Updated Safety and Efficacy Results of RM-001, Autologous HBG1/2 Promoter-Modified CD34+ Hematopoietic Stem and Progenitor Cells, in Treating Transfusion-Dependent β-Thalassemia

Introduction : RM-001 is a novel non-viral cell therapy for β-hemoglobinopathies, which is designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the binding site of BCL11A on the promoter of the γ-globin genes (HBG1/2). Here we report that in both investigator initiated trial (IIT) and phase I trial, all the patients (pts) with transfusion-dependent β-thalassemia (TDT) achieved transfusion-free after RM-001 treatment. Methods: Both IIT (ChiCTR2100053406 and ChiCTR2100052858, n =7) and phase I trial (ChiCTR2300069244, n =12) have been conducted to evaluate the safety and efficacy of RM-001 in treating TDT. Patients (6-35 y of age) with TDT and a history of ≥100 mL/kg/y or ≥10 units/y packed red blood cell (pRBC) transfusions in the 2 years before screening were eligible. Primary efficacy endpoint is transfusion independence defined as proportion of pts maintaining a weighted average hemoglobin (Hb) ≥9 g/dL without pRBC transfusion for ≥12 consecutive months (TI12). Key secondary endpoint is proportion of pts maintaining a weighted average Hb ≥ 9 g/dL without RBC transfusion for ≥ 6 consecutive months (TI6). Evaluation of TI12 and TI6 started 60 days after last pRBC transfusion. Pts completing the 24-month trial will be enrolled in a long-term follow-up study. Results: As of July 24, 2024, 19 pts (mean age 15.9, 5 pts aged ≥18, 7 pts aged ≥12 to <18y and 7 pts aged ≥6 to <12y) have received RM-001, with a median follow-up of 14.5 (7-32.6) months. Pts received a mean of 53.0 (35.3-106.3) units/y pRBC transfusions before enrollment; 13 pts (68.4%) have the most severe genotype (β0/β0), 5 pts (26.3%) have β0/β+ genotype and the remaining one (5.3%) has a β+/β+ genotype. Following infusion, all pts engrafted neutrophils and platelets (median 15 and 21 days, respectively). All of 19 (100%) pts stopped transfusions and maintained transfusion-free ≥ 6 (6-31.8) months. Pts stopped transfusions at a median of 22 (10-95) days post-RM-001 infusion and achieved stable Hb ≥9 g/dL at a median of 31 (14-127) days. Of the 9 pts had ≥15 months of follow-up after RM-001 infusion, 9 (100%) achieved TI12; of the 16 pts had ≥9 months of follow-up, all (100%) achieved TI6; the remaining 3 pts had ≥7 months of follow-up, all of them are transfusion-free ≥ 6 months. For all pts, the mean total Hb and HbF were 10.8 g/dL and 9.2 g/dL at Month 3, respectively. Of the 13 pts had ≥12 months of follow-up, the mean total Hb and HbF were 11.8 (10.1-13.3) g/dL and 11.7 (10.0-13.2) g/dL at Month 12, respectively. Proportion of edited HBG1/2 alleles was stable over time in bone marrow cells. The first 5 pts have finished 24-month follow-up and enrolled in a long-term study. No RM-001-related serious adverse event report. All of adverse events have been resolved. There were no deaths, discontinuations, or malignancies. Conclusion: The data from 19 TDT pts infused with RM-001 demonstrated clinically meaningful and sustained increases in total Hb and HbF, leading to transfusion-free in all of subjects. The safety profile of RM-001 is very well and no product-related serious adverse event was reported during the study. These results indicate that RM-001 has the potential to cure TDT with one-time treatment.