sabatolimab (MBG453)

P1/2, N=59, Recruiting, Novartis Pharmaceuticals | N=27 --> 59 | Trial completion date: Apr 2027 --> Aug 2024 | Trial primary completion date: Nov 2024 --> Jul 2024 | Active, not recruiting --> Recruiting

P2, N=70, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2028 --> Feb 2028

P2, N=90, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2026 --> Jul 2024 | Trial primary completion date: Mar 2026 --> Jul 2024

P2, N=90, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2025 --> Jun 2024 | Trial primary completion date: Jan 2024 --> Sep 2023

P1/2, N=0, Withdrawn, Novartis Pharmaceuticals | N=63 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=27, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=59 --> 27

P2, N=20, Recruiting, Massachusetts General Hospital | Not yet recruiting --> Recruiting | Trial completion date: Dec 2022 --> Jan 2026 | Trial primary completion date: Jun 2022 --> Jun 2024

P3, N=530, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2027 --> Sep 2024 | Trial primary completion date: Jan 2027 --> Sep 2024

P1/2, N=45, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Jul 2024

P1, N=16, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Notably, azacitidine + venetoclax, azacitidine + sabatolimab, and azacitidine + magrolimab have shown exciting results in large, single-arm studies and have completed accrual in placebo-controlled, double-blind studies with OS as a primary endpoint. We all eagerly await the results of these studies.

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.

Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia.

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.

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.

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.

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.

P1, N=33, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=90 --> 33 | Trial completion date: Sep 2024 --> May 2024 | Trial primary completion date: Sep 2024 --> May 2024

Galectin-9-induced effects on cytotoxicity can be abrogated using the clinical-grade anti-TIM-3 blocking antibody, MBG453...This may be due to higher intratumoral galectin-9 protein expression in HPV+ HNSCC lesions. Conclusions Our data stress the importance and complexity of TIM-3 in the context of NK cells and suggest that targeting the TIM-3/galectin-9 pathway may be a cogent immunotherapeutic strategy to reinvigorate NK cell effector function in HPV+ HNSCC patients.

P1, N=16, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2024 --> Sep 2025

P1/2, N=59, Recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2026 --> Mar 2027 | Trial primary completion date: Jun 2024 --> Oct 2024

P2, N=20, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P1b, N=241, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: May 2023 --> Sep 2023 | Trial primary completion date: Apr 2023 --> Sep 2023

In addition, the model predicted membrane-bound TIM-3 occupancy in the bone marrow was above 95% in over 95% of patients. Therefore, these results support the selection of the 400-mg Q2W and 800-mg Q4W dosing regimens for the STIMULUS clinical trial program.

A systematic literature review (SLR) was conducted using MEDLINE, Embase, and Cochrane to identify studies published in 2002-2022, explicitly targeting drug-induced myelosuppression with current and emerging treatments for MDS and/or AML (venetoclax [VEN], azacitidine [AZA], magrolimab, sabatolimab, decitabine [DEC], cedazuridine, lenalidomide [LEN], low-dose cytarabine [LDAC], intensive chemotherapy [IC]) in terms of drug- induced AEs, treatment discontinuation, quality of life (QOL), and medical resource use (MRU). This SLR suggests that combining ≥2 myelosuppressive drugs may result in increased toxicity; however, the lack of evidence on the impact of myelotoxicity on QOL and MRU with ≥2 myelosuppressive drugs limits informed decision-making in routine clinical practice. Further research is needed to explore the impact of drug-induced myelosuppression in patients with MDS or AML. Systematic review, MDS/AML, Myelosuppression

Here, we describe the aims and design of the phase III STIMULUS-MDS2 trial, which aims to demonstrate the potential for sabatolimab plus azacitidine to improve survival for patients with higher-risk MDS and CMML-2 (NCT04266301). Clinical Trial Registration: NCT04266301 (ClinicalTrials.gov).

These data supported the phase 3 study of APR-246 in combination with azacitidine versus azacitidine alone (NCT03745716)...We have reported the phase Ib study combining magrolimab with azacitidine in treatment-naïve higher risk MDS patients (26% with TP53 mutations) with the most recent data update at EHA 2022 11...Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune cells and myeloid leukemic progenitors 13...Lastly, venetoclax is an oral BCL-2 inhibitor with promising synergy with azacitidine and is a standard of care for elderly AML patients 15...TP53 mutant MDS/AML patients represent a molecular cohort with very poor outcomes and lack of disease modifying therapy. Ideally, future translational data will further elucidate the underpinnings driving the poor outcomes for this molecular subgroup to lead to additional novel therapeutic strategies.

P1, N=52, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2023 --> Dec 2023 | Trial primary completion date: Apr 2023 --> Dec 2023

Here, we report the biological activities, the efficacy and toxicities of humanized antibodies and antibody-drug conjugates that targets surface antigens as CD33 (gemtuzumab ozogamicine) or CD123 (pivekimab sunirine). We further explore mechanisms and effectiveness of medications that modify the microenvironment, such as glasdegib, or that harness the immune system against leukemia, such as CD47 antibody magrolimab, PD1/PDL1 inhibitors pembrolizumab and nivolumab, TIM3 inhibitor sabatolimab, T-cell and NK-cell engagers...In this scenario, a brief overview of the mechanism of action of target agents is provided, particularly with respect to their biological mechanisms. Overall, this therapeutic armamentarium will constitute the basis for multimodal and personalized combinations that, in the idea of precision medicine, will enormously benefit elderly AML patients.

P1, N=52, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=80 --> 52

By targeting TIM-3, a receptor expressed on various immune effector cells as well as myeloid cells, multiple mechanisms of action that are distinct from canonical immune checkpoint inhibitors are in play - (i) blockade of TIM-3 and its ligands PtdSer/galectin-9, (ii) modulation of leukemic cell self-renewal as well as (iii) antibody-dependent phagocytosis of TIM-3-expressing leukemic cells. Novel immunotherapies such as sabatolimab which enhance the antitumor immune response on converging fronts represent the promise of a continuously replenished armoury for the treatment of cancer.

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.

Pts were randomized 1:1 to sabatolimab+HMA (azacitidine [AZA] or decitabine) or placebo+HMA in MDS1, and to sabatolimab+AZA or placebo+AZA in MDS2. Pts in MDS1 had poorer prognosis features (baseline blasts, cytogenetics and higher IPSS-R) compared with MDS2 study. This preliminary analysis is among the first in large, well-controlled trials to assess IPSS-M and shows higher-risk categories compared with IPSS-R. Until molecular testing is routine globally, pt selection for clinical trials is still dependent on IPSS-R.

A prospective pilot study utilizing low-dose cytarabine (LDAC) plus venetoclax (VEN) for patients with MRD relapse or oligoblastic relapse (5-15% marrow blasts) demonstrated a high response rate and durable outcomes (Tiong, ASH 2021)...For example, a patient with rising FLT3-ITD MRD meeting relapse criteria may be allocated to treatment with gilteritinib + VEN, rising IDH1 mutation to ivosidenib + VEN, rising KMT2A::X to SNDX-5613, rising NPM1 to LDAC + VEN or alternatively, to SNDX-5613. Where no specific targeted treatment is available, patients will be randomly allocated to non-targeted therapies, if more than one applicable arm exists, to arms including sabatolimab, sabatolimab + azacitidine, ASTX727 + VEN or LDAC + VEN...Key secondary endpoints will be nadir MRD response, MRD clearance rate, median time to and duration of MRD response, relapse-free survival, overall survival and quality of life measures. Exploratory objectives will include analysis of drug resistance mechanisms and correlates of response.

P1, N=80, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2022 --> Apr 2023 | Trial primary completion date: Dec 2022 --> Apr 2023

Galectin-9-induced effects on cytotoxicity can be abrogated using the clinical-grade anti-TIM-3 blocking antibody, MBG453...This may be due to higher intratumoral galectin-9 protein expression in HPV+ HNSCC lesions, as well as higher frequencies of circulating and tumor-infiltrating TIM-3+ NK cells in HPV+ patients. Conclusions Our data stress the importance of TIM-3 in the context of NK cells and suggest that targeting the TIM-3/galectin-9 pathway may be a cogent immunotherapeutic strategy to reinvigorate NK cell effector function in HPV+ HNSCC patients.

P1, N=16, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Active, not recruiting

The CD47 targeting agent, magrolimab, has shown promising activity when combined with azacitidine in early phase trials conducted in AML and higher-risk MDS, especially among patients harboring a TP53 mutation. Similarly, sabatolimab (an anti-TIM-3 monoclonal antibody) plus hypomethylating agents have shown durable responses in higher-risk MDS and AML in early clinical trials. Randomized trials are currently ongoing to confirm the efficacy of these agents. In this review, we will present the current progress and future directions of immune checkpoint inhibition in AML and MDS.

Magrolimab antagonizes CD47, which is overexpressed by AML and MDS cells, thus inducing macrophage phagocytosis with clinical activity in AML/MDS. Sabatolimab, an inhibitor of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which disrupts its binding to galectin-9, has shown promising results in AML/MDS, enhancing the effector functions of lymphocytes and triggering tumor cell death...These novel mAbs are currently under investigation for use as monotherapy or in combination with hypomethylating agents, BCL2 inhibitors, and chemotherapy in various clinical trials at different phases of development. Here, we review the main molecular targets and modes of action of novel mAb-based immunotherapies, which can represent the future of AML and higher risk MDS treatment.

Early phase clinical trials with different anti-TIM-3 monoclonal antibodies have shown a safe toxicity profile, as cobolimab, LY3321367, or sabatolimab; however, the general antitumor activity remains to be determined and further investigations are needed. However, the TIM-3 pathway is highly complex in terms of non-canonical signaling, broad expression by different immune cells and multiple ligands. Different anti-TIM-3 inhibitors are currently on research, either as monotherapy or in combination with other immunotherapies or chemotherapy, aiming to overcome resistance.