in the past. See Also: Sumitomo Pharma’s DSP-5336 gains FDA fast track for AML AstraZeneca completes Amolyt Pharma acquisition Anti PD-1 checkpoint inhibitor drugs, such as BMS’ Opdivo, enhance the immune system’s ability to fight cancer by blocking the PD-1 receptor on T cells, a checkpoint that normally helps keep immune responses in check. Cancer cells often exploit this pathway to avoid being attacked by the immune system. Elevated GDF-15 levels in cancers can cause anti-PD-1 drugs to fail by creating an immunosuppressive tumour environment that hinders T cell activation and recruitment, which visugromab is designed to target. Checkpoint inhibitors have pulled in billions over the last few years. MSD’s PD-1 checkpoint inhibitor Keytruda (pembrolizumab) was the world’s top-selling drug last year, making $25bn. BMS’ Opdivo generated $9bn in the same year, as per the company financials. One of the reasons for the high sales is the drugs’ ability to be paired with other anti-cancer medicines. In the announcement accompanying the funding, CatalYm’s CEO Phil L’Huillier said: “We continue to demonstrate visugromab’s potential to induce cancer remission depth and durability across multiple solid tumour indications, emphasising the substantial role that visugromab could play in a novel anti-cancer therapy regimen.”

ImmunotherapyASCOPhase 2Clinical ResultAcquisition

100 Deals associated with Enzomenib

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Phase 2	US	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	JP	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	BE	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	CA	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	FR	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	IT	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	SG	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	KR	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	ES	Sumitomo Pharma America, Inc.	28 Feb 2022
Acute Lymphoblastic Leukemia	Phase 2	TW	Sumitomo Pharma America, Inc.	28 Feb 2022

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