A Pilot Study on the Safety and Efficacy of YOLT-204 for Transfusion-Dependent Beta-Thalassemia

This study is a single-arm, open-label, dose-escalation trial, planning to enroll 3-9 patients with transfusion-dependent β-thalassemia, aimed at assessing the safety and tolerability of a single-dose of YOLT-204 in patients with transfusion-dependent β-thalassemia; to preliminarily evaluate the impact of a single -dose of YOLT-204 on the levels of fetal hemoglobin in the plasma

Study Overview

• Status: Not yet recruiting
• Conditions: Transfusion Dependent Beta Thalassemia
• Intervention / Treatment: Drug: YOLT-204

• Study Type: Interventional
• Enrollment (Estimated): 3
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Rongrong Liu; Phone Number: +86 0771 5356510; Email: liurongrong@stu.gxmu.edu.cn

Study Locations

• China
  • Guangxi
    • Nanning, Guangxi, China, 530000
      • The First Affiliated Hospital of Guangxi Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria：

1. Age between 18 to 35 years, gender not limited.
2. The patient has fully understood this study and voluntarily signed an informed consent form.
3. Clinically diagnosed as a patient with transfusion-dependent β-thalassemia, excluding the genotype: β0β0.
4. Karnofsky Performance Status (KPS) score of at least 70.
5. Obtain detailed medical records of red blood cell transfusions within 2 years prior to the patient signing the informed consent form, including the volume or units of transfusion and the levels of red blood cells and hemoglobin before and after transfusion.
6. No severe hematopoietic dysfunction, with heart, lung, liver, and kidney functions essentially normal.
7. Coagulation function: International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) both ≤1.5×ULN (Upper Limit of Normal).
8. Renal function: Creatinine ≤1.5×ULN, or when creatinine >1.5×ULN, the creatinine clearance is >50ml/min (calculated according to the Cockcroft-Gault formula).
9. Liver function: Alanine Aminotransferase (ALT) ≤3×ULN and Aspartate Aminotransferase (AST) ≤3×ULN; Direct Bilirubin ≤2.5×ULN.
10. Cardiac function: Left Ventricular Ejection Fraction (LVEF) ≥50%.
11. Good compliance, willing to adhere to visit schedules, trial plans, laboratory tests, and other trial steps.
12. Willing to participate in long-term follow-up studies.

Exclusion Criteria:

1. History of multiple drug allergies or a history of allergic reactions to oligonucleotides or lipid nanoparticles (LNPs).
2. Diagnosed with compound alpha-thalassemia.
3. Clinically significant active bacterial, viral, fungal, or parasitic infections at the time of screening, as judged by the investigator.
4. White blood cell count (WBC) <3×10^9/L and/or platelet count <100×10^9/L not due to hypersplenism, as judged by the investigator.
5. Uncorrected bleeding disorders.
6. Received treatment with erythropoietin (EPO) within the three months prior to enrollment.
7. Severe iron overload, with serum ferritin levels ≥5000 ng/ml.
8. Positive for hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus, antibodies to human immunodeficiency virus (HIV), or specific antibodies to Treponema pallidum (syphilis).
9. History of hematopoietic stem cell transplantation, gene therapy, or gene editing therapy.
10. Participation in another clinical study and use of investigational drugs within 3 months prior to starting the study drug.
11. History or current presence of malignant tumors or myeloproliferative diseases or immunodeficiency diseases.
12. Presence of severe mental illness that prevents cooperation with treatment; significant pulmonary arterial hypertension requiring medical intervention; recent malaria; a history of hematological tumors in immediate family members.
13. Any past or current disease, treatment, or laboratory abnormality that may interfere with the study results, affect the patient's full participation in the study, or that the investigator deems unsuitable for participation in this clinical study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: The intervention group will receive YOLT-204 on day0	Drug: YOLT-204; The intervention group will receive YOLT-204 on day0

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-Emergent Adverse Events	Number of Participants with Treatment-Emergent Adverse Events	52 weeks after dose
Laboratory Test Findings	Number of Participants with Clinically Significant Clinical Laboratory Test Findings	52 weeks after dose
Safety Measurements	Number of Participants with Clinically Significant Safety Measurements	52 weeks after dose
3 months of sustained transfusion reduction	Analysis begins one month after treatment with YOLT-204, and the proportion of patients who achieve at least 3 months of sustained transfusion reduction (sustained TR3) is obtained.	4 months after dose
3 months of transfusion independence	Analysis begins one month after treatment with YOLT-204, and the proportion of patients who achieve at least 3 months of transfusion independence (sustained TI3) is obtained.	4 months after dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 months of sustained transfusion reduction	Analysis begins one month after treatment with YOLT-204, and the proportion of patients who achieve at least 6 months of sustained transfusion reduction (sustained TR6) is obtained.	7 months after dose
6 months of transfusion independence	Analysis begins one month after treatment with YOLT-204, and the proportion of patients who achieve at least 6 months of transfusion independence (sustained TI6) is obtained.	7 months after dose
The proportion of alleles with intended modifications	The proportion of alleles with intended modifications in peripheral blood leukocytes and bone marrow cells over time.	52 weeks after dose
Fetal hemoglobin concentration	The change in fetal hemoglobin concentration over time after YOLT-204 infusion	52 weeks after dose
Total hemoglobin concentration	The change in total hemoglobin concentration over time after YOLT-204 infusion.	52 weeks after dose

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Guangxi Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): December 31, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: October 31, 2024
• First Submitted That Met QC Criteria: November 5, 2024
• First Posted (Estimated): November 7, 2024

Study Record Updates

• Last Update Posted (Estimated): November 7, 2024
• Last Update Submitted That Met QC Criteria: November 5, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Thalassemia; beta-Thalassemia
• Other Study ID Numbers: YOLT-204-IIT

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No