sabatolimab (MBG453) / Novartis - LARVOL DELTA

EFFICACY AND OUTCOMES OF NOVEL THERAPEUTIC AGENTS AS MONOTHERAPY OR IN COMBINATION WITH CONVENTIONAL THERAPY IN MYELODYSPLASTIC SYNDROME: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2025) - "Newer agents included Rigosertib (41%, n=312/770), Imetelstat (15%, n=118/770), Pembrolizumab (8%, n=65/770), Enasidenib (9%, n=67/770), and Sabatolimab (7%, n=53/770) Ivosidenib (6%, 45/770), Elritercept 2%, n=15 /770), Pevonedistat (3%, 21/770), Emavusertib (2%, 15/770), Atezolizumab (6%, 46/770), and Olutasidenib (2%, n=13/770). The most commonly used conventional agent was azacitidine (19%, n= 147/770)... This study highlights promising results with the investigational agents for MDS. However, large studies with more power are needed to strengthen our understanding of these investigational agents in MDS patients."

Combination therapy • Monotherapy • Retrospective data • Review • Anemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia

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

STIMULUS-AML2: Sabatolimab as a Treatment for Patients With Acute Myeloid Leukemia and Presence of Measurable Residual Disease After Allogeneic Stem Cell Transplantation. (clinicaltrials.gov) - P1/2 | N=24 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; Study was stopped following a strategic decision from the Sponsor. It was not based on any safety findings or safety concerns with sabatolimab.

Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation

Little to show for much effort and investment: An industry perspective on MDS drug development (MDS 2025) - "Randomized studies incorporated lenalidomide, vorinostat, entinostat (MS-275), durvalumab, valproic acid, idarubicin, eltrombopag, pevonedistat (MLN4924), eprenetapopt (APR-246), sabatolimab (MBG453), magrolimab (Hu5F9-G4), or tamibarotene (SY-1425)...While the approval of luspatercept and imetelstat for lower-risk patients provides a glimmer of hope, this track record of failure in higher-risk MDS is enough to make a prudent investor or senior pharmaceutical executive think twice before committing further resources to development in this difficult group of diseases...Nor is it because the existing therapies are so good that they're hard to beat, although the practice of giving a few cycles of azacitidine or decitabine in local clinics before referring a patient to a trial center has been an unfortunate barrier to accrual...In this session I will discuss some potential fixes for a few of these problems. But solutions to other barriers are less clear, and will require..."

Acute Myelogenous Leukemia • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • FLT3 • TP53

Immunomodulation and immunotherapy in MDS (MDS 2025) - "Abstract Body The standard of care for higher risk myelodysplastic syndromes (MDS) has unfortunately been unchanged for almost 2 decades with hypomethylating agent therapy (HMA, i.e. azacitidine), representing the only agent to have a positive phase 3 trial to date in this patient population with improved overall survival (OS) versus conventional care therapy that included best supportive care, low-dose cytarabine, or intensive chemotherapy...The two most heavily investigated novel IO agents are the CD47 inhibitor magrolimab and the anti-TIM inhibitor sabatolimab...Ideally, future translational data in earlier randomized studies will improve our understanding of novel IO therapies to better inform pivotal trials and subsets of patients that will best respond as well as mechanisms of resistance. Hopefully, we will have our first breakthroughs in HR-MDS and TP53 mutant MDS/AML patients in the near future."

Immunomodulating • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53

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

STIMULUS-AML-1: A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy (clinicaltrials.gov) - P2 | N=90 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; The study was terminated because results from 2 trials in the program were negative (including the main trial) and Novartis decided to terminate the program all together.

Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

STIMULUS-MDS1: A Study of MBG453 in Combination With Hypomethylating Agents in Subjects With IPSS-R Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS). (clinicaltrials.gov) - P2 | N=127 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; In December 2023, Novartis decided to terminate the sabatolimab clinical development program early after Phase II and III studies failed to meet their primary objectives. The termination was not due to safety concerns.

Trial termination • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

STIMULUS-MDS3: A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants (clinicaltrials.gov) - P2 | N=20 | Completed | Sponsor: Novartis Pharmaceuticals | Terminated ➔ Completed

Trial completion • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

STIMULUS-MDS2: Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2) (clinicaltrials.gov) - P3 | N=530 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; Despite positive trends identified post unblinding after Overall Survival primary analysis, the study did not show statistical significance in its primary endpoint, overall survival. No new safety findings were detected.

Trial termination • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

STIMULUS-AML-1: A Study of MBG453 in Combination With Azacitidine and Venetoclax in AML Patients Unfit for Chemotherapy (clinicaltrials.gov) - P2 | N=90 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Roll-over Study for Patients Who Have Completed a Prior Novartis-sponsored Sabatolimab (MBG453) Study and Are Judged by the Investigator to Benefit From Continued Treatment With Sabatolimab. (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Nov 2025 ➔ Feb 2028 | Trial primary completion date: Nov 2025 ➔ Feb 2028

Trial completion date • Trial primary completion date • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Roll-over Study for Patients Who Have Completed a Prior Novartis-sponsored Sabatolimab (MBG453) Study and Are Judged by the Investigator to Benefit From Continued Treatment With Sabatolimab. (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=70 ➔ 33 | Trial completion date: Feb 2028 ➔ Nov 2025 | Trial primary completion date: Feb 2028 ➔ Nov 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • 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=12 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting | Initiation date: Apr 2025 ➔ Dec 2024

Enrollment open • Trial initiation date • Acute Myelogenous Leukemia

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

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

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

STIMULUS-AML2: Sabatolimab as a Treatment for Patients With Acute Myeloid Leukemia and Presence of Measurable Residual Disease After Allogeneic Stem Cell Transplantation. (clinicaltrials.gov) - P1/2 | N=24 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Aug 2024 | Trial primary completion date: Dec 2024 ➔ Aug 2024

Trial completion • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation

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=12 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P1/2 trial • Acute Myelogenous Leukemia

STIMULUS-MDS2: Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2) (clinicaltrials.gov) - P3 | N=530 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Managing the unmanageable: evidence-driven approaches to real-world patient prototypes of TP53-mutant myelodysplastic neoplasms and acute myeloid leukemia. (PubMed, Leukemia) - "The debate regarding whether allogeneic stem cell transplant should be offered to these patients is summarized. Finally, this review explores the recent unfortunate news of pauses in clinical trials for the leading investigational agents - eprenetapopt, magrolimab, sabatolimab, and idasanutlin - and offers solutions toward re-invigorating the pipeline of precision therapeutics in 2025."

Journal • Real-world • Real-world evidence • Review • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

STIMULUS MDS-US : Sabatolimab Added to HMA in Higher Risk MDS (clinicaltrials.gov) - P2 | N=39 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS) (clinicaltrials.gov) - P1 | N=52 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business decision

Combination therapy • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Myelofibrosis

Role of TIM-3 in regulating anti-tumor immunity in AML (CRI-ENCI-AACR ICIC 2024) - "In fact, the anti-Tim-3 antibody (MBG453, Sabatolimab) has shown a promising response rate in AML/myelodysplastic syndrome (MDS) patients...Overall, the characterization of the TIM-3 blockade in both AML cells and immune cells in leukemia will provide critical information for understanding the use of checkpoint inhibitors in the treatment of liquid tumors, in which PD-1 blockade has shown limited efficacy. As anti-TIM-3 might suppress AML cell growth and boost anti-tumor immune response, this strategy may have a "one stone kills two birds" effect, which could provide new immune-based therapeutic rationale and regimens for tackling blood cancers."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • CD8 • HAVCR2 • IFNG • PTPRC