OP-2100 / Ohara Pharma - LARVOL DELTA

METABOLIC REWIRING VIA METFORMIN RESTORES VENETOCLAX SENSITIVITY IN AML (EHA 2026) - P | "The DNMT1-targeting hypomethylating agent OR-2100 (decitabine prodrug; jRCT2071220035) was evaluated alone or in combination with MET. MET reprograms metabolic rewiring leading to downregulation of MCL1 and upregulation of BAX. The combination treatment of VEN, MET, and OR-2100 may constitute a clinically feasible metabolic-priming approach."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BAX • DNMT1 • MCL1

CRBN-INDEPENDENT IKZF1 DEGRADATION VIA TRIM21 BY DNA DEMETHYLATING AGENTS AS A NOVEL THERAPEUTIC MECHANISM FOR MULTIPLE MYELOMA (EHA 2026) - P | "Aims This study aimed to examine the efficacy of a new DNA demethylating agent, OR2100 which we developed as an orally bioavailable decitabine prodrug, on a multiple myeloma...Furthermore, TRIM21 knockdown or proteasome inhibition (bortezomib) attenuated the OR2100 ‑ induced decrease in IKZF1, with TRIM21 knockout reducing IKZF1 ubiquitination, supporting TRIM21 ‑ mediated, ubiquitin–proteasome–dependent degradation...Summary/Conclusion We demonstrated that DNA hypomethylation induced by OR2100 upregulates TRIM21 and reduces IKZF1, an essential survival factor for myeloma cells, thereby exerting antitumor effects in a CRBN ‑ independent manner. We are currently conducting a Phase I study of OR2100 for myelodysplastic syndrome (MDS), with the first step being to obtain approval for the treatment of MDS in Japan (jRCT2071220035), and we hope that OR2100 will be approved for the treatment of MM."

Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Targeted Protein Degradation • CRBN • IKZF1 • TRIM21

PHASE I STUDY OF OP-2100, AN ORALLY BIOAVAILABLE PRODRUG OF DECITABINE, FOR PATIENTS WITH RELAPSED OR REFRACTORY HIGH-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA (EHA 2026) - P | "By IPSS-R, 3 patients (27.3%) were intermediate, 3 (27.3%) high, and 5 (45.5%) very high risk; 10 patients (90.9%) had received prior azacitidine. At 50 mg, OP-2100 achieved a sustained-release PK profile and an AUC equivalent intravenous DEC. These results support further investigation on the 50 mg dose in Phase II studies."

Clinical • P1 data • Chronic Myelomonocytic Leukemia • Constipation • Gastroenterology • Gastroesophageal Reflux Disease • Gastrointestinal Disorder • Hematological Malignancies • Leukemia • Leukopenia • Myelodysplastic Syndrome • Neutropenia • Thrombocytopenia

Orally available decitabine prodrug OR-2100 induces mitotic perturbation for the treatment of double-hit lymphoma. (PubMed, Blood Neoplasia) - "The standard chemoimmunotherapy comprising R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) yields an unsatisfactory treatment response. The combination of CHOP and OR-2100 reduced the tumor weight significantly in a xenograft mouse model without increased toxicities. The induction of mitotic perturbation might be a key antilymphoma mechanism for OR-2100, and the combination of OR-2100 and CHOP might be a promising treatment strategy for DHL."

Journal • B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BIRC5 • CDCA8 • DNMT1 • E2F1 • MYC • TP53

ORALLY AVAILABLE DECITABINE PRODRUG OR-2100 TARGETS MITOSIS-ASSOCIATED GENES VIA THE RB/DREAM PATHWAY FOR DOUBLE-HIT LYMPHOMA (EHA 2025) - "Standard chemoimmunotherapy comprising rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) yields an unsatisfactory treatment response; more advanced therapeutic approaches are needed...Cell growth assays of azacitidine (AZA), decitabine (DAC), and OR-2100 were performed for five DHL cells (RC, DOHH2, OCI-Ly18, SU-DHL-10, and SU-DHL-6)... OR-2100 demonstrated anti-DHL efficacy especially for TP53-WT. OR-2100 plus CHOP might be an effective treatment option for DHL. OR-2100 downregulated the mitosis related genes and induced abnormal mitosis namely "mitotic perturbation" more profoundly than AZA."

IO biomarker • B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BIRC5 • CDCA8 • E2F1

DEGRADATION OF IKZF1 VIA E3 UBIQUITIN LIGASE X BY DNA DEMETHYLATING AGENTS IS A POTENTIAL THERAPEUTIC TARGET FOR MULTIPLE MYELOMA (EHA 2025) - "Aims: This study aimed to examine the efficacy of a new DNA demethylating agent, OR2100 which we developed as an orally bioavailable decitabine prodrug, on a multiple myeloma. We have demonstrated that DNA hypomethylation induced by OR2100 upregulates the E3 ubiquitin ligase X, leading to a decrease in IKZF1, a critical factor for the survival of myeloma cells, thereby exerting its antitumor effects. We are currently conducting a Phase I study of OR2100 for myelodysplastic syndrome (MDS), with the first step being to obtain approval for the treatment of MDS in Japan (jRCT2071220035), and we hope that OR2100 will be approved for the treatment of MM."

Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • CRBN • IKZF1

A Combination of Alectinib and DNA-Demethylating Agents Synergistically Inhibits Anaplastic-Lymphoma-Kinase-Positive Anaplastic Large-Cell Lymphoma Cell Proliferation. (PubMed, Cancers (Basel)) - "Crizotinib and alectinib are first- and second-generation ALK TKIs, respectively, approved for the treatment of ALK-positive ALCL (ALK ALCL) and ALK NSCLC...Thus, to improve the clinical outcomes of ALK ALCL therapy, we investigated the synergistic efficacy of the combination of alectinib and the DNA-demethylating agent azacytidine, decitabine, or OR-2100 (an orally bioavailable decitabine derivative)...The combination of alectinib and OR-2100 markedly altered gene expression in ALCL cells, including that of genes implicated in apoptotic signaling, which possibly contributed to the synergistic anti-ALCL effects of this drug combination. Therefore, alectinib and OR-2100 combination therapy has the potential to improve the outcomes of patients with ALK ALCL."

Journal • Chronic Myeloid Leukemia • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ALK • STAT3

Combination of a New Oral Demethylating Agent, OR2100, and Venetoclax for Treatment of Acute Myeloid Leukemia. (PubMed, Cancer Res Commun) - "The standard treatment for elderly patients with acute myeloid leukemia (AML) is venetoclax (Ven), a BCL-2-selective inhibitor, combined with hypomethylating agents (HMA) such as azacitidine or decitabine. The standard treatment for elderly patients with AML is Ven combined with HMAs. OR21, a new oral HMA plus Ven showed synergistic antileukemia effects in vitro and vivo, suggesting that the combination of OR2100 plus Ven is a promising candidate oral therapy for AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2

Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL. (PubMed, Blood Adv) - "Here, we investigated the effect of combination treatment with DNA demethylating agents (azacytidine (AZA), decitabine (DAC), and OR-2100 (OR21), which is silylated derivative of decitabine) and inhibitors of enhancer of zeste homolog 2 (EZH2) (EPZ-6438 and DS-3201b) which catalyze trimethylation of H3K27, in ATL. DUSP5 was downregulated by DNA methylation and H3K27me3 accumulation in the promoter region in HTLV-1-infected cells from ATL patients during ATL leukemogenesis. The present results demonstrate that dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth by restoring DUSP5, and the dual targeting of aberrant DNA and histone methylation is a feasible therapeutic approach for ATL."

Epigenetic controller • Journal • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD4

Adult T-cell leukemia-lymphoma acquires resistance to DNA demethylating agents through dysregulation of enzymes involved in pyrimidine metabolism. (PubMed, Int J Cancer) - "Recently, we reported that regional DNA hypermethylation in HTLV-1-infected T-cells reflects the disease status of ATL and the anti-ATL effects of DNA demethylating agents, including azacitidine (AZA), decitabine (DAC), and a new DAC prodrug, OR-2100 (OR21), which we developed. Both genomic mutations might lead to loss of protein expression. Thus, inactivation of UCK2 and DCK might be a putative cause of phenotypes that are resistant to AZA and DAC/OR21, respectively."

Clinical • Journal • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • DCK • DNMT1

Targeting DNMT1 by demethylating agent OR-2100 increases tyrosine kinase inhibitors-sensitivity and depletes leukemic stem cells in chronic myeloid leukemia. (PubMed, Cancer Lett) - "We investigated the efficacy of OR-2100 (OR21), the first orally available single-compound prodrug of decitabine...OR21 in combination with imatinib significantly suppressed tumor growth in a xenotransplant model...These results demonstrate that targeting DNMT1 using OR21 exerts anti-tumor effects and impairs LSCs in CML. Therefore, combination treatment of TKIs and OR21 represents a promising treatment strategy in CML."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • ABL1 • BCR • DNMT1

[VIRTUAL] ABERRANT EPIGENETIC REGULATION THROUGH METABOLIC REPROGRAMMING IN ATL LEUKEMOGENESIS (EHA 2021) - "OR-2100, which we developed as a novel decitabine prodrug with enhanced oral bioavailability, suppressed tumor cell growth and global DNA hypomethylation. Conclusion Based on these results, we think that the epigenetic state of some HTLV-1-infected cells is regulated by methionine metabolism. Targeting methionine incorporation or metabolism to change epigenetic reprogramming could constitute a novel therapeutic strategy for the treatment of ATL."

IO biomarker • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Effects of elevated temperature and pCO on the respiration, biomineralization and photophysiology of the giant clam Tridacna maxima. (PubMed, Conserv Physiol) - "We investigated physiological responses of 4-year-old Tridacna maxima to realistic levels of temperature (+1.5°C) and partial pressure of carbon dioxide (pCO) (+800 μatm of CO) predicted for 2100 in French Polynesian lagoons during the warmer season...Present thermal conditions (29.2°C) appeared to be sufficiently stressful to induce a host acclimatization response. All these observations indicate that temperature and pCO are both forcing variables affecting T. maxima's physiology and jeopardize its survival under environmental conditions predicted for the end of this century."

Journal

Population size, fertility, migration and life expectancy: Worldwide and Latin American changes for 2100 (PubMed, Rev Med Chil) - No abstract available

Clinical • Journal

The role of the European small ruminant dairy sector in stabilising global temperatures: lessons from GWP* warming-equivalent emission metrics. (PubMed, J Dairy Res) - "In our study, using this GWP* methodology and different modelling approaches, we first examined the historical (1990-2018) contribution of European dairy small ruminant systems to additional atmosphere warming levels and then studied different emission target scenarios for 2100...The estimations of warming for future scenarios suggest that to achieve climate neutrality, understood as not adding additional warming to the atmosphere, modest GHG reductions of sheep and goat GHG would be required (e.g. via feed additives). This reduction would be even lower if potential soil organic carbon (SOC) from associated pastures is considered."

Clinical • Journal

[VIRTUAL] Reinvigorating an Internal Audit Program: Augmenting Comprehensive Data Quality (TCT-ASTCT-CIBMTR 2021) - "Post-transplant data is evaluated on the 100-day 2450 follow-up form or 2100 comprehensive research form (CRF) and corresponding disease-specific form... Our audit workflow is designed to provide multiple levels of review, to recognize as many potential errors as possible, to guide further staff education, and to minimize future recurrence. Modifications under consideration include expansion of the audited data fields as well as development of disease-specific, cellular therapy and real-time audits."

Developmental Disorders • Transplantation

[VIRTUAL] Reinvigorating an Internal Audit Program: Augmenting Comprehensive Data Quality (TCT-ASTCT-CIBMTR 2021) - "Post-transplant data is evaluated on the 100-day 2450 follow-up form or 2100 comprehensive research form (CRF) and corresponding disease-specific form... Our audit workflow is designed to provide multiple levels of review, to recognize as many potential errors as possible, to guide further staff education, and to minimize future recurrence. Modifications under consideration include expansion of the audited data fields as well as development of disease-specific, cellular therapy and real-time audits."

Developmental Disorders • Transplantation

[VIRTUAL] Reinvigorating an Internal Audit Program: Augmenting Comprehensive Data Quality (TCT-ASTCT-CIBMTR 2021) - "Post-transplant data is evaluated on the 100-day 2450 follow-up form or 2100 comprehensive research form (CRF) and corresponding disease-specific form... Our audit workflow is designed to provide multiple levels of review, to recognize as many potential errors as possible, to guide further staff education, and to minimize future recurrence. Modifications under consideration include expansion of the audited data fields as well as development of disease-specific, cellular therapy and real-time audits."

Developmental Disorders • Transplantation

[VIRTUAL] Reinvigorating an Internal Audit Program: Augmenting Comprehensive Data Quality (TCT-ASTCT-CIBMTR 2021) - "Post-transplant data is evaluated on the 100-day 2450 follow-up form or 2100 comprehensive research form (CRF) and corresponding disease-specific form... Our audit workflow is designed to provide multiple levels of review, to recognize as many potential errors as possible, to guide further staff education, and to minimize future recurrence. Modifications under consideration include expansion of the audited data fields as well as development of disease-specific, cellular therapy and real-time audits."

Developmental Disorders • Transplantation

[VIRTUAL] Reinvigorating an Internal Audit Program: Augmenting Comprehensive Data Quality (TCT-ASTCT-CIBMTR 2021) - "Post-transplant data is evaluated on the 100-day 2450 follow-up form or 2100 comprehensive research form (CRF) and corresponding disease-specific form... Our audit workflow is designed to provide multiple levels of review, to recognize as many potential errors as possible, to guide further staff education, and to minimize future recurrence. Modifications under consideration include expansion of the audited data fields as well as development of disease-specific, cellular therapy and real-time audits."

Developmental Disorders • Transplantation

Impacts of hypoxic events surpass those of future ocean warming and acidification. (PubMed, Nat Ecol Evol) - "Here, we implemented sequential hierarchical mixed-model meta-analyses (721 control-treatment comparisons) to compare the impacts of oxygen conditions associated with the current and continuously intensifying hypoxic events (1-3.5 O mg l) with those experimentally yielded by ocean warming (+4 °C) and acidification (-0.4 units) conditions on the basis of IPCC projections (RCP 8.5) for 2100...Our findings call for a refocus of global change experimental studies, integrating oxygen concentration drivers as a key factor of ocean change. Given potential combined effects, multistressor designs including gradual and extreme changes are further warranted to fully disclose the future impacts of ocean oxygen loss, warming and acidification."

Journal

[VIRTUAL] A Novel Oral Demethylating Agent, or-2100, in Combination with Tyrosine Kinase Inhibitors Overcomes Resistance in Chronic Myeloid Leukemia (ESH - iCMLf 2020) - No abstract available

Combination therapy • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

Long-term environmental tolerance of the non-indigenous Pacific oyster to expected contemporary climate change conditions. (PubMed, Mar Environ Res) - "Neither predicted increases in seawater temperature nor reduced pH had a long-term physiological effect, indicating conditions predicted for 2100 will not affect adult physiology and survival. These results suggest that M. gigas will remain a globally successful NIS and predicted CCC will continue to facilitate their competitive dominance in the near future."

Journal

Multigenerational experimental simulation of climate change on an economically important insect pest. (PubMed, Ecol Evol) - "We designed a long term (i.e., over 10 generations), experimental simulation of climate change by increasing temperature and CO air concentration in controlled conditions according to model predictions for 2100...After 10 generations of simulation, genetic adaptation was detected for total lipid content only, however, other traits showed signs of such process. Future experimental designs and methods similar to ours, are key for studying long-term effects of climate change through multigenerational experimental designs."

Journal • Transplantation

Microdamage formation in individual bovine trabeculae during fatigue testing. (PubMed, J Biomech) - "Eight individual trabeculae were tested for 1500 cycles, six for 2100 cycles and seven for 3000 cycles (close to failure)...Only one to three large microdamage sites were observed in the central region, connected to the trabecular surface with small straight cracks. The presented procedure is a first step to better understand how microdamage formation is influenced by material properties in aged and diseased bone, independently of deteriorated trabecular microarchitecture."

Clinical • Journal • Fatigue • Osteoporosis • Rheumatology