YOLT-204 in Patients With Hemoglobinopathies

Lab values

• 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.

• 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.