A Non-randomized, Open-label, Dose-escalation, Phase I/II Study to Evaluate the Safety, Tolerability, Kinetics and Efficacy of a Single Intravenous Infusion of ZS801 in Hemophilia B Subjects With Endogenous FIX ≤2%.
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 21
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events
Study Overview
Brief Summary
A non-randomized, open-label, dose-escalation, phase I/II study to evaluate the safety, tolerability, kinetics and efficacy of a single intravenous infusion of ZS801 in hemophilia B subjects with endogenous FIX ≤2%.
Detailed Description
This study will seek to determine the safety, tolerability, kinetics and efficacy of a single IV infusion of ZS801.
Hemophilia B is a genetic bleeding disorder resulting in the lack of ability to produce blood-clotting factor IX (FIX). Individuals with hemophilia B 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 FIX protein products, either prophylactically or in response to bleeding.
ZS801 is an adeno-associated viral (AAV) vector designed to drive expression of the human factor IX (hFIX) transgene and raise circulating levels of endogenous FIX.
Dose-escalation phase: 16 patients will be enrolled sequentially every 3 weeks or more between cohorts and administered with single infusion of ZS801. Dose escalation may occur based on the safety and FIX activity on steady state. The dose levels are as follows: 2.0×10^12vg/kg, 5.0×10^12vg/kg, 1.0×10^13vg/kg.
Dose-expansion phase: 5 patients will be enrolled and be administrated of ZS801.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male ≥18 years of age;
- •Confirmed diagnosis of hemophilia B, and endogenous FIX ≤2%;
- •Have had ≥100 prior exposure days (EDs) to any recombinant and/or plasma-derived FIX protein products;
- •The subject had at least 3 or more bleeding events and/or chronic hemophilia arthritis in one or more joints in the previous 1 year requiring treatment with FIX;
- •Agree to use reliable barrier contraception and prohibition of sperm donation until 52 weeks after the administration of ZS
- •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 FIX inhibitor as assessed by laboratory, or documented history of FIX 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 active hepatitis C infection (HCVAb positive), or are currently receiving hepatitis B or hepatitis C antiviral therapy;
- •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 FIX 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 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.
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Baseline up to Week 52
An adverse event (AE) is any medical occurrence, the event will not relate to the treatment.
Number of participants with clinically significant change from baseline in vital signs
Time Frame: Baseline up to Week 52
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.
Number of participants with clinically significant change from baseline in physical examination findings
Time Frame: Time Frame: Baseline up to Week 52
Findings will be considered to be clinically significant based on the investigator's decision.
Number of participants with clinical laboratory abnormalities
Time Frame: Baseline up to Week 52
Findings were considered to be clinically significant based on the investigator's decision.
Antibody against AAV capsid protein
Time Frame: Baseline up to Week 52
Immune response against AAV capsid will be evaluated by measurement of the binding antibody and neutralizing antibody against AAV capsid protein in plasma samples.
Secondary Outcomes
- Vector-derived FIX activity levels(Baseline up to Week 52)
- Vector-derived FIX antigen levels(Baseline up to Week 52)
- Vector shedding of ZS801(Baseline up to Week 52)