Safety and Efficacy Study of NGGT002 in cPKU Adult Subjects

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

Study Overview

• Status: Recruiting
• Conditions: Phenylketonurias
• Intervention / Treatment: Genetic: NGGT002

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Huan Zhou, PhD; Phone Number: 8613665527160; Email: zhouhuanbest@vip.163.com

Study Locations

• China
  • Shanghai, China
    • Recruiting
    • Xinhua Hospital Affifiated to Shanghai Jiao Tong University School of Medicine
    • Contact: Wenjuan Qiu, PhD
    • Principal Investigator: Wenjuan Qiu, PhD
  • Anhui
    • Bengbu, Anhui, China
      • Recruiting
      • First Affiliated Hospital of Bengbu Medical College
      • Contact: Huan Zhou, PhD; Phone Number: 8613665527160; Email: zhouhuanbest@vip.163.com

Participation Criteria

Eligibility Criteria

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

Description

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. Subjects whose disease is well-controlled with existing therapies, such as those currently receiving medications like Sapropterin Dihydrochloride tablets, Pegvaliase-pqpz, etc.;

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 subject 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. Subjects with a history of substance abuse (e.g., alcohol, heroin, amphetamines, etc.);
13. Subjects who have received gene therapy at any time in the past.
14. Subjects 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. Subjects 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. Subjects weighing more than 100 kg;
18. Subjects whose daily diet includes excessive natural protein intake (>2 g/kg/day).

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: NGGT002; Six to eighteen patients will be enrolled into three cohorts at three dose levels.	Genetic: NGGT002; adeno-associated viral vector with human phenylalanine hydroxylase gene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of Adverse Events (AEs)	Incidence and severity of AEs, including serious AEs (SAEs) as assessed by CTCAE v5.0 of a single administration of NGGT002.	Baseline to Week 52
Change from baseline in average Plasma Phe Concentration	To evaluate the efficacy in change of average plasma Phe concentration of IV infusion of NGGT002 in adults with classic PKU at Week 12, Week 28, Week 52	Week 12, Week 28, Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of sustained plasma Phe concentration of ≤360 μmol/L (6 mg/dL) at Week 12, Week 28, Week 52 post dose	Subjects achieving a sustained plasma Phe concentration ≤360 μmol/L (6 mg/dL) at Week 12, Week 28, Week 52 post dose.	Week 12, Week 28, Week 52
Occurred Day to first reach Phe ≤ 360 μmol/L and the duration（days） of Phe ≤ 360 μmol/L in each dose group following NGGT002 administration	Time（days） to first reach Phe ≤ 360 μmol/L and the duration（days） of Phe ≤ 360 μmol/L in each dose group following NGGT002 administration	Week 52
Change from baseline in Phe and total protein intake at Week 28, Week 52 post dose	Subject achieving a change from baseline in Phe and total protein intake at Week 28, Week 52 post dose.	Week 28, Week 52
Score change in Phenylketonuria Quality of Life Questionnaire (PKU-QOL)	Score change in PKU-QOL at Week 28, Week 52 post dose	Week 28, Week 52

Collaborators and Investigators

• Sponsor: NGGT (Suzhou) Biotechnology Co., Ltd.
• Investigators: Principal Investigator: Jianping Weng, PhD, First Affiliated Hospital of Bengbu Medical College

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2024
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): July 30, 2031

Study Registration Dates

• First Submitted: November 11, 2024
• First Submitted That Met QC Criteria: November 12, 2024
• First Posted (Estimated): November 14, 2024

Study Record Updates

• Last Update Posted (Estimated): November 14, 2024
• Last Update Submitted That Met QC Criteria: November 12, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: NGGT002-P-2302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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