FDA greenlights pivotal trial of gene-editing therapy for PH1

The FDA has granted clearance to an Investigational new drug (IND) application to initiate a pivotal trial of YOLT-203, an investigational in vivo gene-editing therapy for primary hyperoxaluria type 1 (PH1), YolTech Therapeutics announced in a news release.¹

The multicenter, double-blind study will assess the safety and efficacy of YOLT-203 in reducing urinary oxalate levels and improving long-term renal outcomes in patients with PH1. According to the company, this is the first pivotal trial of an in vivo gene-editing therapy for this patient population. 

YOLT-203 is designed to be a “once-and-done” treatment for PH1. The therapy “aims to reduce the oxalate overproduction in patients [with PH1] by deactivating glycolate oxidase (GO), an enzyme encoded by HAO1 gene and suppressing the synthesis of oxalate precursors.”

The FDA previously granted YOLT-203 Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation in September 2024. The European Medicines Agency has also granted an ODD to the therapy.

Previous Data on YOLT-203

In February 2025, YolTech Therapeutics shared early phase 1 data on YOLT-203 from the YOLT-203-101 trial (NCT06511349).² Overall, the therapy showed show encouraging safety, tolerability, and efficacy amongst the first 7 patients with PH1 who were enrolled in the trial.

For the study, patients received YOLT-203 intravenously at 1 of 2 dose levels: 0.3 mg/kg or 0.45 mg/kg.³ All patients were enrolled through a single center in China.

In the highest dose cohort, patients achieved a nearly 70% reduction in 24-urinary oxalate levels, which were sustained through 16-week follow-up. Treatment was well tolerated across all dose levels. No serious adverse events (AEs), treatment discontinuations, or patient withdrawals had been observed at the time of data report.

In total, the open-label, dose-escalation/dose-expansion study plans to enroll 21 patients. To be eligible for enrollment, patients need to be 2 years of age or older, harbor AGXT gene mutations, have an eGFR of at least 30 mL/min/1.73m², and have at least 2 instances of 24-hour urinary oxalate levels of 0.7 mmol/1.73m² or greater per day or the ratio of urinary oxalate to creatinine in a single urine collection must be higher than the upper limit of normal for the patients’ age group. Additionally, if patients are treated with vitamin B6, the treatment must be stable for 90 days before enrollment and the treatment plan must remain stable for the duration of the study.

The primary end point for the trial is safety and tolerability, measured by the incidence and severity of AEs and serious AEs through week 52. Secondary end points include pharmacokinetic measures such as the peak plasma concentration through day 14, as well as several pharmacodynamic measures such as changes in estimated glomerular filtration rate at various time points.

Patients in the study will continue to be followed through week 52 in the trial, with final completion planned for December 2026. Following the 1-year main study, the sustained safety and efficacy of the treatment will continue to be monitored in patients for up to 15 years.

REFERENCES

1. YolTech Therapeutics receives FDA IND clearance to initiate global pivotal trial of in vivo gene-editing therapy YOLT-203 for primary hyperoxaluria type 1 (PH1). News release. YolTech Therapeutics. November 18, 2025. Accessed November 20, 2025. https://www.businesswire.com/news/home/20251117980866/en/YolTech-Therapeutics-Receives-FDA-IND-Clearance-to-Initiate-Global-Pivotal-Trial-of-In-Vivo-Gene-Editing-Therapy-YOLT-203-for-Primary-Hyperoxaluria-Type-1-PH1

2. YolTech Therapeutics announces positive clinical data for YOLT-203, an in vivo gene editing therapy for primary hyperoxaluria type 1 (PH1). News release. YolTech Therapeutics. Published online and accessed February 25, 2025. https://www.yoltx.com/news/press-release/74

3. Clinical exploration study of YOLT-203 in the treatment of type 1 primary hyperoxaluria (PH1). ClinicalTrials.gov. Last updated December 19, 2024. Accessed February 25, 2025. https://clinicaltrials.gov/study/NCT06511349