magrolimab (ONO-7913) / Ono Pharma, Gilead - LARVOL DELTA

Magrolimab plus azacitidine vs physician's choice for untreated TP53-mutated acute myeloid leukemia: the ENHANCE-2 study. (PubMed, Blood) - P3 | "Patients determined inappropriate for intensive therapy were randomized to receive Magro/Aza or venetoclax plus azacitidine (Ven/Aza); those appropriate for intensive therapy were randomized to receive Magro/Aza or 7+3 induction chemotherapy. ENHANCE-2 did not meet its primary endpoint of OS in TP53-mutated AML but provides important data informing future studies in this challenging population. This trial was registered at www.clinicaltrials.gov as #NCT04778397."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • TP53

Azacitidine, Venetoclax and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase 1b/2 Study and Correlative Analysis. (PubMed, Clin Cancer Res) - "The triplet regimen was safe but did not lead to promising survival outcomes."

Journal • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • CD47 • IFNG • TNFA • TP53

IgG4 anti-CD47: Erythrophagocytosis and potential transfusion complications. (PubMed, Transfusion) - "IgG4 RBC antibodies, generally not considered clinically significant for transfusion, can result in erythrophagocytosis providing an explanation for anemia related to anti-CD47 mediated by FcγRI and FcγRIIa. Enhanced phagocytosis of alloantibody-coated RBCs with concurrent blocking CD47 suggests potential for enhanced complications for patients who develop RBC alloantibodies while receiving cancer therapies targeting CD47."

Journal • Hematological Disorders • Oncology

MORPHEUS mUC: Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC) (clinicaltrials.gov) - P1/2 | N=272 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

Trial completion • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

Atezolizumab Plus Magrolimab, Niraparib, or Tocilizumab in Platinum-Refractory Metastatic Urothelial Carcinoma: A Phase Ib/II Open-Label, Randomized Umbrella Study. (PubMed, Clin Cancer Res) - P1/2 | "The evaluated regimens in MORPHEUS-UC were tolerable. However, response rates for the combinations did not meet the criteria for further development in platinum-experienced locally advanced or mUC."

IO biomarker • Journal • Metastases • P1/2 data • Tumor mutational burden • Oncology • Solid Tumor • Urothelial Cancer • PD-L1 • TMB

Phase 1b/2 Study of Magrolimab (Magro), Azacitidine (AZA) and Venetoclax (VEN) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High Risk Acute Myeloid Leukemia (AML) and Relapsed Refractory (R/R) AML: Final Clinical Data and Genomic Markers of Resistance/Relapse (ASH 2024) - "Interestingly, pts with TP53mut AML who underwent alloSCT had med EFS 12 mos and med OS NR. Potential mechanisms of resistance/relapse included erythroid differentiation, inflammatory tumor microenvironment, and CD47 upregulation."

Clinical data • P1/2 data • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • CD47 • IFNG • TNFA • TP53

MAGROLIMAB (MAGRO) + AZACITIDINE (AZA) VS PLACEBO (PBO) + AZA IN PATIENTS (PTS) WITH UNTREATED HIGHER-RISK (HR) MYELODYSPLASTIC SYNDROMES (MDS): PHASE 3 ENHANCE STUDY FINAL ANALYSIS (EHA 2024) - P3 | "In the ENHANCE study, Magro+AZA did not meet the primary endpoint of OS and CRR and showed moresevere TEAEs overall, including a higher rate of Gr ≥3 TEAEs, in treatment-naïve pts with HR-MDS. Confounding factors, such as imbalance in pts eligible for transplant and a partial clinical hold duringenrollment, may limit data interpretation. Findings highlight challenges of developing anti-CD47 therapies andother new treatments in HR-MDS."

Clinical • P3 data • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • TP53

Clinical advances in CD47-SIRPα axis-targeted cancer immunotherapy: Mechanisms, strategies, challenges, and future perspectives. (PubMed, Biochem Biophys Res Commun) - "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."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • SIRPA

Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: Phase 1b results. (ASCO 2022) - P1b, P3 | "In high-risk frontline TP53m AML pts unsuitable for intensive chemotherapy, magrolimab+AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial in TP53m AML (ENHANCE-2; NCT04778397) of this combination vs standard of care is ongoing."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Constipation • Cough • Fatigue • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Infectious Disease • Neutropenia • Pneumonia • Respiratory Diseases • Thrombocytopenia • TP53

Nature of Clinical Response and Depth of Molecular Response in Patients with TP53 Mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) Treated with Magrolimab with Azacitidine (ASH 2022) - P1b | "In AML, VAF 0.10 at all timepoints. Conclusions In this phase 1b study, magrolimab demonstrated a reduction in the allele frequency of TP53 mutations as early as cycle 3 in patients with MDS or AML treated with magrolimab + azacitidine, potentially altering the course of disease in patients with TP53-mutated malignancies."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • CALR • DNMT3A • NRAS • RUNX1 • TET2 • TP53

Magrolimab in combination with azacitidine for untreated higher-risk myelodysplastic syndromes (HR-MDS): 5F9005 phase 1b study results. (ASCO 2022) - P1b, P3 | "Magrolimab+AZA was well tolerated with promising efficacy in pts with untreated HR-MDS including those with TP53-mut and TP53-wt disease. A Phase 3 trial of magrolimab/placebo+AZA (ENHANCE: NCT04313881) is ongoing."

Combination therapy • P1 data • Anemia • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • CD47 • TP53

Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML (ASH 2022) - P1/2, P3 | "The triplet combination of AZA VEN Magro appears safe with encouraging CR rates in a cohort of ND pts with 93% adverse risk ELN and 71% with adverse cytogenetic features. Responses in R/R AML were modest with prior VEN exposed pts faring poorly. Further trial enrollment and correlative analysis is underway and a phase III placebo controlled, randomized, international study to evaluate this triplet in ND AML has been initiated (ENHANCE-3, NCT05079230)."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Malignancies • Hepatology • Idiopathic Arthritis • Infectious Disease • Neutropenia • Pneumonia • Respiratory Diseases • Transplantation • TP53

MAGROLIMAB VS PLACEBO IN COMBINATION WITH VENETOCLAX AND AZACITIDINE IN PREVIOUSLY UNTREATED PATIENTS WITH ACUTE MYELOID LEUKEMIA WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY: THE ENHANCE-3 STUDY (EHA 2024) - P3 | "In pts with newly diagnosed AML ineligible for intensive chemotherapy, Magro + VEN + AZA did not improveOS or CR, with a higher incidence of fatal AEs occurring in pts treated with Magro. The study was stopped earlyas the prespecified futility boundary for OS (HR, 1. 1) was crossed."

Clinical • Combination therapy • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Transplantation • TP53

Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Acute Myeloid Leukaemia. (PubMed, EJHaem) - P2 | "This phase 2 study evaluated magrolimab+venetoclax (VEN)+azacitidine (AZA) in untreated, unfit acute myeloid leukaemia (AML) and magrolimab+mitoxantrone+etoposide+cytarabine in relapsed/refractory (R/R) AML. Magrolimab was safely combined with existing AML therapies with no new safety signals. This trail was registered at www.clinicaltrials.gov as NCT04778410."

Journal • P2 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study. (PubMed, J Clin Oncol) - P1b, P3 | "Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ENHANCE: NCT04313881)."

Combination therapy • Journal • P1 data • Bone Marrow Transplantation • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Thrombocytopenia • Transplantation • TP53

A phase 1b/2 study of pivekimab sunirine (PVEK, IMGN632) in combination with venetoclax/azacitidine or magrolimab for patients with CD123-positive acute myeloid leukemia (AML). (ASCO 2023) - P1b/2 | "The PVEK+Magro doublet (Regimen E) is planned to be open for enrollment mid-2023 at sites in the USA. Clinical trial information: NCT04086264."

Clinical • Combination therapy • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123

Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results. (PubMed, J Clin Oncol) - P1b, P3 | "Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML."

Journal • P1 data • Acute Myelogenous Leukemia • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • TP53

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

CD47 expression in solid tumors correlates with phagocytic tumor-associated macrophage gene signature. (PubMed, Front Immunol) - "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."

Biomarker • Gene Signature • Journal • Breast Cancer • Colorectal Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD47 • SPP1

Rhabdomyolysis in patients taking isocitrate dehydrogenase inhibitors for R/R Acute Myeloid Leukemia (ASH 2025) - "She was started on treatment with azacitidine, venetoclax, and magrolimab and achieved MRD-negative CR after cycle 1, then went on to complete 6 cycles of therapy, followed by 4 cycles of maintenance therapy with combination decitabine/cedazuridine and venetoclax prior to relapse. She was then treated with combination decitabine/cedazuridine, venetoclax, and ivosidenib...Azacitidine was discontinued after C33, at which time she continued on enasidenib monotherapy...She was on a stable dose of atorvastatin at the time of this event and had recently started azithromycin for symptoms of upper respiratory tract infection...al 2015). We hypothesize that rhabdomyolysis observed with IDH inhibitors may reflect a convergence of metabolic stressors, particularly in susceptible populations such as elderly patients with low muscle mass, and those on concomitant statins."

Clinical • Acute Myelogenous Leukemia • Brain Cancer • Constipation • Gastroenterology • Gastrointestinal Disorder • Glioma • Hematological Disorders • Hematological Malignancies • Hepatology • Infectious Disease • Leukemia • Musculoskeletal Pain • Myelodysplastic Syndrome • Respiratory Diseases • Solid Tumor • Thrombocytopenia • IDH1 • IDH2

Dichotomy of TP53 mutant AML MRD microenvironment: Spatially segregated immunosuppressive mechanisms and niche-specific structural support (ASH 2025) - "Patients received either Aza/Ven- or Ara-C/Idarubicin-based regimens combined with magrolimab or gilteritinib. single-cell proteomics analysis of bone marrow biopsies provides a spatially resolved view of the TP53mut AML microenvironment, uncovering persistent p53+ MRD cells enriched for erythroid phenotypes. Their structural niches suggest MRD-protective roles of MSCs and adipocytes, and immunosuppressive features such as spatial separation between T-cell clusters and p53+ cells, involvement of Tregs within lymphocyte clusters and a distance-dependent TIGIT surge of T and NK-cells in proximity to p53+ cells. This comprehensive spatial analysis offers new insights into the mechanisms of immune escape and MRD persistence in TP53mut AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD14 • CD34 • FOXP3 • NPM1 • TFRC • TIGIT • TP53

CD43 functions as a CD47 independent "don't eat me" signal and novel immune checkpoint in AML (ASH 2025) - "However, the CD47-targeting monoclonal antibody magrolimab recentlyfailed to meet its primary endpoint in Phase III ENHANCE trial in myeloid malignancies...These findings for the first timesuggest that CD43 on AML blasts promotes an immunosuppressive tumor microenvironment andcontributes to poor patient outcomes. Collectively, our work identifies O-glycosylated CD43 as a novel "don't eat me" immune checkpoint thatoperates independently of CD47, providing a promising therapeutic target to enhance macrophage-mediated tumor clearance in hematologic malignancies."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Lymphoma • ADAM10 • ADAM17 • CD4 • CD47 • GLI2 • SIGLEC1 • SIRPA • SLC35C1 • SPN

CD47-blockade induces programmed necroptosis and complements the effects of BCL-2 inhibition in lymphoid malignancies (ASH 2025) - "Methodology: The fully humanized anti-CD47 monoclonal antibodies, SRF231, magrolimab, as well as themouse monoclonal anti-CD47 antibody, B6H12, were evaluated in this study. Our study unravels a novel, critical non-canonical cell death mechanism of targeting CD47 vianecroptosis. We also demonstrate the complementary and distinct cell death mechanisms of SRF231-induced necroptosis and venetoclax-induced apoptosis, a combination worthy of further study in theclinic specifically against BCL-2-dependent lymphoid malignancies."

Acute Lymphocytic Leukemia • B Cell Lymphoma • Burkitt Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5

Durability of complete response outperforms complete response rates as a surrogate endpoint for advancing to phase III trials in high-risk myelodysplastic syndromes (ASH 2025) - "The HMA plus venetoclax cohort (n=59) had a CRrate of 11.9% (7/59) with 8.5% (5/59) durable CR, equating to 71% (5/7) of CRs durable. Clinical trial pts(n=41) receiving HMA plus novel agents (magrolimab, eprenetapopt, or tamibarotene) had a higher CRrate of 29.3% (12/41) with 24.4% (10/41) durable CR, translating into 83% (10/12) of CRs being durable.In subgroup analysis of pts with TP53-mutated MDS treated with HMA alone (n=242), achieving a durableCR was associated with a 38% reduction in risk of death (HR 0.62; 95% CI 0.39–0.97; p=0.037). Only durable CR translates into a survival benefit in HR-MDS. CR >6 months is a practical, clinicallymeaningful surrogate endpoint and may improve assessment of treatment efficacy and accelerate drugdevelopment in HR-MDS."

Clinical • P3 data • Hematological Malignancies • Myelodysplastic Syndrome • TP53

PNOC025: A phase 1 study assessing the safety and tolerability of magrolimab in children and adults with recurrent or progressive malignant brain tumors (SNO 2025) - "Magrolimab is safe and well-tolerated in children and adults with recurrent or progressive malignant brain tumors. Unfortunately, the magrolimab program was discontinued by the Sponsor before enrollment was completed, for reasons unassociated with this trial. Biologic and clinical correlate analyses are underway."

Clinical • P1 data • Brain Cancer • Ependymoma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Primary Spinal Cord Tumor • Solid Tumor