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

Study Overview

• Status: Active, not recruiting
• Conditions: Type 1 Primary Hyperoxaluria
• Intervention / Treatment: Drug: YOLT-203

• Study Type: Interventional
• Enrollment (Estimated): 2
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510623
      • Guangzhou Women and Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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.

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  • 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open Label single dose; YOLT-203	Drug: YOLT-203; The IP is administered intravenously at the predetermined dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse events	An Adverse Event(AE) is any untoward medical occurrence in a participant or clinical investigational participant adminstered a medicinal product and which does not necessarily have a casual relationship with this treatment	through week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Peak Plasma Concentration (Cmax) of YOLT-203	The Peak Plasma Concentration (Cmax) of YOLT-203 in the plasma after a dose is given	through Day 14
Area under the plasma concentration versus time curve (AUC)of YOLT-203	Area under the plasma concentration versus time curve (AUC). 0.5 predose,6,24,48,144,and312 hours after treatment	through Day 14
Time to Maximum Plasma Concentration (Tmax)of YOLT-203	Tmax is the time it takes for YOLT-203 to reach the maximun concentration (Tmax) after administration	through Day 14
Drug half-life (T1/2)of YOLT-203	The amount of time it takes for the plasma YOLT-203 drug concentration to drop to half	through Day 14
The changes in blood glycolic acid levels	After medication, at 1, 2, 4, 8, 16, 24, 36, and 52 weeks, the changes in blood glycolic acid levels	through week 52
The changes in 24-hour urinary oxalic acid excretion	After medication, at 1,2,4, 8, 16, 24, 36and 52 weeks, the changes in 24-hour urinary oxalic acid excretion compared to the baseline value.	through week 52
The changes in 24-hour urinary glycolic acid excretion	After medication, at 1, 2, 4, 8, 16, 24, 36, and 52 weeks, the changes in 24-hour urinary glycolic acid excretion	through week 52
The changes in eGFR	After medication, at 1, 2, 4, 8, 16, 24, 36, and 52 weeks, the changes in eGFR.	through week 52

Collaborators and Investigators

• Sponsor: Guangzhou Women and Children's Medical Center
• Investigators: Principal Investigator: Wenhao Zhou, PhD, MD, Guangzhou Women and Children's Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2025
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: February 26, 2025
• First Submitted That Met QC Criteria: March 18, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 18, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Carbohydrate Metabolism, Inborn Errors; Hyperoxaluria; Hyperoxaluria, Primary
• Other Study ID Numbers: PH1-YOLT-203-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No