sabatolimab (MBG453)

We examine the current landscape of TIM-3-targeted agents, from monoclonal antibodies like sabatolimab to bispecifics and CAR-T cells, and critically evaluate rational combination strategies with hypomethylating agents, venetoclax, and other immunotherapies. Finally, we discuss the challenges of patient stratification, resistance mechanisms, and on-target toxicity, outlining a roadmap for converting the multifaceted biology of TIM-3 into transformative clinical benefit for AML patients.

P1/2, N=3, Active, not recruiting, M.D. Anderson Cancer Center | N=12 --> 3 | Recruiting --> Active, not recruiting

P2, N=10, Terminated, 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.

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.

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.

P2, N=20, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting | Trial completion date: Jan 2026 --> Nov 2026 | Trial primary completion date: Jun 2024 --> Nov 2024

P1, N=16, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2025 --> Sep 2026

Functional assays demonstrated that TIM3 blockade with sabatolimab restored T cell cytotoxicity, leading to enhanced leukemia cell apoptosis in ER patients. These findings highlight TIM3 as a critical regulator of T cell exhaustion and immune suppression in patients with ER and provide a rationale for the therapeutic use of TIM3 blockade in preventing and treating relapses after allo-HSCT.

P1/2, N=45, Terminated, Novartis Pharmaceuticals | Completed --> Terminated; Sponsor Decision

P2, N=39, Terminated, Novartis Pharmaceuticals | Completed --> Terminated; Lack of efficacy in the program as demonstrated in the earlier CMBG453B12301 (STIMULUS MDS-2) study.

P1/2, N=24, Terminated, 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.