A Clinical Exploratory Study of YOLT-204 in the Treatment of Hemoglobinopathies

A Clinical Exploratory Study on the Safety and Efficacy of YOLT-204 in the Treatment of Hemoglobinopathies (Sickle Cell Disease and Transfusion-Dependent Thalassemia)

This is a single-arm, open-label, dose-escalation study designed to enroll approximately 5-30 patients with TDT or SCD. The objectives are to evaluate the safety and tolerability in patients following intravenous administration of YOLT-204 and to preliminarily assess its effect on fetal hemoglobin levels in plasma.

In this study, the maximum screening period of the main study is 60 days, the treatment day is Day 0 (D0), and the safety follow-up period is up to Week 52 after administration.

Common inclusion criteria:

1. Male or female subjects aged 14 to 35 years (inclusive).

2. The subject and/or their legal guardian has been fully informed about the study and has voluntarily signed a written ICF.

3. KPS score ≥ 70 for subjects aged 16 years or older; LPS score ≥ 70 for subjects under 16 years of age.

4. Detailed medical records regarding red blood cell transfusions within the 2-year period prior to signing the ICF are available, including the volume or number of units transfused, as well as pre- and post-transfusion red blood cell and hemoglobin levels.

5. No severe hematopoietic abnormalities; cardiac, pulmonary, hepatic, and renal function are generally normal.

6. Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time (APTT) both ≤ 1.5 × ULN (upper limit of normal).

7. Renal function: Creatinine ≤ 1.5 × ULN, or if creatinine > 1.5 × ULN, calculated endogenous creatinine clearance > 50 mL/min (according to the Cockcroft-Gault formula).

8. Hepatic function: Alanine aminotransferase (ALT) ≤ 3 × ULN and aspartate aminotransferase (AST) ≤ 3 × ULN.

9. Cardiac function: Left ventricle ejection fraction (LVEF) ≥ 50%.

10. Good compliance and willingness to adhere to visit schedules, study plans, laboratory tests, and other study procedures.

11. Subjects agree to use at least one effective method of contraception from the time of signing the ICF through the end of the main study (W52 visit).

12. Willingness to participate in the long-term follow-up study.

    Additional criteria for SCD cohort only:

13. Genotyping performed during the screening period confirms HbSS, HbSβ0, or HbSβ+ phenotype; previous test reports are acceptable upon assessment by the investigator.

14. For subjects using L-glutamine, the regimen must have been stable for at least 3 months prior to study drug administration. For subjects using hydroxyurea, it must be discontinued for 8 weeks or more prior to study drug administration. For subjects using luspatercept, it must be discontinued for 3 months or more prior to study drug administration.

15. Meets criteria for severe SCD: At least 2 occurrences of one or more of the following events within 1 year prior to screening, despite standard supportive care (including but not limited to analgesic therapy, hydroxyurea):

Severe episodic acute pain requiring medical intervention; Acute chest syndrome, defined as new pulmonary infiltrate on chest imaging accompanied by pneumonia-like symptoms, pain, or pyrexia; Splenic sequestration crisis, characterized by splenomegaly, left upper quadrant pain, and an acute decrease in hemoglobin level > 20 g/L.

Common exclusion criteria:

1. History of multiple drug allergies or allergic reaction history to oligonucleotides or LNP;

2. Presence of clinically significant active bacterial, viral, fungal, or parasitic infection as judged by the investigator at screening;

3. White blood cell (WBC) count < 3 × 109/L and/or platelet count < 100 × 109/L at screening (using pre-lymphodepletion results if lymphodepletion is considered);

4. Uncorrected hemorrhagic disorders;

5. Severe splenomegaly at screening, defined as the spleen extending beyond the level of the umbilicus (or >4 cm below the costal margin), and deemed unsuitable for enrollment by the investigator;

6. Serum ferritin ≥ 5000 ng/mL, or evidence of severe cardiac or hepatic iron overload as indicated by magnetic resonance imaging (MRI)-T2*;

7. Positive for one or more of the following: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody, anti-human immunodeficiency virus antibody, or anti-Treponema pallidum specific antibody;

8. Prior hematopoietic stem cell (HSC) transplantation, gene therapy, or genome editing therapy; or eligible for allogeneic HSC transplantation with an identified HLA-matched related donor;

9. Participation in another clinical trial with administration of an investigational product within 3 months prior to study drug administration;

10. History or current diagnosis of malignancy, myeloproliferative disorder, or immunodeficiency disease;

11. Presence of severe psychiatric illness that precludes compliance with treatment; significant pulmonary hypertension requiring medical intervention; recent history of malaria; family history (first-degree relative) of hematologic malignancy;

12. Female subjects with a positive pregnancy test at screening, or who are pregnant or breastfeeding;

13. Any prior or current disease, treatment, or laboratory abnormality that may interfere with study results or affect the patient's full participation in the study, or any condition that, in the investigator's judgment, makes the patient unsuitable for participation in this clinical study.

    Additional criteria for TDT cohort only:

14. Receipt of any of the following treatments within 3 months prior to study drug administration: erythropoiesis-stimulating agents (e.g., erythropoietin [EPO]), thalidomide, hydroxyurea, or luspatercept.

    Additional criteria for SCD cohort only:

15. Abnormal transcranial Doppler (TCD), defined as flow velocity ≥ 200 cm/s in the middle cerebral artery or internal carotid artery.

16. History of moyamoya disease, or evidence of moyamoya at screening with an increased risk of hemorrhage as assessed by the investigator.