sabatolimab (MBG453) / Novartis - LARVOL DELTA

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

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 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study. (PubMed, BMJ Open) - P1/2 | "Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types."

Combination therapy • IO biomarker • Journal • P2 data • Colorectal Cancer • Dermatology • Hematological Disorders • Infectious Disease • Lung Cancer • Melanoma • Musculoskeletal Diseases • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Renal Disease • Respiratory Diseases • Solid Tumor • CD8 • LAG3

Investigating the Therapeutic Potential of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes: A Comprehensive Review and Analysis (SOHO 2024) - "Interventions: Interventions include PD-1 inhibitors (eg, pembrolizumab, nivolumab), CTLA-4 inhibitors (eg, ipilimumab), TIM-3 inhibitors (eg, MBG453), and anti-CD47 monoclonal antibodies, administered as monotherapy or in combination with other agents such as HMAs (eg, azacitidine, decitabine). Combination therapies involving PD-1 and CTLA-4 inhibitors exhibit promising activity and tolerability. However, larger studies with longer follow-up are needed to fully understand the effectiveness of these regimens and identify biomarkers for response or resistance. The integration of ICIs into MDS treatment strategies has the potential to improve patient outcomes and advance personalized therapeutic approaches."

Checkpoint inhibition • IO biomarker • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • HAVCR2

CPDR001X2105: Study of PDR001 and/or MBG453 in Combination With Decitabine in Patients With AML or High Risk MDS (clinicaltrials.gov) - P1 | N=241 | Completed | Sponsor: Novartis Pharmaceuticals | Phase classification: P1b ➔ P1

Phase classification • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

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 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Aug 2024 ➔ Dec 2024 | Trial primary completion date: Aug 2024 ➔ Dec 2024

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

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=70 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Sep 2027 ➔ Feb 2028

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