| Eligibility |
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
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