Phase I/II Open-Label Study of GNT0003 for Safety and Efficacy in Severe Crigler-Najjar Syndrome Requiring Phototherapy

The primary objective of this study is to evaluate the **safety** and tolerability of an intravenous single-dose administration of GNT0003 in patients with severe Crigler-Najjar syndrome requiring phototherapy. This is clinically relevant as it aims to ensure that the treatment is safe for patients, which is a critical step before assessing its therapeutic potential. Additionally, the study seeks to assess the efficacy of the intravenous single-dose administration of a selected dose of GNT0003 in the same patient population, which is crucial for determining the treatment's potential to reduce the need for phototherapy.

Secondary objectives include:

• Assessing the **pharmacokinetics** of GNT0003 during the dose escalation part.
• Evaluating the efficacy of the intravenous single-dose administration of GNT0003 in patients with severe Crigler-Najjar syndrome requiring phototherapy during the dose escalation part.
• Assessing the safety of the intravenous single-dose administration of the selected dose of GNT0003 during the confirmatory part.
• Evaluating the impact of the selected dose of GNT0003 on patients' Quality of Life during the confirmatory part.
• Assessing the pharmacokinetics of the selected dose of GNT0003 during the confirmatory part.
• Assessing the pharmacodynamics of the selected dose of GNT0003 during the confirmatory part.

The clinical trial involves participants diagnosed with **severe Crigler-Najjar syndrome**, specifically those requiring phototherapy. The study population includes both male and female subjects, encompassing a broad age range from infants to adults. Participants are selected based on the necessity for daily phototherapy, defined as six or more hours per day, and must have molecular confirmation of mutations in the UGT1A1 gene through DNA sequencing. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and ethical treatment. However, the sponsor has not provided information regarding the total number of participants involved in the study. Lifestyle factors such as diet and physical activity are not specified, focusing instead on the medical condition and genetic criteria for inclusion.

The clinical trial is designed as a **phase I/II**, open-label study to evaluate the safety and efficacy of an intravenous injection of GNT0003, an **adeno-associated viral vector serotype 2/8 containing the human UGT1A1 gene**, in patients with severe **Crigler-Najjar syndrome** requiring phototherapy. The trial is structured into two parts: a dose escalation part and a confirmatory part. The primary objective of the dose escalation part is to assess the safety and tolerability of a single-dose administration of GNT0003, while the confirmatory part aims to evaluate the efficacy of the selected dose. The trial is expected to conclude by October 2037, with recruitment having commenced in December 2017.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as the requirement for daily phototherapy and molecular confirmation of mutations in the UGT1A1 gene. Following the screening, participants will receive the investigational medicinal product (IMP) and will be monitored through regular follow-up visits. These visits will assess the incidence of treatment-emergent adverse events (TEAEs) and changes in laboratory parameters, vital signs, and physical examinations. The end-of-study visit will evaluate the long-term efficacy and safety outcomes, including the proportion of patients achieving serum total bilirubin levels ≤ 300 µmol/L without phototherapy.

The expected length of participant involvement varies between the dose escalation and confirmatory parts, with the latter extending up to 48 weeks post-IMP infusion. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or non-compliance with study protocols. The trial's endpoints include both primary and secondary measures, such as the time to GNT0003 vector clearance from biological samples and changes in health-related quality of life. The study employs a rigorous methodology to ensure the collection of comprehensive safety and efficacy data, contributing to the understanding of gene therapy's potential in treating severe Crigler-Najjar syndrome.

The clinical trial involves the administration of **rAAV8-hUGT1A1**, an experimental gene therapy product. This product is a **solution for infusion** containing an **adeno-associated viral vector serotype 2/8** that carries the human **UGT1A1** gene. The primary objective is to restore the expression of the UGT1A1 enzyme in hepatocytes, which is expected to facilitate the glucuronidation of bilirubin. The administration route is **intravenous infusion**, and the study is designed to evaluate the safety and efficacy of a single-dose administration in patients with severe Crigler-Najjar syndrome requiring phototherapy.

In addition to the experimental treatment, several non-experimental treatments are utilized in the study. **Sirolimus**, an immunosuppressant, is administered orally. The pharmaceutical form is coded as PHF00009MIG. The specific dosage and frequency of administration are not detailed in the provided data.

**Methylprednisolone**, a corticosteroid, is administered intravenously. The pharmaceutical form is coded as PHF00243MIG and contains **lidocaine hydrochloride monohydrate** and **methylprednisolone acetate** as active substances. The exact dosing schedule is not specified.

**Amoxicillin**, an antibiotic, is administered orally. The pharmaceutical form is coded as PHF00231MIG. The dosage and frequency of administration are not provided in the data.

**Prednisone**, another corticosteroid, is administered orally. The pharmaceutical form is coded as PHF00245MIG. The specific dosing regimen is not detailed in the available information.

**Prednisolone**, also a corticosteroid, is administered orally. The pharmaceutical form is coded as PHF00082MIG. The data does not specify the dosage or frequency of administration.

Participant compliance with the dosing schedules is monitored throughout the trial, although specific methods of compliance monitoring are not described in the provided data. The trial aims to ensure the safety and efficacy of the experimental treatment while managing any potential interactions with the non-experimental treatments.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In the dose escalation part of the study, primary endpoints include the incidence of treatment-emergent adverse events (TEAEs) or treatment-emergent serious adverse events (TESAEs) up to Week 17, as well as changes in laboratory parameters, vital signs, and physical examination from baseline to Week 17. In the confirmatory part, the primary endpoint is the proportion of patients who have received the selected dose of GNT0003 with serum total **bilirubin** levels ≤ 300 µmol/L at Week 48 after investigational medicinal product (IMP) infusion and without phototherapy from Week 16.

Secondary endpoints for the dose escalation part include the time to GNT0003 vector clearance from blood, urine, saliva, and feces, and the number of patients with serum total **bilirubin** ≤ 300 µmol/L within 7 days after interruption of daily phototherapy. In the confirmatory part, secondary endpoints encompass the incidence of TEAEs or TESAEs up to Week 48, changes in laboratory parameters, vital signs, and physical examination from baseline up to Week 48, changes in serum total **bilirubin** and **bilirubin**/albumin ratio from baseline up to Week 48, and changes in health-related quality of life as measured by QOL questionnaires, SF-36 (adult) and PedsQL (pediatric), and the quality of sleep questionnaire from baseline up to Week 48. Additionally, the time to GNT0003 vector clearance from blood, urine, saliva, and feces will be evaluated.