Background: β-hemoglobinopathies, such as β-thalassemia and sickle cell disease (SCD), result from mutations in the β-globin gene (HBB). Hereditary persistence of fetal hemoglobin (HPFH) is a natural condition where high levels of fetal hemoglobin (HbF) continue into adulthood, mitigating the severity of these disorders, highlighting the therapeutic potential of increasing HbF levels as a treatment strategy. We use transformer Base Editor (tBE) to edit the transcription repressor BCL11A binding site at the promoter region of the γ-globin genes (HBG1/2) in chromosome 11, installing the HPFH single nucleotide variants (SNVs). tBE-mediated editing reactivates HbF production in patients, offering a potential curative strategy for β-hemoglobinopathies.

Methods: Participants aged 12-35 years with transfusion-dependent β-thalassemia (TDT) with a history of ≥ 8 units packed RBC transfusions in the past 12 months prior to the screening were eligible to participate in 1 of the 2 ongoing CS-101 clinical trials (NCT06024876, NCT06291961). After enrollment, participants undergo collection of autologous hematopoietic stem cells (HSCs), ex vivo base editing, busulfan conditioning to prepare the bone marrow, infusion of CS-101 product (the edited HCSs), and subsequent monitoring for safety, efficacy, and clinical outcomes. Key safety endpoints include adverse events, and engraftment. Key efficacy endpoint includes total hemoglobin and fetal hemoglobin levels and proportion of participants achieving transfusion independence (defined as maintaining a weighted average Hb ≥ 90 g/L without RBC transfusion) for at least 6 consecutive months.

Results: As of the data cut-off (31 Jul 2025), 14 participants (including 8 with severe genotype β0/β0, 1 with a history of splenectomy) received CS-101. The average transfusion volume during the past 12 months before screening is 1.43 u/kg. The median follow-up duration is 12.7 months. After the infusion, all participants engrafted neutrophils and platelets (median 15 and 24 days, respectively). The median time for the last RBC transfusion is day 15 post-infusion. All participants remained transfusion-free after the last RBC transfusion and the mean duration of transfusion freedom was 10.7 months. The mean total Hb reached 128.3 g/L at Month 3 and remained above 120.0 g/L thereafter. The mean HbF levels were 27.0 g/L, 90.7 g/L, and 119.3 g/L at Month 1, Month 2, and Month 3, respectively, and remained above 120.0 g/L from Month 4 onwards. The mean F-cell percentages were 31.2%, 78.1%, and 94.4% at Months 1, 2, and 3, respectively, and remained above 98.0% from Month 4 onwards. The allele base editing efficiency in bone marrow and peripheral blood nucleated cells was stable over time.

All participants had ≥1 adverse event (AE) of Grade 3 or 4 severity (including laboratory-based AEs). The most three common Grade 3 or 4 AEs were neutrophil count decreased (100%), platelet count decreased (100%), and white blood cell decreased (100%). Most AEs were commonly observed AEs after myeloablative busulfan conditioning and no AEs were reported as related to CS-101 in the 14 patients. No SAEs, discontinuations, or malignancies were reported.

Among the 14 participants, 12 reached the pre-defined timepoint for transfusion independence of six months (TI 6) assessment, with 100% (12/12) achieving TI 6.

Conclusion: The data demonstrate clinically significant increases in both total Hb and HbF, prompt and durable engraftment, and therapeutic benefits for all the participants who received CS-101 infusion. The treatment prompted an early and substantial elevation in HbF level, pancellular distribution, and stable editing efficiency. CS-101 represents the first reported clinical base editing therapy for β-hemoglobinopathies and has the potential to become the best-in-class gene editing therapy for TDT.

Submitted on behalf of the CS-101 Investigators.

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2025
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