Clinical trial NCT06687733: Safety and Efficacy Study of NGGT002 in cPKU Adult Subjects
Official title: A Phase I/II Study for the Safety and Efficacy of Intravenous Infusion With NGGT002 in Adults Patients With Classic Phenylketonuria
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Phenylketonurias
Lead sponsor: NGGT (Suzhou) Biotechnology Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2024-11-14
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Incidence and severity of Adverse Events (AEs)
timeFrame: Baseline to Week 52
measure: Change from baseline in average Plasma Phe Concentration
timeFrame: Week 12, Week 28, Week 52
Secondary outcomes:
measure: Incidence of sustained plasma Phe concentration of ≤360 μmol/L (6 mg/dL) at Week 12, Week 28, Week 52 post dose
timeFrame: Week 12, Week 28, Week 52
measure: 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
timeFrame: Week 52
measure: Change from baseline in Phe and total protein intake at Week 28, Week 52 post dose
timeFrame: Week 28, Week 52
measure: Score change in Phenylketonuria Quality of Life Questionnaire (PKU-QOL)
timeFrame: Week 28, Week 52
Other outcomes:
Locations:
city: Bengbu
country: China
facility: First Affiliated Hospital of Bengbu Medical College
state: Anhui
city: Shanghai
country: China
facility: Xinhua Hospital Affifiated to Shanghai Jiao Tong University School of Medicine
Study officials:
affiliation: First Affiliated Hospital of Bengbu Medical College
name: Jianping Weng, PhD
role: PRINCIPAL_INVESTIGATOR
References: