An Open-Label, Multiple-Center, Phase I/II Dose Escalation Study for the Safety and Efficacy of NGGT002 in Adults With Classic Phenylketonuria
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Phenylketonurias
- Sponsor
- NGGT INC.
- Enrollment
- 12
- Locations
- 5
- Primary Endpoint
- Change from baseline in clinical laboratory values
- Status
- Recruiting
- Last Updated
- 5 months ago
Overview
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 an 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 two dose cohorts in adult subjects with diagnosis of classic PKU, a condition characterized by severe PAH deficiency with no residual enzyme activity. NGGT002 will be administered through intravenous infusion. In Part 1 of the study, subjects will receive NGGT002 at the low dose. Dosing of the first 3 subjects will be staggered. Following evaluation of data from the first 3 subjects, a decision can be made to either escalate to the high dose level or expand the low dose cohort with additional 3 subjects. Upon completion of Part 1 study, based on the evaluation of and safety and efficacy, the study may be stopped or proceed to Part 2. In Part 2, the same process will be conducted with 3 -6 subjects dosed at the high dose.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Is willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures; a legally authorized representative may provide written consent and assent may be requested.
- •Male and female subjects with diagnosis of classic PKU, a condition characterized by severe PAH deficiency with confirmed PAH mutations predicted with no residual enzyme activity. A list of PAH mutations for classic PKU based on in vitro PAH activity (Himmelreich et al., 2018) and the genotype-phenotype correlation (Garbade et al., 2019) can be found in BIOPKU genotypes database (http://www.biopku.org/pah).
- •Adults aged 18-55 at the time of informed consent
- •Subjects intolerant or unresponsive to available medical therapies, such as Kuvan, Playnzip, etc.
- •Subjects who have been on medications, such as Kuvan, Palynziq, etc but have come off for medical reasons or the patient's decision at least 28 days prior to signing the consent form (Subjects who have good disease control on these existing therapies will not be included in this study).
- •At least 1 documented measurements of Phe ≥ 600 μmol/L while on usual diet in the preceding 6 months.
- •Subjects are willing to record their diet and follow the instruction of dietitians during the trial.
- •Willingness and capable per Investigator opinion to comply with study procedures and requirements.
- •Women of child bearing potential must be confirmed as negative non pregnant subjects by blood pregnancy test from day -28 to day
- •Subjects must agree to use a highly effective form of contraception from the time of NGGT002 administration until a minimum of 1 year after NGGT002 administration, and for male subjects, a minimum of 3 consecutive semen samples are negative for AAV8 after administration of NGGT
Exclusion Criteria
- •Subjects with PKU that is not due to PAH mutation
- •Presence of anti-AAV8 neutralizing antibodies
- •Prior to dosing, subjects exceed the limit of any of the following liver function and hematology tests in two consecutive blood laboratory tests:
- •Alanine aminotransferase (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
- •Blood creatinine (Scr) \>1.5×ULN
- •Hematology values outside of the normal range (Hemoglobin \<110 g/L (male), \<100 g/L (female), white blood cell \<3.0×10\^9/L, neutrophil \<1.5×10\^9/L, platelet \<100×10\^9/L)
- •Hemoglobin A1c \>6% or fasting glucose \>6.1 mmol/L
Outcomes
Primary Outcomes
Change from baseline in clinical laboratory values
Time Frame: Baseline to Week 52 and during Year 1 to 5
Change in chemistry values including liver function tests, hematology and urinalysis.
Change from baseline in Plasma Phe Concentration
Time Frame: Baseline to Week 52 and during Year 1 to 5
To evaluate the efficacy in change of plasma Phe concentration of IV infusion of NGGT002 in adults with classic PKU at Week 12, Week 28, Week 52 and during Year 1 to 5.
Incidence and severity of Adverse Events (AEs)
Time Frame: Baseline to Week 52 and during Year 1 to 5
Incidence and severity of AEs, including serious AEs (SAEs) as assessed by CTCAE v5.0 of a single administration of NGGT002.
Change from baseline in 12-lead electrocardiograms (ECGs), vital signsand physical examinations
Time Frame: Baseline to Week 52 and during Year 1 to 5
Subjects change from baseline in 12-lead electrocardiograms (ECGs), vital signs and physical examinations.
Secondary Outcomes
- Incidence of sustained plasma Phe concentration of ≤360 μmol/L (6 mg/dL) at Week 12, Week 28, Week 52 and during Year 1 to 5 post dose(Baseline to Week 52 and during Year 1 to 5)
- Change from baseline in total protein intake at at Week 28, Week 52 and during Year 1 to 5 post dose(Baseline to Week 52 and during Year 1 to 5)
- Change in Phenylketonuria Quality of Life Questionnaire (PKU-QOL)(Baseline to Week 52 and during Year 1 to 5)