On November 21, 2023, BRL Medcine announced that two studies of BRL-101, a gene therapy product for transfusion-dependent β -thalassemia, and BRL-201, a product for relapsed / refractory B cell non-Hodgkin's lymphoma, were selected for the 65th American Society of Hematology (ASH) Annual Meeting, and the latest data will be announced in the form of poster presentations.

About the BRL-101

1、Research name

Efficacy and Safety of Brl-101, CRISPR-Cas9-Mediated Gene Editing of the BCL11A Enhancer in Transfusion-Dependent β-Thalassemia

2. Abstract number

4995

On August 16, 2022, the clinical trial application (IND) of BRL-101 of BRL Medcine was officially approved by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration and entered the registered clinical stage. Its main indication is transfusion-dependent β-thalassemia, which is a gene therapy product developed based on the hematopoietic stem cell platform (ModiHSC ^® ) independently developed by BRL Medcine . ModiHSC® mainly utilizes the gene editing system to genetically modify the hematopoietic stem cells of the patient, and the modified hematopoietic stem cells are infused back into the patient's body to rebuild the modified cell population through self-renewal and differentiation, so as to achieve the purpose of treating hematological diseases . At present, BRL Medcine utilizes the gene therapy of BRL-101 to successfully help many patients with thalassemia to get rid of dependence worldwide.

The conference announced the results of the IIT and IND Phase 1 clinical studies of BRL-101, which is a study conducted in China to evaluate "Safety and Efficacy of γ-globin  reactivated autologous hematopoietic stem cells transplantation for the treatment of severeβ-thalassemia ( thalassemia) ". Thalassemia is an inherited hemolytic disease that is prevalent worldwide and is the largest single-gene mutation genetic disease. Thalassemia patients are mainly due to deletions or mutations of a fragment of the HBB gene, resulting in the severe deficiency of functional β-globin, causing severe anemia and related complications. Whereas hereditary  sustained expression of fetal hemoglobin (HbF) can alleviate the symptoms of anemia, therefore, this clinical study used CRISPR/Cas9-mediated mutation of the BCL11A erythrocyte enhancer to reduce the expression of BCL11A, which can induce the expression of fetal γ-hemoglobin, which is a feasible therapeutic strategy for the treatment of transfusion-dependent β-thalassemia (TDT).

A total of 10 patients aged 6-26 years old were enrolled in the study, and all of them were cured. Clinical treatment results show that the overall Hb and HbF levels increased significantly in all patients undergoing gene-edited HSC transplantation, andthe vast majority of adverse events coincided with hematopoietic stem cell mobilization/apheresis, busulfan myeloablative conditioning and autologous hematopoietic stem cell transplantation throughout the treatment process. All adverse events can be recovered after medical intervention, and the vast majority of adverse events were converted to recovery / resolution. There was no occurrence of GVHD or subject withdrawal from the study or death due to adverse events. In addition, autologous hematopoietic stem progenitor cells (HSPCs) edited by CRISPR/Cas9 were transplanted and differentiated into multiple gene-edited cell lines. As of July 20, 2023, 10 patients were followed up for 24.6 months (4.3-39.2)  after administration  of HSPCs , and 10 patients (100%) were divorced from transfusion dependence, and the longest TI duration has reached 37.2 months. This study shows that 's BRL-101 of BRL Medcine gene therapy is more efficient, convenient and safe, with the advantages of good targeting, high safety, wide range of action ,significant therapeutic effect, etc. It can achieve lifelong cure with one treatment, and is expected to become a more beneficial therapy for the public.

About BRL-201

1. Research name

Long Term Follow-up Results of Brl-201 Phase I Study, a Crispr-Based Non-Viral PD-1 Locus Specific Integrated Anti-CD19 CAR-T Cells in Treating Relapsed or Refractory Non-Hodgkin's Lymphoma

2. Abstract number

2108

On December 14 , 2022 , the clinical trial application (IND) of BRL-201 of BRL Medcine was officially approved by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration and entered the registered clinical stage. It is a CAR-T product developed using the non-viral targeted integration of CAR-T platform (Quikin CART^®) independently developed by BRL Medcine, which is also the world's first non-viral PD1-CAR-T product targeting CD19, and the indication is relapsed  /refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). Non-Hodgkin's lymphoma is a hematological malignancy originating in lymphoid tissue, accounting for 80%-90% of all lymphomas, andalthough patients achieve disease remission after initial treatment, they often relapse later. Although CAR-T products have been approved for the clinical treatment of relapsed/refractory non-Hodgkin lymphoma, the overall efficacy still needs to be improved, and the toxic side effects caused by the release of a large amounts of cytokines during the treatment also need to be reduced.

The conference is the latest clinical data of BRL-201 in the IIT study, which used CRISPR/Cas9 technology to prepare novel PD1-CAR-T cell products through non-virus-mediated gene-specific integration, breaking the limitation of using virus and random integration in the preparation of traditional CAR-T cell ,also relieving the  immune suppression of tumor to CAR-T cells. The study results showed that in 21 patients were enrolled, the objective response rate (ORR) of the patients reached 100%, and the complete response rate (CR) reached 85.7%. While achieving significant efficacy, it did not cause grade 2 or higher cytokine release syndrome or neurotoxicity in any patient; as of May 17, 2023, the median progression-free survival (mPFS) reached 20.8 months, and the long-term benefits of patients was significantly higher than existing similar viral CAR-T products. So far, the first patient in the world to receive BRL-201 treatment of BRL Medcine has survived cancer-free for more than 3 years. This study demonstrates the excellent clinical safety and efficacy of the BRL-201 product, and is arguably the best clinical results of high remission rates and low toxic in refractory relapsed lymphoma to CAR-T cell therapy worldwide. In addition, the research results of this product were published in the top international academic journal Nature on August 31, 2022 .