The Efficacy and Safety of ZS802 in Chinese Hemophilia A Patients.

Study Overview
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Brief Summary
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A non-randomized, open-label, dose-escalation study to evaluate the safety, tolerability, kinetics and efficacy of a single intravenous infusion of ZS802 in hemophilia A subjects with endogenous FVIII ≤2%.

Detailed Description
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This study will seek to determine the safety, tolerability, kinetics and efficacy of a single IV infusion of ZS802. Hemophilia A is a genetic bleeding disorder resulting in the lack of ability to produce blood-clotting factor VIII (FVIII). Individuals with hemophilia A suffer repeated bleeding events, which can cause chronic joint disease and sometimes leads to death due to the inability for blood to clot efficiently. The current treatment is intravenous infusion of FVIII protein products, either prophylactically or in response to bleeding. ZS802 is an adeno-associated viral (AAV) vector designed to drive expression of the human factor VIII (hFVIII) transgene and raise circulating levels of endogenous FVIII. 6 patients will be enrolled sequentially every 3 weeks or more between cohorts and administered with single infusion of ZS802. Dose escalation may occur based on the safety and FVIII activity on steady state. The dose levels are as follows: 1. 2.0×10^13vg/kg; 2. 6.0×10^13vg/kg. Subjects will provide informed consent and then undergo screening assessments up to 6-8weeks prior administration of ZS802. All subjects will undergo 52 weeks safety and efficacy observation.

Official Title
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A Non-randomized, Open-label, Dose-escalation Study to Evaluate the Safety, Tolerability, Kinetics and Efficacy of a Single Intravenous Infusion of ZS802 in Hemophilia A Subjects With Endogenous FVIII ≤2%.

Conditions
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Hemophilia A

Intervention / Treatment
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* Genetic: ZS802


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male ≥18 years and ≤65years of age; Confirmed diagnosis of hemophilia A, and endogenous FVIII ≤2%: <1% (<1 IU/dL) endogenous FVIII activity levels as historically documented by a certified laboratory or screening data results; OR 1%-2% (1-2 IU/dL) endogenous FVIII activity levels and >10 bleeding events per year (in the last 52 weeks prior to screening); OR 1%-2% (1-2 IU/dL) endogenous FVIII activity levels and on prophylaxis; Have had ≥150 prior exposure days (EDs) to any recombinant and/or plasma-derived FVIII protein products. Agree to use reliable barrier contraception and prohibition of sperm donation until 52 weeks after the administration of ZS802. Subjects voluntarily participate and are fully informed, fully understand the research and can comply with the requirements of the research protocol, are willing to complete the research as planned, and voluntarily cooperate with the provision of biological samples for testing. Exclusion Criteria: Hypersensitivity to any component of the study drug (including immunosuppressants) or a condition that can not use. Inability to tolerate immunosuppressants or steroid drugs. Have no measurable FVIII inhibitor as assessed by laboratory; or documented no prior history of FVIII inhibitor. Who have a history or are currently suffering from any of the following serious clinical diseases: History of malignancy or current presence of any malignancy; Have active autoimmune disease; Severe heart disease, including angina pectoris, myocardial infarction, heart failure, clinically significant congenital heart disease, heart valve disease, arrhythmia and atrioventricular block, etc.; Have underlying liver disease or history of liver disease (such as portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy or hepatic fibrosis); Have active hepatitis B infection (HBsAg positive or HBV-DNA positive) or active hepatitis C infection (HCVAb positive), or are currently receiving hepatitis B or hepatitis C antiviral therapy; Have history of chronic infection or other chronic disease that the Investigator considers to constitute an unacceptable risk; Diabetes mellitus that is poorly controlled after drug treatment; Uncontrolled hypertension or hypotension; laboratory values: Hemoglobin<110g/L; Platelets<100×10^9/L; AST, ALT, alkaline phosphatase>2×ULN; Total bilirubin>1.5×ULN; Creatinine>ULN; Albumin<LLN; HIV antibody positive or Treponema pallidum antibody positive. Have AAV5 capsid neutralizing antibody titers >1:5. Those who have received clinical trials of gene therapy before screening, or have used FVIII clinical trial drugs within 1 month, or participated in other drug/device clinical trials within 3 months, or plan to participate in other clinical trials during this study. Those who have planned surgery within 52 weeks after the infusion. Those who donated or lost more than 400 mL of blood within 3 months before screening. Those with epilepsy, history of mental illness (such as schizophrenia, depression, mania or anxiety) or obvious mental disorder, incapacitated or incapacitated by other reasons. Patients with a history of drug abuse or alcoholism. Investigators believe that subjects have poor compliance or are expected to be less likely to complete follow-up. There are clinically significant diseases or other reasons that the researcher and/or collaborators consider unsuitable to participate in this researcher.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Hemophilia A patients
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZS802<br>Single intravenous (i.v.) infusion of ZS802 Intervention: Gene Therapy / Gene Transfer | Genetic: ZS802<br>* A novel, bioengineered adeno-associated viral (AAV) vector carrying human factor VIII variant. The dose levels are as follows: 1. 2.0×10^13vg/kg; 2. 6.0×10^13vg/kg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | An adverse event (AE) is any medical occurrence, the event will not relate to the treatment. | Baseline up to Week 52 | 
| Number of participants with clinically significant change from baseline in vital signs | Vital signs will be obtained with participants in the seated position, after having sat calmly for at least 5 minutes. The clinical significance of vital signs will be determined at the investigator's discretion. | Baseline up to Week 52 | 
| Number of participants with clinically significant change from baseline in physical examination findings | Findings will be considered to be clinically significant based on the investigator's decision. | Baseline up to Week 52 | 
| Number of participants with clinical laboratory abnormalities | Findings were considered to be clinically significant based on the investigator's decision. | Baseline up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vector-derived FVIII:C Activity | Peak and steady-state vector-derived circulating FVIII activity levels, and changes of FVIII activity levels after treatment compared with baseline. | Baseline up to Week 52 | 
| Vector-derived FVIII antigen levels | Peak and steady-state vector-derived circulating FVIII antigen levels, and changes of FVIII antigen levels after treatment compared with baseline. | Baseline up to Week 52 | 
| Vector shedding of ZS802 | Blood, saliva, urine and semen will be collected to assess clearance of vector genomes. | Baseline up to Week 52 | 
| Antibody against AAV capsid protein | Immune response against AAV capsid will be evaluated by measurement of the binding antibody and neutralizing antibody against AAV capsid protein in plasma samples. | Baseline up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene therapy, Adeno-associated virus, Hemophilia A