ENHANCE

Background

Phase 3 ENHANCE study. Randomised, double-blind, placebo-controlled. N=539 treatment-naïve intermediate- to very-high-risk (IPSS-R) myelodysplastic syndromes (MDS). Tests the CD47-targeted antibody magrolimab added to azacitidine. Dual primary endpoints: complete remission (CR) rate and overall survival (OS).

Results

Interventions and follow up: Arm A: Magrolimab (priming 1 mg/kg D1,4; 15 mg/kg D8; 30 mg/kg D11,15 then weekly ×5, then 30 mg/kg q2w maintenance) + azacitidine 75 mg/m² D1–7 (n=268)
Arm B: Placebo + azacitidine 75 mg/m² (n=271)
Primary endpoint: CR rate (IWG 2006) and OS
mFollow up: final analysis
Results: CR rate: 21.3% vs 23.6%; OR 0.876, 95% CI 0.585–1.312, P=.5218.
OS: 15.9 vs 18.6 mo; HR 1.203, 95% CI 0.947–1.528, P=.1299.
Both primary endpoints not met (numerically favored placebo).

Adverse events

Grade ≥3 (any): 92.8% vs 79.2%.
Serious AE: 71.9% vs 51.5%.
Fatal AE: 15.2% vs 9.8%.
Discontinuation (AE): 24.0% vs 12.1%.

Conclusions

ENHANCE did not meet either primary endpoint: adding magrolimab to azacitidine failed to improve CR or OS in higher-risk MDS and increased severe and fatal toxicity. The trial formally documents the failure of CD47 blockade in this setting.

Key Limitations

Negative trial with a possible detrimental signal (numerically worse OS, more fatal AEs, higher discontinuation); complex magrolimab priming/dosing; result consistent with the broader collapse of the CD47 program across MDS and AML.

Clinical Context

Gilead discontinued the ENHANCE study in July 2023 for futility and halted all magrolimab hematologic development in February 2024 after an FDA clinical hold for increased mortality across the ENHANCE program. Azacitidine remains the hypomethylating-agent backbone for higher-risk MDS; no CD47-directed agent is approved. This publication is the definitive negative readout.

References