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 follow-up. 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 V1.4 , 28 Aug 2024

As of December 2024, the clinical study of YOLT-203 for the treatment of type 1 primary hyperoxaluria (PH1) has completed enrollment and dosing for two cases at 0.3mg/kg and three cases at 0.45mg/kg, as well as a 28-day follow-up for all participants. On December 6, 2024, a meeting was held to discuss the safety and efficacy data of all participants in the two dosage groups and to make decisions on the next steps of the research plan.

Based on the safety and efficacy data from all participants in this project, the sponsor and investigators reached a consensus after a meeting discussion: YOLT-203 has good safety, and 0.45mg/kg is the anticipated biologically effective dose (OBD). According to the protocol design, the meeting decision was made to stop dose escalation and repeat a group at the anticipated effective dose (0.45mg/kg), continuing to enroll 1-3 more participants for exploratory studies.

Eligibility Criteria:
Inclusion Criteria:

* The age is ≥ 2 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 extra-renal 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 half-lives (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.
* 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.