Safety and Efficacy Study of NGGT002 in Adult Patients With Phenylketonuria

A Phase I/II Study for the Safety and Efficacy of Intravenous Infusion With NGGT002 in Adults Patients With Phenylketonuria

This is a Phase 1/2, open-label, multiple-center, dose escalation and cohort expansion study to evaluate the safety and efficacy of NGGT002 in adult subjects with classic Phenylketonuria (PKU). NGGT002 is a rAAV8 based vector carrying a functional copy of the human PAH gene.

Participants will receive a single administration of NGGT002 and will be followed for safety and efficacy for 5 years.

This study will evaluate the safety and efficacy of NGGT002 gene therapy with three dose cohorts in adult subjects with a diagnosis of classic PKU, a condition characterized by severe PAH deficiency with no residual enzyme activity. NGGT002 will be administered through intravenous infusion.

Inclusion Criteria:

1. Voluntarily participating in the study and signing the informed consent form;
2. Gender is not limited; patients must carry biallelic pathogenic or likely pathogenic variants in the PAH gene;
3. Adult patients aged 18 to 55 years;
4. In the past 24 months, at least two blood Phe concentrations have been ≥600 μmol/L (10 mg/dL), with at least one of these measurements taken within 6 months prior to the screening period;
5. Willing and able to manage their diet;
6. According to the investigator's opinion, willing and able to comply with the study procedures and requirements;
7. Women of childbearing potential must have a negative serum HCG test within 7 days before dosing. Participants must agree to use highly effective contraceptive measures for at least one year after receiving NGGT002.

Exclusion Criteria:

1. Presence of anti-AAV8 neutralizing antibodies（≥1:5）

2. Participants whose disease is well-controlled with existing therapies, such as those currently receiving medications like Sapropterin Dihydrochloride tablets, Pegvaliase-pqpz, etc. (excluding participants who have previously received the above-mentioned drug therapies but did not respond, and have been off treatment for more than 6 weeks);

3. Before dosing, the patient's hematological laboratory tests exceed any of the following limits:

   • Alanine Transaminase (ALT) > 1.5×ULN and/or Aspartate Aminotransferase (AST) > 1.5×ULN
   • Alkaline Phosphatase (ALP) > 1.5×ULN
   • Total Bilirubin (TBil) > 1.5×ULN, Direct Bilirubin > 1.5×ULN
   • International Normalized Ratio (INR) > 1.5
   • Serum Creatinine (Scr) > 1.5×ULN
   • Hematological values outside the normal range (Hemoglobin: <110 g/L for males, <100 g/L for females, White Blood Cells <3.0×10^9/L, Neutrophils <1.5×10^9/L, Platelets <100×10^9/L)
   • Glycated Hemoglobin (HbA1c) > 6% or Fasting Blood Glucose > 6.1 mmol/L

4. At screening, clinically significant abnormal vital signs, physical examination, laboratory test results, or other relevant findings that, in the investigator's opinion, make the subject unsuitable for inclusion;

5. In the investigator's assessment, the participant has contraindications to corticosteroid use or conditions that could lead to a worsening of the condition;

6. Hepatitis A virus infection, active or occult hepatitis B virus infection, active hepatitis C virus infection, positive for Human Immunodeficiency Virus (HIV) antibodies, positive syphilis test, active or latent tuberculosis (TB) infection;

7. A significant history of liver disease, such as steatosis, fibrosis, non-alcoholic steatohepatitis, and cirrhosis, biliary diseases, within 6 months prior to signing the informed consent form, except for Gilbert's syndrome;

8. History of malignant tumors;

9. Imaging (liver ultrasound) evidence of severe liver diseases such as hepatic fibrosis or cirrhosis;

10. In the investigator's assessment, the subject has a history of serious cardiovascular, respiratory, gastrointestinal, endocrine, renal, hematological, neurological, psychiatric, or other systemic diseases before screening;

11. History of allergy to human serum albumin;

12. Participants with a history of substance abuse (e.g., alcohol, heroin, amphetamines, etc.);

13. Participants who have received gene therapy at any time in the past.

14. Participants who have participated in other non-gene therapy drug clinical trials and received the investigational drug within 3 months (or 5 half-lives of the other investigational drug) prior to screening;

15. Participants with elevated Alpha-fetoprotein (AFP);

16. Other conditions that, in the investigator's opinion, make the subject unsuitable for inclusion, such as severe comorbidities associated with PKU (e.g., renal insufficiency or renal failure, osteoporosis, anemia, gastroesophageal reflux or peptic ulcer, major depressive disorder, epilepsy, etc.);

17. Participants whose daily diet includes excessive natural protein intake (>2 g/kg/day).