A Phase 2 Safety and Efficacy Study Evaluating CS-101 in Participants With β-Thalassemia Major

CS-101 is an autologous CD34+(Cluster of differentiation 34) cell suspension, edited by ex vivo base editing technology, which modifies the BCL11A binding site in HBG(Hemoglobin Subunit Gamma) promoter, so that it loses the ability to bind to BCL11A, which can re-induce the production of γ-globin chain and increase the concentration of HbF(fetal hemoglobin) in the blood, compensating for the function of missing HbA(adult hemoglobin) to achieve clinical cure. The therapy addresses two major challenges in the current treatment of the disease: lack of matching donors and graft-versus-host diseases in allogeneic hematopoietic stem cell transplantation.

Inclusion criteria

• Voluntarily signed informed consent. Male or female participants aged 12 to 35 years (inclusive). The participant or their legally authorized representative must sign the informed consent. If the participant is under 18 years of age, their legally authorized representative must also sign the informed consent.
• Diagnosed with β-thalassemia major (transfusion-dependent). Received at least 8 units of red blood cell transfusions within 12 months prior to screening, and documented hemoglobin level ≤ 70 g/L pre-transfusion.
• Good general condition: Karnofsky score (≥16 years of age) ≥ 60, or Lansky Play-Performance score (<16 years of age) ≥ 60.
• For females of childbearing potential: From the start of the screening, highly effective contraception or complete abstinence (if this is their usual lifestyle), and agree to maintain such contraception throughout the study.
• For males of childbearing potential: Use condoms or other methods to ensure effective contraception for sexual partners continuously from mobilization through the study period.

Exclusion criteria

• Received other investigational products or other experimental interventions within 30 days prior to signing informed consent or within 6 elimination half-lives of the drug (whichever is longer).
• Received or is receiving thalidomide, hydroxyurea, and/or luspatercept within 3 months prior to screening.
• Previous received allogeneic hematopoietic stem cell transplantation, gene therapy, or gene-editing therapy; or participants who can be maintained with standard therapy.
• Participants with a matched sibling donor, or with a matched unrelated / haploidentical related donor and judged by the investigator to have no high-risk factors for allogeneic hematopoietic stem cell transplantation.
• Participants with coexisting α-thalassemia with more than 2 α-globin chain gene deletions or non-deletional mutations.
• Known hypersensitivity to drugs used during autologous hematopoietic stem cell transplantation, excipients, or devices, judged by the investigator to be ineligible for this study.
• Infection with HIV, cytomegalovirus, Epstein-Barr virus, or Treponema pallidum during screening; active HBV or HCV infection (participants with stable hepatitis B after treatment (HBV-DNA negative) and cured hepatitis C (HCV-RNA negative) may be included). Known active bacterial, viral, fungal, or parasitic infection.
• Echocardiographic ejection fraction < 50%.
• Laboratory abnormalities: AST or ALT > 3 × upper limit of normal (ULN); or International normalized ratio (INR) > 1.5 × ULN.
• Cardiac severe iron overload detected by MRI during screening, judged by the investigator to be unsuitable for hematopoietic stem cell transplantation.
• Current or history of malignancy.
• Participants with known neurological consciousness disorders, psychological problems, or psychiatric diseases judged by the investigator to be unable to comply with study procedures.
• Participants with known history of uncontrolled seizures judged by the investigator to be ineligible for this study.
• Uncontrolled bleeding disorders.
• Leukocyte count < 3 × 10⁹/L and/or platelet count < 100 × 10⁹/L not due to hypersplenism.
• Participants with other severe cardiovascular, pulmonary, renal, gastrointestinal, hepatic diseases, and/or other organ disorders judged by the investigator to be ineligible for this study.
• Pregnant or lactating females; females of childbearing potential with a positive serum pregnancy test.
• Received live or live-attenuated vaccine within 90 days prior to myeloablation.
• Participants with autoimmune diseases