AAV Gene Therapy Clinical Study in Adult Classic PKU

An Open-Label, Multiple-Center, Phase I/II Dose Escalation Study for the Safety and Efficacy of NGGT002 in Adults 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 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Phenylketonurias
• Intervention / Treatment: Genetic: NGGT002

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.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yiting Liu; Phone Number: (717) 480-0202; Email: yitingliu@nggtbio.com
• Study Contact Backup: Name: Jinxiao Xu; Phone Number: 8651283912888; Email: jxxu@nggtbio.com.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. 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
2. 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)
3. Adults aged 18-55 at the time of informed consent
4. Subjects' intolerant or unresponsive to available medical therapies, such as Kuvan, Playnzip, etc.
5. 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. (Patients who have good disease control on these existing therapies will not be included in this study).
6. At least two documented measurements of Phe ≥ 600 μmol/L in the preceding 24 months with one measurement obtained > 6 months prior to enrollment and one measurement obtained < 6 months prior to enrollment. All Phe levels should be drawn while patients are on a Phe restricted diet and in the absence of acute illness.
7. Subject has the record of at least 3 months of stable Phe-restricted diet as their baseline diet, but with persistently elevated phenylalanine (Phe) levels despite dietary adherence and has willingness to follow the instruction of dietitians to manage the diet for the duration of the trial.
8. Willingness and capable per Investigator opinion to comply with study procedures and requirements

9. Women of childbearing potential must be confirmed as negative non pregnant patients by blood pregnancy test from day -28 to day 0. 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 NGGT002. Highly effective birth control methods include:

   • documented vasectomy or permanent sterilization
   • condom
   • combined (estrogen and progestogen-containing) hormonal contraception (oral, intravaginal or transdermal)
   • progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable)
   • intrauterine device
   • intrauterine hormone-releasing system
   • sexual abstinence is acceptable only as true abstinence and when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, hypothermal, post-ovulation) is not acceptable as a form of abstinence.

Exclusion Criteria:

1. Subjects with PKU that is not due to PAH mutation
2. Presence of anti-AAV8 neutralizing antibodies

3. Prior to dosing, patients 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×ULN
   • 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
4. At the time of screening, abnormal vital signs (i.e. Temperature˂36.3°C or >37.4°C; Blood pressure<100/60 mmHg or >130/80 mmHg; heart rate <60/min or>100/min; respiratory rate ˂12/min or >18/min; oxygen saturation<95%), physical examination, laboratory tests, or other related results that have clinical significance, and the researchers believe they are unsuitable for enrollment.
5. Contraindications to corticosteroid use or possible deterioration of corticosteroid use assessed and determined by the Investigator.
6. Active infection with hepatitis A virus (HAV ribonucleic acid [RNA] positive), active or occult hepatitis B virus infection (positive HBV-DNA or anti-HBc positive with negative HBsAg, HBV surface antigen), active infection with hepatitis C virus (HCV RNA positive), infection with the human immunodeficiency virus (HIV) as measured by quantitative polymerase chain reaction (qPCR), or active or latent infection with tuberculosis (TB) measured by QuantiFERON Gold, or infection with syphilis by rapid plasma reagin (RPR)
7. Subjects with history of liver disease such as clinically significant steatosis, fibrosis, non-alcoholic steatohepatitis (NASH) and cirrhosis, biliary disease within 6 months of informed consent; except for Gilbert's syndrome.
8. History of malignancy
9. Severe live diseases like Liver fibrosis with Metavir score ≥3 points and cirrhosis of the liver
10. Severe diseases in the cardiovascular, respiratory, digestive tract, endocrine, kidney, blood, nervous, mental and other systems before screening.
11. History of allergy to Albumin (Human)
12. The subjects who have substance use disorder (for example alcohol, heroin, amphetamine, etc)
13. The subjects who have received any gene therapy in the past, regardless of when it was administered.
14. The subjects who have received any investigational treatment and took drugs within 3 months before screening (or 5 half-lives, if longer)
15. Subjects with elevated circulating serum alpha-fetoprotein (AFP)
16. Other conditions that the Investigators deemed inappropriate for enrollment, such as PKU severe comorbidities and conditions (i.e. renal insufficiency or kidney failure, osteoporosis, anemia, acid reflux or gastro-esophageal ulcer, major depression, epilepsy, etc.), which may be deteriorated with the potential risks of NGGT002. And conditions which may be deteriorated with the potential risks of NGGT002 as listed in Section 10. Potential Risks and Solutions
17. Subjects who are presently on available medications for the treatment of PKU, such as Kuvan, Palynziq, etc.
18. Subjects who weight over 100 Kg (obesity)
19. Subjects who consume too much protein (>2 mg/Kg body weight/day) in their daily diet

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; Low dose and high dose group Six to twelve patients will be enrolled into two cohorts at two dose levels. The safety of this study can be ensured by selecting the highest dose under the No Observed Adverse Effect Level (NOAEL) doses observed in preclinical toxicology studies.	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 and during Year 1 to 5
Change from baseline in clinical laboratory values	Change in chemistry values including liver function tests, hematology and urinalysis.	Baseline to Week 52 and during Year 1 to 5
Change from baseline in 12-lead electrocardiograms (ECGs), vital signsand physical examinations	Subjects change from baseline in 12-lead electrocardiograms (ECGs), vital signs and physical examinations.	Baseline to Week 52 and during Year 1 to 5
Change from baseline in Plasma Phe Concentration	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.	Baseline to Week 52 and during Year 1 to 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of sustained plasma Phe concentration of ≤360 μmol/L at Week 12, Week 28, Week 52 and during Year 1 to 5 post dose	Subjects achieving a sustained plasma Phe concentration ≤360 μmol/L 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	Subject achieving a change from baseline in total protein intake 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 PKU Profile of Mood States (POMS)	Change in PKU Profile of Mood States (POMS) 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)	Change in PKU-QOL at Week 28, Week 52 and during Year 1 to 5 post dose.	Baseline to Week 52 and during Year 1 to 5

Collaborators and Investigators

• Sponsor: NGGT (Suzhou) Biotechnology Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): May 22, 2024
• Primary Completion (Estimated): December 30, 2030
• Study Completion (Estimated): December 30, 2030

Study Registration Dates

• First Submitted: February 7, 2024
• First Submitted That Met QC Criteria: March 22, 2024
• First Posted (Actual): March 27, 2024

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: PAH; Phenylalanine; Phenylalanine Hydroxylase
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: NGGT002-P-2301

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