magrolimab (ONO-7913)

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.

This challenge was underscored by a pivotal setback in the field: the Phase III trial of Magrolimab, the first anti-CD47 therapy to reach this stage, which failed to meet its primary endpoint and ultimately led to the discontinuation of its development program...Furthermore, we summarize the major clinical challenges, including safety concerns, resistance mechanisms, and diagnostic complexities. By synthesizing these key findings, this review provides valuable insights for optimizing future drug design, refining combination regimens, and guiding patient selection strategies, thereby offering a crucial reference for overcoming current limitations and fully realizing the therapeutic potential of this promising axis.

P1/2, N=272, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Investigational agents targeting CD47, such as magrolimab, aim to induce phagocytosis of tumor cells by TAMs...Compared to relatively low CD47 expression in primary CRC tumors, CRC liver metastases had very high CD47 expression. Quantification of TAM signatures and CD47 expression represent key biomarkers to monitor in patient samples during exploration of CD47-blockade agents in the clinic.

CD47-targeted combinations demonstrate encouraging early phase efficacy and manageable safety in hematologic malignancies, with signals of benefit in higher-risk MDS, TP53-mutant AML, relapsed/refractory DLBCL, and rituximab-refractory iNHL. However, recent Phase III trials in newly diagnosed AML Daver et al. [27], and Zeidner et al. [26] did not confirm this benefit, underscoring that CD47 blockade remains investigational and requires validation in rigorously designed randomized studies.

Hu5F9-G4 demonstrates potential as a therapeutic agent in CRC by promoting M2d-to-M1 macrophage polarization, suppressing tumor progression, and influencing the autophagy pathway. These findings highlight CDKN1A and MAP1LC3B as promising targets for CRC therapy.

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.

HCB101 demonstrates high-affinity binding to CD47, robustly promotes macrophage-mediated phagocytosis of tumor cells without affecting red blood cells and exhibits unique advantages over current CD47-targeting agents, including Hu5F9-G4, TTI-622, and ALX148. Additionally, HCB101 treatment increased the M1/M2 macrophage ratio in the tumor microenvironment, suggesting repolarization of tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype. No dose-limiting toxicities or hematologic adverse effects were observed in murine or non-human primate studies.

These findings emphasize the need for awareness and adaptation in immunohematology practices as anti-CD47 drugs continue to advance in clinical development, and highlight the utility of antigen masking strategies to enhance the safe administration of blood products to treated patients.

Immune checkpoint inhibitors (ICIs), such as anti-PD-1 nivolumab and anti-CD47 magrolimab, combined with hypomethylating agents (HMAs), enhance T-cell activity and phagocytosis, especially in TP53-mutated AML. Integrating these innovations may transform AML into a chronic condition, bridging preclinical potential to clinical impact. In this review, we aim to evaluate mechanisms, challenges, and future directions of immunotherapies in AML with highlighting ICIs and vaccination to improve therapeutic outcomes.

P1/2, N=272, Active, not recruiting, Hoffmann-La Roche | Trial completion date: May 2026 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

When combined with a prophagocytic signal from an anti-CD20 antibody rituximab, it has shown activity in relapsed or refractory FL and MZL. In this phase 1 study, adding the BCL2-inhibitor venetoclax to magrolimab and the anti-CD20 antibody obinutuzumab resulted in complete responses in 6 of 10 (60%) evaluable patients with FL, MZL or CLL. Notably, we did not observe increased risk of infections previously reported from studies of magrolimab in acute myeloid leukaemia and higher risk myelodysplastic syndromes.