Phase I Exploratory Study of YOLT-203 in Patients With Primary Hyperoxaluria Type 1 (PH1)

Inclusion criteria

Subjects must meet ALL of the following criteria to be eligible for participation in this study:

Age ≥ 6 years at the time of signing the informed consent form. Documented confirmation of Primary Hyperoxaluria Type 1 (PH1) diagnosis via genetic analysis prior to enrollment.

Mean 24-hour urinary oxalate excretion level ≥ 0.7 mmol/24 h/1.73 m² obtained from at least two valid 24-hour urine collections.

If the subject is receiving vitamin B6, the stable treatment regimen must have been maintained for a minimum of 90 days prior to enrollment, and the subject is willing to continue this regimen from administration of study drug through the end of the study.

The subject is capable of understanding, willing, and able to comply with study requirements, and provides written informed consent. For subjects below the legal age of consent, a legal guardian must sign the informed consent form, and the subject shall provide assent in accordance with local and national requirements.

Exclusion criteria

• Subjects with any of the following conditions will be excluded:

Patients who respond well to vitamin B6 (pyridoxine) treatment, with urinary oxalate excretion returning to normal after treatment.

Clinical evidence of extrarenal systemic oxalosis.

Any of the following laboratory test results observed at screening:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN).
• Total bilirubin > 1.5 × ULN. Subjects diagnosed with Gilbert syndrome whose total bilirubin < 2 × ULN may be enrolled.
• International normalized ratio (INR) > 1.5 (subjects taking oral anticoagulants such as warfarin with INR < 3.5 are allowed to participate).

Known history of HIV infection or evidence of HIV infection (positive HIV antibody); active or chronic hepatitis C virus (HCV) infection (positive HCV antibody and positive HCV RNA polymerase chain reaction) or hepatitis B virus (HBV) infection (positive hepatitis B surface antigen [HBsAg]).

Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m² at screening (for subjects ≥ 18 years old: calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; for subjects < 18 years old: calculated using the Schwartz bedside equation).

Receiving dialysis treatment (peritoneal dialysis [PD] and/or hemodialysis [HD]) or expected to require dialysis treatment during the study period.

Received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to administration of the study drug, or participated in follow-up of another clinical study before enrollment.

Prior receipt of gene editing therapy, or receipt of small interfering ribonucleic acid (siRNA) therapy within the following timeframes (based on drug half-life and dosing frequency). RNAi therapy is prohibited unless administered as rescue therapy:

i. Lumasiran: less than 15 months from the last dose to administration of the study drug.

ii. Nedosiran: less than 150 days from the last dose to administration of the study drug.

History of kidney or liver transplantation, or expected to require liver and/or kidney transplantation during the study period.

Other medical conditions or comorbidities that, in the Investigator's judgment, may interfere with study compliance or data interpretation.

History of multiple drug allergies or hypersensitivity reactions to oligonucleotides or lipid nanoparticles (LNPs).

Unwilling to comply with contraception requirements throughout the entire study participation period until 6 months after the end of the study.

Female subjects who are pregnant, planning to become pregnant, or breastfeeding.

Unwilling or unable to limit alcohol intake throughout the study period. Daily alcohol intake exceeding 2 standard units during the study (1 standard unit: approximately 125 mL wine = approximately 29 mL spirits = approximately 284 mL beer).

History of alcohol abuse or substance abuse within 12 months prior to screening as judged by the Investigator.

Inability to adhere to standard supportive care (adequate water intake, potassium citrate, dietary requirements, etc.).