Clinical Exploration Study of YOLT-203 in the Treatment of Type 1 Primary Hyperoxaluria (PH1)

This study is a single-arm, open-label, single-dose, dose-escalation trial, aiming to evaluate the safety and tolerability of YOLT-203 in the Chinese population with type 1 primary hyperoxaluria (PH1); and to preliminarily assess the effect of a single dose of YOLT-203 on the plasma oxalate level.In this study, the maximum screening period of the main study is 60 days, the treatment day is Day 1 (D1), and the safety follow-up period is up to Week 52 after administration. In addition, subjects within the first dose group can voluntarily receive a second treatment with the test drug at the effective dose level. After the end of the main study, the subjects will undergo long-term followup. According to the requirements of the "Technical Guidelines for Long-Term Follow-up Clinical Studies of Gene Therapy Products (Trial)" issued by the CDE, the long-term follow-up is up to 15 years after administration. The most updated protocol is V1.2 , 22 Jan 2025


Eligibility Criteria:
Inclusion Criteria:

* The age is 2≤ years \<18 years old at the time of signing the informed consent.

  * Have AGXT gene mutations and be diagnosed with primary hyperoxaluria (PH1); eGFR ≥ 30 ml/min/1.73m2.
  * At least 2 times of 24-hour urinary oxalate excretion ≥ 0.7 mmol/1.73m2/ day or the ratio of urinary oxalate to creatinine in a single urine collection must be higher than the upper limit of normal (ULN) for the corresponding age.
  * If treated with vitamin B6, the treatment has been stable for 90 days before enrollment in the study and is willing to maintain the stable treatment plan unchanged during the study.
  * The patient himself/herself or the guardian voluntarily signs the informed consent.

Exclusion Criteria:

* The investigator judges that there is clinical evidence of systemic extrarenal oxalate deposition.

  * Have any of the following laboratory parameter assessment results at screening:

    1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2 x the upper limit of normal (ULN).
    2. Total bilirubin \> 1.5 x ULN. If the increase in total bilirubin is caused by diagnosed Gilbert's syndrome and the total bilirubin \< 2 x ULN, it is eligible.
    3. International normalized ratio (INR) \> 1.5 (Patients on oral anticoagulants \[such as warfarin\] and with INR \< 3.5 will be allowed to participate).
  * Known to have active human immunodeficiency virus (HIV) infection; or have evidence of current or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection.
  * The estimated glomerular filtration rate (GFR) at screening is less than 30 mL/min/1.73m² (For patients ≥ 18 years old, it will be calculated according to the Modification of Diet in Renal Disease \[MDRD\] formula; for patients \< 18 years old, it will be calculated according to the Schwartz bedside formula). See the attachment.
  * Have received an investigational drug within the last 30 days or 5 halflives (whichever is longer) before the first administration of the study drug, or have participated in the follow-up of another clinical study before randomization.
  * Have a history of kidney or liver transplantation.
  * According to the investigator's opinion, have other medical conditions or comorbidities that may interfere with study compliance or data interpretation.
* Page 4 of 5 \[DRAFT\] -

  * Have a history of multiple drug allergies or allergic reaction history to oligonucleotides or LNP.
  * Have a history of subcutaneous injection intolerance.
  * Unwilling to comply with contraceptive requirements throughout the study participation period until 6 months after the end of the main study trial.
  * Female patients are pregnant, planning to become pregnant or breastfeeding.
  * Unwilling or unable to limit alcohol consumption throughout the study. Alcohol consumption during the study exceeds 2 units per day (1 unit: approximately 125 ml of wine = approximately 29 ml of spirits = approximately 284 ml of beer, will be excluded.
  * The investigator believes that there is a history of alcohol abuse within 12 months before screening.