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4960 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

Program: Oral and Poster Abstracts
Session: 801. Gene Therapies: Poster III
Hematology Disease Topics & Pathways:
Clinical trials, Research, Clinical Research, Thalassemia, Hemoglobinopathies, Diseases, Gene Therapy, Treatment Considerations, Biological therapies, Technology and Procedures, Gene editing
Monday, December 9, 2024, 6:00 PM-8:00 PM

Rongrong Liu1*, Li Wang2*, Hui Xu, PhD3, Jianpei Fang4*, Sixi Liu5*, Xiaolin Yin6*, Junbin Liang3*, Xinyu Li4*, Yue Li5*, Gaohui Yang1*, Yaoyun Li2*, Yali Zhou6*, Lei Shi3*, Yongrong Lai, MD1*, Junjiu Huang, PhD7* and Xinhua Zhang, MD8*

1Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
2Department of Pediatrics, 923rd Hospital of the People's Liberation Army, Nanning, China
3Reforgene Medicine, Guangzhou, China
4Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China
5Department of Pediatrics, Shenzhen Children’s Hospital, Shenzhen, China
6Department of Hematology, 923rd Hospital of the People's Liberation Army, Nanning, China
7School of Life Sciences, Sun Yat-sen University, Guangzhou, China
8923rd Hospital of the People's Liberation Army, Nanning, Guangxi, China

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 (β00), 5 pts (26.3%) have β0+ genotype and the remaining one (5.3%) has a 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.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH