sabatolimab (MBG453) / Novartis - LARVOL DELTA

PRIMARY RESULTS STIMULUS-AML1: A LARGE, INTERNATIONAL, PHASE II STUDY OF SABATOLIMAB COMBINED WITH AZACITIDINE AND VENETOCLAX AS FRONTLINE THERAPY FOR UNFIT ACUTE MYELOID LEUKEMIA (AML) PATIENTS (PTS) (EHA 2025) - P2 | "Despite an observed CR rate higher than in historic controls (DiNardo et al. NEJM 2021), STIMULUS-AML1 results did not achieve the predetermined statistical significance over AZA+VEN. The combination of SABA with AZA+VEN is feasible without evidence of increased toxicity."

Clinical • IO biomarker • P2 data • Acute Myelogenous Leukemia • Constipation • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • HAVCR2 • TP53

Νοvel Therapies in High-Risk Myelodysplastic Syndromes. (PubMed, Eur J Haematol) - "Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies."

Journal • Review • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • HAVCR2 • IDH1 • IDH2

Few Drug Approvals in MDS: Lessons and Insights from a Decade of Clinical Trials (ICKSH 2026) - "Aside from allogeneic transplantation, the current standard of care approach for higher -risk myelodysplastic syndromes/neoplasms (HR -MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazurid ine...In this lecture , I will discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR -246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, I will advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, I will emphasize the need for the scientific community to access patient -level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials."

Clinical • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • TP53

MBG453 in Lower Risk MDS (clinicaltrials.gov) - P2 | N=10 | Terminated | Sponsor: Massachusetts General Hospital | N=20 ➔ 10 | Trial completion date: Nov 2026 ➔ Nov 2025 | Active, not recruiting ➔ Terminated; The trial closed early due to changes in support for the study drug.

Enrollment change • Trial completion date • Trial termination • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

ALLG AMLM26 INTERCEPT (Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in AML): A Multi-arm, Precision-based, Recursive, Platform Trial (clinicaltrials.gov) - P1/2 | N=3 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | N=12 ➔ 3 | Recruiting ➔ Active, not recruiting

Enrollment change • Enrollment closed • Acute Myelogenous Leukemia

[VIRTUAL] Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients with Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS): Updated Results from a Phase 1b Study (ASH 2020) - P1b | "Study Design and This is a phase Ib, open-label, multicenter, dose-escalation study of sabatolimab + HMA (decitabine [Dec] or azacitidine [Aza]) in patients (pts) with AML or HR-MDS (NCT03066648). Sabatolimab + HMA is well tolerated in pts with AML and HR-MDS and continues to show promising antileukemic activity and emerging durability. These results support TIM-3 as a potential therapeutic target and provide a basis for further development of sabatolimab + HMA in pts with AML or higher-risk MDS. Co-senior authors Uma Borate and Andrew H. Wei contributed equally to the work."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Endocrine Disorders • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Rheumatology • Septic Shock • Thrombocytopenia • Transplantation • HAVCR2

ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis. (PubMed, Blood Adv) - P1/2 | "Forty-four patients were enrolled in Part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821."

Journal • Hematological Disorders • Myelofibrosis • Neutropenia • Thrombocytopenia • GDF15

Primary Results of Stimulus-MDS1: A Randomized, Double-Blind, Placebo-Controlled Phase II Study of TIM-3 Inhibition with Sabatolimab Added to Hypomethylating Agents (HMAs) in Adult Patients with Higher-Risk Myelodysplastic Syndromes (MDS) (ASH 2022) - P2, P3 | "Pts were randomized 1:1 to sabatolimab+HMA or placebo+HMA and stratified by risk category (per investigator assessment) and type of HMA (azacitidine [AZA] or decitabine [DEC]; per investigator discretion). Additional exploratory and biomarker analyses will be reported in the meeting. The ongoing Ph III STIMULUS-MDS2 with a primary endpoint of OS (NCT04266301) has completed accrual and will definitively inform on the impact of sabatolimab in higher-risk MDS."

Clinical • IO biomarker • P2 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Constipation • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Inflammation • Leukopenia • Myelodysplastic Syndrome • Neutropenia • Pneumonia • Thrombocytopenia • Transplantation • HAVCR2

PRIMARY RESULTS OF THE PHASE III STIMULUS-MDS2 STUDY OF SABATOLIMAB + AZACITIDINE VS PLACEBO + AZACITIDINE AS FRONTLINE THERAPY FOR PATIENTS WITH HIGHER-RISK MDS OR CMML-2 (EHA 2024) - P2, P3 | "Despite a favorable trend in OS, CR rate, PFS, and LFS, STIMULUS-MDS2, to our knowledge the largestrandomized trial conducted in higher-risk MDS, did not meet its primary EP of OS. The safety profile ofSABA+HMA was consistent with Ph Ib/II trials. Additional analyses will be provided at the meeting."

Clinical • P3 data • Anemia • Chronic Myelomonocytic Leukemia • Fatigue • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia

Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial. (PubMed, Lancet Haematol) - P2 | "The addition of sabatolimab to hypomethylating agents in this study did not result in a significant improvement in complete response rates or progression-free survival. Sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes. A randomised phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting."

Journal • P2 data • Constipation • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Inflammation • Leukopenia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Thrombocytopenia • HAVCR2

TIM-3 Inhibitor Sabatolimab for Patients with Acute Myeloid Leukemia (AML) with Measurable Residual Disease (MRD) Detected after Allogeneic Stem Cell Transplantation (AlloSCT): Preliminary Findings from the Phase Ib/II Stimulus-AML2 Study (ASH 2023) - P1/2 | "In adult pts with AML who are in hematological CR with MRD+ after alloSCT, sabatolimab 400 mg and 800 mg monotherapies were well tolerated. Cytopenias occurred at low rates, were generally G1–2 and mostly related to imminent relapse. Importantly, there were no cases of GvHD reported or any immune-related AEs commonly seen with checkpoint inhibitors."

Clinical • P1/2 data • Residual disease • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Neutropenia • Oncology • Thrombocytopenia • Transplantation • CD34 • HAVCR2 • IDH2 • NPM1 • WT1

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

Clinical characteristics and molecular profiling of SF3B1-mutated myelodysplastic syndrome (MDS) in a real-world practice (ASH 2025) - "Seven of the 19 patients received treatment for MDS – 4 received a hypomethylating agent, 1 was recruited onto the MBG453 trial (Tim-3 Antibody), 2 received intensive chemotherapy, and one went on to receive allogeneic hematopoietic stem cell transplant...We demonstrated that the number and type of co-mutations affected the prognosis of patients. Identifying these features is crucial for risk stratification and personalized treatment in MDS."

Clinical • IO biomarker • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • HAVCR2 • SF3B1

Elevated TIM3 expression on bone marrow T cells drives immune dysfunction in early relapsed blood cancer after allogeneic hematopoietic stem cell transplantation (ASH 2025) - "And we performed cytotoxicity assay with BM T cell from thepatients using sabatolimab (TIM3 blockade)... our data reveal that early post-transplant relapse is associated with TIM3-mediated immunedysfunction in both DNT and Treg populations. Elevated TIM3 expression contributes to impaired T cellcytotoxicity and increased immunosuppressive tumor microenvironment. Importantly, the TIM3 blockaderestored cytotoxic function in vitro, suggesting a promising therapeutic approach for patientsexperiencing early relapse after allo-HSCT."

IO biomarker • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • CCR7 • CD226 • CD8 • FAS • FASLG • GZMA • GZMB • HAVCR2 • IFNG • IKZF2 • IL2RA • IL6 • IL7R • LAG3 • PRF1 • TIGIT • TNFA

Anti-TIM3 with hypomethylating agent revives NK and cytotoxic CD4+ T cell activity in patients with AML or MDS (ASH 2025) - P1 | "TIM3 is acheckpoint molecule expressed both on immune and leukemic cells, making it an interestingtarget in AML.Here, we conducted a comprehensive immunomonitoring of a phase Ib trial (NCT03066648)evaluating decitabine in combination with anti-TIM3 antibody sabatolimab (MBG453). We demonstrate that TIM3 blockade modulates the immune landscape by activatingmature and adaptive NK cells, promotes cytotoxic CD4+ T cells, and primes small CD8+ T cellclones for expansion. Our results suggest that cytotoxic CD4+ T-LGLL cells may boost responses toimmune checkpoint therapy in AML."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CD4 • CD8 • IFNG • PD-L1

Sabatolimab in Combination with Hypomethylating Agents (HMAs) Was Safe in Patients (Pts) with Intermediate-, High-, or Very-High-Risk Myelodysplastic Syndrome (MDS) (ASH 2023) - P2 | "Pts received an HMA of investigator's choice (decitabine/cedazuridine 35 mg/100 mg oral days 1-5, decitabine 20 mg/m2 IV days 1-5, or azacitidine 75 mg/m2 IV or subcutaneous [SC] days 1-7 or days 1-5 plus days 8 and 9) with sabatolimab 800 mg IV every 4 weeks starting at day 8 or any day between days 5 to 8. This interim analysis of the STIMULUS-MDS US study demonstrated that sabatolimab in combination with an oral, IV, or SC HMA was safe and well tolerated, with AEs consistent with previous reports for pts with MDS treated with HMAs. Response rates for the combination are preliminary, and more information will be provided with longer follow-ups."

Clinical • Combination therapy • Anemia • Cardiovascular • CNS Disorders • Febrile Neutropenia • Hematological Malignancies • Hypertension • Infectious Disease • Myelodysplastic Syndrome • Neutropenia • Pneumonia • Respiratory Diseases

Single-Cell Multiomics Analysis Reveals Potential Drivers of Response to the Anti-TIM3 Inhibitor Sabatolimab Combined with Azacitidine in MDS and CMML (ASH 2023) - P1 | "Conversely, we observed a down-regulation of metallothionein genes (MT1E, MT1G, MT2A) as well as a collection of transcription factors (NR4A1, FOSL2, JUN, CEBPB, CEBPD), NF-κB inhibitors (NFKBIZ, NFKBIA) and CXCL8 in the post-treatment samples (FDR <0.1). Conclusions Our study provides one of the most comprehensive evaluations of the cellular dynamics of anti-TIM3 immunotherapy in patients to date, allowing for the nomination of novel putative predictive biomarkers of response and identification of potential immunomodulatory mechanisms induced by the combination of sabatolimab with azacitidine in MDS and CMML for further future analysis."

IO biomarker • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • CD74 • CD8 • CEBPB • CXCL8 • FOSL2 • GZMA • HLA-DPA1 • HLA-DRB1 • IFI27 • IFIT1 • IFIT2 • IFNG • IL32 • MT1E • NFKBIA • NR4A1

Clinical Characteristics and Outcomes of Myeloid Neoplasms with Mecom Rearrangement: Results from a Nationwide Multicenter Study (ASH 2023) - "Among 3 MDS with MECOM rearrangement, one patient received azacitidine with investigational drug (sabatolimab/placebo) and achieved complete hematologic response. Chemotherapy should be avoided in this subtype due to non-responsiveness, hypomethylating agent showed benefit and can be considered as a bridging treatment before stem cell transplantation. Novel therapy targeting MECOM gene should be further explored to improve outcomes in this AML subtype."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • MECOM

Molecular Measurable Residual Disease (MRD) Clearance (≤1%) Is Associated with Improved Clinical Outcomes in Patients with Higher-Risk Myelodysplastic Neoplasms (HR-MDS): An Exploratory Analysis of Stimulus-MDS1 in Patients Receiving Sabatolimab or Placebo + Hypomethylating Agent (HMA) (ASH 2023) - P2, P3 | " Treatment-naive pts aged ≥18 years with intermediate (+ ≥5% bone marrow [BM] blasts), high or very high risk MDS by Revised International Prognostic Scoring System were randomized to sabatolimab or placebo added to azacitidine/decitabine (Zeidan AM, et al. We present the first results from a prospective, controlled, randomized study demonstrating the potential prognostic value of MRD for PFS and OS in HR-MDS. Our results demonstrate high NGS concordance between PBMC and BMMC on-treatment samples, indicating that PBMC could represent an alternative for clonal monitoring. Interestingly, more pts treated with sabatolimab + HMA reached MRD negativity while in remission, potentially explaining the longer DoR in pts receiving sabatolimab + HMA vs placebo + HMA."

Clinical • Clinical data • IO biomarker • Residual disease • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • ASXL1 • DNMT3A • TET2

Safety and Activity of the TIM3 Inhibitor Sabatolimab in Patients with Lower-Risk Myelodysplastic Syndromes (ASH 2024) - "Sabatolimab combined with azacitidine was studied in the phase III STIMULUS MDS2 study in higher-risk MDS, which failed to reach its primary endpoint; responses in that trial modestly favored the combination and no new safety signals were identified. Sabatolimab produced hematological responses in this cohort, including two patients with erythroid responses and one with neutrophil recovery. This study suggests clinical activity in blocking the TIM3 axis in lower-risk MDS and supports further evaluation of this target."

Clinical • Anemia • Atrial Fibrillation • Cardiovascular • Heart Failure • Hematological Disorders • Hematological Malignancies • Infectious Disease • Myelodysplastic Syndrome • Myocardial Infarction • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Thrombocytopenia • HAVCR2 • LGALS9

Clinical Features and Preliminary Investigation of PPM1D-Mutated Myeloproliferative Neoplasms (ASH 2024) - "74% (n=14) received hydroxyurea initially, 11% (n=2) received HMA containing therapy and 11% (n=2) were observed or treated with phlebotomy. One patient who had CMML-2 with high-risk features was treated with azacitidine and sabatolimab at diagnosis...Thus, expanded clinical cohorts to further refine the relationship between PPM1D mutations and MPN disease phenotypes coupled with additional mechanistic studies of PPM1D in MPN pathogenesis are required. These findings underscore the complexity of MPNs and highlight avenues for future exploration in precision medicine for patients with PPM1D mutations."

Clinical • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • CALR • JAK2 • PPM1D

Combined PD-1 and Tim-3 Blockade Improves the in Vitro Anti-Myeloma Activity of T Cells of Patients on Talquetamab (ASH 2024) - P1, P2 | "We further established an in vitro assay to measure the cytotoxic capability of patient T cells obtained from different time points against the GPRC5D-expressing MM1S cell line in the presence of Tal with and without nivolumab and sabatolimab, targeting PD-1 and Tim-3, respectively. Presence of CD8+ Tem cells at baseline resulted in longer PFS, whereas more CD8+ TEMRA cells predicted shorter PFS. While our in vitro model has limitations, it shows that targeting the checkpoint markers PD-1 and Tim-3 may improve potency of BiAbs."

IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • CD8 • GPRC5D • HAVCR2 • PD-1 • SDC1

The role of TIM-3 in AML and its potential as a therapeutic target to enhance T cell-based cancer immunotherapy (DGHO 2025) - "Our study provides the first evidence of a combination therapeutic approach consisting of TCR-therapy along with hypomethylation drug and TIM-3 checkpoint-blockade as a potential strategy to circumvent immune evasion in AML. Further investigation on the role of TIM-3 and its potential in enhancing immunotherapy is ongoing."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HAVCR2 • LGALS9

The conundrum of drug development in higher-risk MDS: Lessons learned from recently failed phase 3 clinical trials. (PubMed, Blood) - "Aside from allogeneic transplantation, the current standard of care approach for higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazuridine...In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials."

Journal • P3 data • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

MBG453 in Lower Risk MDS (clinicaltrials.gov) - P2 | N=20 | Active, not recruiting | Sponsor: Massachusetts General Hospital | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2026 ➔ Nov 2026 | Trial primary completion date: Jun 2024 ➔ Nov 2024

Enrollment closed • Trial completion date • Trial primary completion date • Hematological Malignancies • Myelodysplastic Syndrome • Oncology