All 19 subjects with transfusion-dependent β-thalassemia achieved transfusion independence after treatment with RM-001 (autologous HBG1/2 promoter-modified CD34+ hematopoietic stem and progenitor cells)

Abstract Background: RM-001 is a novel non-viral cell therapy for β-hemoglobinopathies that reactivates fetal hemoglobin (HbF) through ex vivo CRISPR-Cas9 editing of the BCL11A binding site in the γ-globin gene (HBG1/2) promoters of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). Methods: Both an investigator-initiated trial (IIT; ChiCTR2100053406 and ChiCTR2100052858, n=7) and a Phase 1 trial (ChiCTR2300069244, n=12) were conducted to evaluate the safety and efficacy of RM-001 in patients with transfusion-dependent β-thalassemia (TDT). Eligible participants were aged 6 to 35 years, with a history of packed red blood cell (pRBC) transfusions ≥100 mL/kg/year or ≥10 units/year during the 2 years preceding screening. The primary efficacy endpoint was transfusion independence (TI12), defined as the proportion of patients maintaining a weighted average hemoglobin level ≥9 g/dL without pRBC transfusion for ≥12 consecutive months. TI12 assessment began 60 days after the last transfusion. Patients completing the 24-month trial will transition to a long-term follow-up study. Results: As of July 15, 2025, 19 patients (mean age, 15.9 years; 5 patients aged ≥18 years, 7 aged ≥12 to <18 years, and 7 aged ≥6 to <12 years) had received RM-001, with a median follow-up of 26.3 months (range, 18.9 to 44.5). Before enrollment, patients received a mean of 56.9 units/year (range, 35.3 to 106.3) of pRBC transfusions. Genotypes included β⁰/β⁰ in 13 patients (68.4%), β⁰/β⁺ in 5 patients (26.3%), and β⁺/β⁺ in 1 patient (5.3%). All patients achieved neutrophil engraftment (median, 15 days) and platelet engraftment (median, 21 days). All 19 patients (100%) discontinued transfusions and remained transfusion-free for ≥15 months (range, 16.2 to 42.0). Patients stopped transfusions at a median of 22 days (range, 10 to 94) after RM-001 infusion, with stable hemoglobin levels ≥9 g/dL at a median of 31 days (range, 14 to 127). All patients had ≥18 months of follow-up after RM-001 infusion, with all (100%) achieving TI12, with mean total hemoglobin levels of 10.8 g/dL at month 3, 11.6 g/dL at month 6, 11.8 g/dL at month 12, and 12.0 g/dL at month 18, and corresponding fetal hemoglobin (HbF) levels of 9.2, 11.4, 11.6, and 12.0 g/dL. HBG1/2 allele editing proportions remained stable in patient´s bone marrow over time. The first 13 patients have finished 24-month follow-up and enrolled in a long-term study. The first 5 patients have been followed over 3 years and their Hb levels maintained stably above 11 g/dL. No treatment-related serious adverse events were reported. All adverse events resolved completely, with no deaths, treatment discontinuations, or malignancies observed. Conclusion: The data from 19 TDT patients infused with RM-001 demonstrated clinically meaningful and sustained increases in total Hb and HbF, leading to transfusion independence in all subjects. The safety profile of RM-001 was excellent and no product-related serious adverse events were reported during the study. These results indicate that RM-001 has potential to cure TDT with one-time treatment.