Safety and Efficacy Clinical Study of Severe Hemophilia B Treatment With KL001

Study Overview
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Brief Summary
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This is an open- label, non- randomized, uncontrolled, dose-escalation pilot study to evaluate the safety and efficacy of KL001 injection solution in hemophilia B subjects with ≤2 IU/dl residual FIX levels.

Detailed Description
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This is an open- label, non- randomized, uncontrolled, dose-escalation pilot study to evaluate the safety and efficacy of KL001 injection solution in hemophilia B subjects with ≤2 IU/dl residual FIX levels. Nine subjects will be enrolled and administered with three different doses of KL001. Subjects will provide informed consent and then undergo screening assessments up to 1 month prior administration of KL001. All subjects will undergo 52 weeks safety observation and will be encouraged to enroll in an extension study to evaluate long- term safety of KL001 for total 5 years.

Official Title
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Safety and Dose Finding Study of KL001 in Moderately Severe to Severe Hemophilia B Subjects

Conditions
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Hemophilia B Without Inhibitor

Intervention / Treatment
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* Drug: Low dose KL001
* Drug: Middle dose KL001
* Drug: High dose KL001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male ≥12 years of age. Moderate/severe or severe hemophilia B (baseline FIX activity ≤2% of normal or documented history of FIX activity ≤2%). At least 3 bleeding episodes per year that require on-demand treatment with FIX or are treated with a prophylactic regimen of FIX. At least 100 days exposure history to recombinant or plasma-derived FIX protein products. No neutralizing antibodies to exogenous FIX protein products. Willing and able to comply with study procedures and requirements. Exclusion Criteria: Suffering from chronic inflammatory muscle disease. Positive in Hepatitis B or Hepatitis C. Infection with HIV-1 or HIV-2 and CD4+T cell count ≤ 200/ μ L. History of thrombosis or susceptibility to thrombosis. Current or previous participation in another gene therapy study. Has any other significant medical condition that the investigator feels would be a risk to the subject or would impede the study.

Ages Eligible for Study
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Minimum Age: 12 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: Sequential Assignment
Interventional Model Description: Low dose group will be administrated with 2.5×10^12 vg/kg; Middle dose group will be administrated with 5.0×10^12 vg/kg; High dose group will be administrated with 1.0×10^13 vg/kg.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KL001 injection solution<br>Subjects will be dosed with three different dose of KL001 injection solution at 2.5x10^12 vg/kg to 1.0x10^13 vg/kg. | Drug: Low dose KL001<br>* Subjects will be dosed with single dose of KL001 at 2.5x10^12 vg/kg.<br>* Other names: rAAV vector;Drug: Middle dose KL001<br>* Subjects will be dosed with single dose of KL001 at 5.0x10^12 vg/kg.<br>* Other names: rAAV vector;Drug: High dose KL001<br>* Subjects will be dosed with single dose of KL001 at 1.0x10^13 vg/kg.<br>* Other names: rAAV vector;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment- related adverse events | Number and severity of adverse events and serious adverse events and relationship to KL001 | Infusion to the completion of study, about 52 weeks | 
| Antibody against KL001 AAV vector capsid protein | Immune response against AAV capsid will be evaluated by measurement of the total antibody and neutralizing antibody against AAV capsid protein in plasma samples collected at multiple timepoints after dosing up to 52 weeks | Infusion to the completion of study, about 52 weeks | 
| Factor IX inhibitor | Development of inhibitor against vector-derived Factor IX protein will be measured using bethesda method. | Infusion to the completion of study, about 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| vector-derived FIX: C activity levels | Peak and steady-state activity levels of vector-derived FIX: C | From dosing day to week 52 | 
| The annualized bleeding rate Before and After KL001 Infusion | The annualized bleeding rate (ABR) will be calculated for all subjects through Week 52 | From dosing day to week 52 | 
| The annualized use of FIX | The use of on-demand FIX replacement therapy was recorded by dose (IU/kg) administered, and the annualized use of FIX replacement therapy was calculated for all subjects through Week 52. | From dosing day to week 52 |