YOLT-204 in Patients With Hemoglobinopathies

Official title

An Exploratory Clinical Study to Evaluate the Safety and Efficacy of YOLT-204 in Patients With Hemoglobinopathies (β-thalassemia and Sickle-cell Disease)

Overview

This is a single-arm, open-label, single-dose, dose-escalation trial that plans to enrol 3-18 patients with transfusion-dependent β-thalassaemia (TDT) or sickle-cell disease (SCD). Its primary aims are to evaluate the safety and tolerability of a single administration of YOLT-204 and to obtain preliminary data on its effect on plasma fetal-haemoglobin levels. The main-study screening period may last up to 60 days; the treatment day is Day 0 (D0). Safety follow-up continues through Week 52 post-dose. After completion of the main study, participants will enter long-term follow-up extending to 15 years post-dose.

Interventions

• Drug YOLT-204
  The intervention group will receive YOLT-204 on day0

Primary outcome measures

• Adverse event rate [Time frame: From baseline to 52 weeks after dose]
• 3 months of sustained transfusion reduction [Time frame: From baseline to 52 weeks after dose]
• 3 months of sustained HbF level ≥20% [Time frame: From baseline to 52 weeks after dose]

Secondary outcome measures (11)

• The proportion of alleles with intended modifications [Time frame: From baseline to 52 weeks after dose]
• Concentration of Hemoglobin [Time frame: From baseline to 52 weeks after dose]
• Concentration of Fetal hemoglobin [Time frame: From baseline to 52 weeks after dose]
• Concentration of proportion of F cell [Time frame: From baseline to 52 weeks after dose]
• 3 months of transfusion independence [Time frame: From baseline to 52 weeks after dose]
• 6 months of sustained transfusion reduction [Time frame: From baseline to 52 weeks after dose]
• 6 months of transfusion independence [Time frame: From baseline to 52 weeks after dose]
• Free of hospitalization due to vaso-occlusive crisis [Time frame: From baseline to 52 weeks after dose]
• Free of any vaso-occlusive crisis [Time frame: From baseline to 52 weeks after dose]
• Change of red-blood-cell transfusions given [Time frame: From baseline to 52 weeks after dose]
• The number of vaso-occlusive crises [Time frame: From baseline to 52 weeks after dose]

Eligibility criteria

Inclusion criteria

• Aged 3-17 years (inclusive); any sex.
• The subject and/or his/her legally authorized guardian/representative must fully understand the study and voluntarily sign a written informed-consent form.
• Karnofsky Performance Status (KPS) ≥ 70 (if ≥ 16 years old) or Lansky Performance Scale (LPS) ≥ 70 (if < 16 years old).
• Detailed medical records of red-cell transfusions during the 2 years before informed-consent signature must be available, including volume or units transfused and pre-/post-transfusion red-cell and hemoglobin levels.
• No severe hematopoietic dysfunction; cardiac, pulmonary, hepatic, and renal function essentially normal.
• Coagulation: international normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × upper limit of normal (ULN).
• Renal function: serum creatinine ≤ 1.5 × ULN; if creatinine > 1.5 × ULN, calculated creatinine clearance > 50 mL/min by the Schwartz formula.
• Hepatic function: alanine aminotransferase (ALT) ≤ 3 × ULN and aspartate aminotransferase (AST) ≤ 3 × ULN.
• Cardiac function: left-ventricular ejection fraction (LVEF) ≥ 50 %.
• Good compliance; willing to adhere to visit schedules, study procedures, laboratory tests, and other protocol requirements.
• Agrees to use at least one highly effective contraceptive method from informed-consent signature through the end of the main study (Week 52 visit).
• Willing to participate in long-term follow-up.
• Screening genotype shows HbSS or HbSβ0; prior reports acceptable if assessed as adequate by the investigator.
• If on L-glutamine, regimen must have been stable for ≥ 3 months before study-drug administration; if on hydroxyurea, must have discontinued ≥ 8 weeks before study-drug administration.
• Meets severe SCD criteria: despite optimal supportive therapy (including, but not limited to, analgesics and hydroxyurea), at least two of the following events occurred in the 12 months before screening:
• Severe intermittent acute pain requiring healthcare-provider management;
• Acute chest syndrome with new pulmonary infiltrate on chest imaging plus pneumonia-like symptoms, pain, or fever;
• Splenic sequestration crisis manifested by enlarged spleen, left upper-quadrant pain, and acute Hb drop > 20 g/L.

Exclusion criteria

• 1.History of multiple drug allergies or hypersensitivity to oligonucleotides or lipid nanoparticles (LNP).

2.Clinically significant active bacterial, viral, fungal, or parasitic infection at screening, as judged by the investigator.

3.White blood cell (WBC) count < 3 × 10⁹/L and/or platelet count < 100 × 10⁹/L at screening.

4.Uncorrected bleeding diathesis. 5.Massive splenomegaly at screening (spleen edge below the umbilicus or > 4 cm below the costal margin) deemed by the investigator to preclude enrollment.

6.Serum ferritin ≥ 5 000 ng/mL, or MRI T2\* evidence of severe cardiac or hepatic iron overload.

7.Positive for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus antibody, anti-HIV antibody, or specific anti-Treponema pallidum antibody.

8.Prior hematopoietic stem-cell transplantation, gene therapy, or gene-editing therapy.

9.Participation in another clinical trial and receipt of investigational product within 3 months before first dose of study drug.

10.Current or prior malignancy, myeloproliferative disorder, or immunodeficiency disease.

11.Severe psychiatric illness precluding cooperation; clinically significant pulmonary hypertension requiring medical intervention; recent malaria; first-degree relative with hematologic malignancy.

12.Positive pregnancy test, pregnancy, or lactation in female subjects at screening.

13.Any condition (past or present) that, in the investigator's opinion, could confound results, compromise participation, or render the patient unsuitable for the study.

14.Use within 3 months before study drug: erythropoietin (EPO), thalidomide, hydroxyurea, luspatercept, or similar agents.

15.In subjects ≥ 12 years, abnormal transcranial Doppler (TCD) with middle cerebral or internal carotid artery velocity ≥ 200 cm/s.

16.History of moyamoya disease or imaging findings consistent with moyamoya at screening, assessed by the investigator as conferring bleeding risk.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Guangzhou women and children's medical center — Guangzhou

Identifiers

NCT: NCT07190001 · YOLT-204-IIT-002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗