Fabry Disease
Conditions
Brief summary
Objective: To explore the safety and tolerability of different doses of EXG110 with Fabre disease
Detailed description
An open-label, multicenter, single-arm, non-randomized, dose-escalation, and recommended dose-extension clinical design was used to evaluate the safety and efficacy of a single intravenous administration of different doses of EXG110 in patients
Interventions
GENETICEXG110 injection
EXG110 is a recombinant adeno-associated virus (rAAV) that not only significantly increases plasma AGA activity, but is also highly expressed in target organs such as the heart and kidneys.EXG110 will be administered in a single dose by intravenous infusion.
Sponsors
The Children's Hospital of Zhejiang University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. At the time of signing the informed consent, age ≥7, male or female 2. Clinical symptoms (at least one Fabry disease related symptom) and genetic diagnosis of Fabry disease, 3. Prior or no prior ERT treatment 4. Have renal or cardiac involvement (adults only) 5. All subjects of reproductive age voluntarily took effective contraception and prohibited sperm donation from entering the screening period until 52 weeks after dosing (main study period) 6. The subjects voluntarily participate and are fully informed, fully understand the research, can comply with the requirements of the research protocol, and are willing to complete the research as planned, and voluntarily provide biological samples for testing according to the requirements of the protocol
Exclusion criteria
1. Screening period laboratory test results: a) aspartate aminotransferase or alanine aminotransferase \> 1.5× upper limit of normal (ULN);b) Total bilirubin \> 1.5× upper limit of normal (ULN);c) Alkaline phosphatase \> 2× upper limit of normal (ULN);d) Albumin \< lower limit of normal (LLN) 2. There was a clinically significant increase in AFP during the screening period 3. Serum virology test: a) Hepatitis B: Hepatitis B virus surface antigen (HBsAg) positive, and hepatitis B virus-deoxyribonucleic acid (HBV-DNA) higher than the upper limit of normal detection;b) Hepatitis C: if the hepatitis C virus (HCV) antibody is positive, and the hepatitis C virus-ribonucleic acid (HCV-RNA) is higher than the upper limit of normal test value;c) Syphilis: positive for syphilis screening (Tp-Ab) and positive for syphile-specific antibodies;d) HIV: Known human immunodeficiency virus (HIV) positive history or HIV screening positive 4. AVT917 (\>1:50), anti-AGA antibody positive(\>1:2560) 5. C3 lower than the normal range, C5b-9 higher than the normal range, anti-AVT917 IgM positive 6. Current or have a history of serious cardiovascular disease and surgical history 7. Current underlying liver disease or history of liver disease, as assessed by the investigator, that may affect the safety assessment of the drug 8. Renal disease in adult and the slope of kidney \>5 mL/min/1.73m²/year 9. Subjects with poorly controlled diabetes after drug treatment (e.g., HbA1c≥8%); 10. Acute/chronic infection or other chronic disease that the investigator determines will increase the risk of participants participating in the study 11. Patients with a history of malignant tumor or currently suffering from any malignant tumor (except for the following tumor diseases: skin basal cell carcinoma, cervical carcinoma in situ, breast carcinoma in situ, skin squamous cell carcinoma has been controlled after treatment); 12. Have malignancy cancer 13. Patients with active autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, immune vasculitis, inflammatory bowel disease, etc.); 14. known history of allergy to the components of the investigational products 15. Patients with a history of drug use or drug abuse or alcoholism 16. Use of systemic (intravenous or oral) immunomodulators within the past 6 months or currently 17. Initiation of treatment with blood pressure lowering drugs that affect proteinuria levels (such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or angiotensin-receptor/enkephalin inhibitors) within 4 weeks prior to screening, or changes in the therapeutic dose of these drugs within 4 weeks prior to screening; 18. Has received, or is currently receiving, a clinical trial of another investigational drug/medical device or treatment (other than vitamins and minerals) within 3 months prior to signing the informed consent (or within 5 half-lives of the investigational drug, whichever is longer) 19. Previous treatment with gene therapy products 20. Those who had received live attenuated vaccine/vaccine within 12 weeks prior to screening or planned to receive it during the study 21. Other clinical conditions that the investigators felt needed to be ruled out
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of adverse events | 52 weeks following EXG110 administration | Safety and tolerability of EXG110 following a single IV dose, as assessed by incidence and severity of adverse events, serious adverse events and dose limiting toxicities, including clinically significant changes from baseline to scheduled time points in safety parameters |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| eGFR change from baseline in mL/min/(1.73m^2); | 52 weeks following EXG110 administration | eGFR change from baseline in mL/min/(1.73m\^2) |
| NYHA cardiac function grade changed from baseline; | 52 weeks following EXG110 administration | NYHA cardiac function grade changed from baseline; |
| Changed from baseline: region and area in mm^2 of skin angiokeratoma The number of Gb3 deposition in skin biopsy under the microscope | 52 weeks following EXG110 administration | Changed from baseline: region and area in mm\^2 of skin angiokeratoma The number of Gb3 deposition in skin biopsy under the microscope |
| Change from baseline in serum AGA activity | 52 weeks following EXG110 administration | Change from baseline in serum AGA activity |
| Change from baseline serum lysoGb3 | 52 weeks following EXG110 administration | Change from baseline serum lysoGb3 |
Countries
China
Contacts
CONTACTJianhua Mao, PhD
PRINCIPAL_INVESTIGATORJianhua Mao, PhD
Children's Hospital, Zhejiang University School of Medicine
Outcome results
None listed