A Trial of the Safety and Efficacy of Single-Dose Administration of ANB-010 in Subjects With Hemophilia A

Study Overview
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Brief Summary
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The goal of this multicenter, two-stage, open-label study is to investigate the safety, immunogenicity, and efficacy of ANB-010 in subjects with hemophilia A. The study will have a dose-escalation design with elements of phase I/II seamless adaptive design.

Detailed Description
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The study will be conducted in 2 stages: Stage 1: pilot efficacy and safety study of different doses to select a potentially therapeutic dose for further study. Stage 2: study of the efficacy and safety of ANB-010 at the selected potentially therapeutic dose. The stage 1 design is typical of phase I clinical trials with a modified 3+3 design and dose escalation. Three subjects are to be sequentially included in each cohort, each of whom will recieved a pre-specified cohort dose of ANB-010 as a single inravenous infusion. Subjects will be monitored for dose-limiting toxicity (DLT) events for 4 weeks after the drug infusion. The decision concerning dose escalation will be made at the Independent Data Monitoring Committee (IDMC) meetings. At the second stage the main study period will include 6 subjects who will receive ANB-010 at the optimal dose selected based on the results of stage 1 data analysis.

Official Title
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An Open-Label Two-Stage Trial of the Safety, Pharmacodynamics, Biodistribution, Immunogenicity and Efficacy of Single-Dose Administration of ANB-010 in Subjects With Hemophilia A

Conditions
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Hemophilia A

Intervention / Treatment
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* Genetic: ANB-010, dose 1
* Genetic: ANB-010, dose 2
* Genetic: ANB-010, dose 3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Male subjects aged ≥18 years at the time of signing the informed consent form. 3. Established diagnosis of hemophilia A with a documented history of endogenous FVIII activity ≤1% AND ≤2% at screening. 4. Therapy with FVIII concentrates for at least 150 exposure days. Exclusion Criteria: History of use of any gene therapy product. Use of emicizumab within less than 6 months before the date of signing the ICF. The presence of other blood or hematopoietic disorders other than hemophilia A. Presence of AAV6 antibodies detected by ELISA. BMI <16 kg/m² or ≥35 kg/m². Diagnosis of HIV infection. HBV infection. HCV infection. Any active systemic infections or recurrent infections requiring systemic therapy at screening. Any other disorders associated with severe immunodeficiency. Relevant hepatic disorders or conditions that can be a symptom of existing liver disorder. Malignancies with remission duration of less than 5 years at the time of signing the ICF, except for cured basal cell carcinoma.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects in Cohort 1 will receive ANB-010 at a dose 1. ANB-010 will be administered to the first subject in group 1. Not earlier than in 28 days, the investigational product will be administered to the next two subjects in Cohort 1 (with an interval of at least 24 hours). | Genetic: ANB-010, dose 1<br>* Adeno-associated viral vector carrying the FVIII gene single infusion at dose 1.<br>|
| Experimental: Cohort 2<br>Subjects in Cohort 1 will receive ANB-010 at a dose 1. Not earlier than 28 days after the ANB-010 administration to the third subject in Cohort 1, the investigational product will be administered to the first subject in Cohort 2. Not earlier than 28 days after the ANB-010 administration to the first subject in Cohort 2, the investigational product will be administered to the next two subjects in Cohort 2 (with an interval of at least 24 hours). | Genetic: ANB-010, dose 2<br>* Adeno-associated viral vector carrying the FVIII gene single infusion at dose 2.<br>|
| Experimental: Cohort 3<br>Subjects in Cohort 1 will receive ANB-010 at a dose 1. Not earlier than 28 days after the ANB-010 administration to the third subject in Cohort 2, the investigational product will be administered to the first subject in Cohort 3. Not earlier than 28 days after the ANB-010 administration to the first subject in Cohort 3, the investigational product will be administered to the next two subjects in Cohort 3 (with an interval of at least 24 hours). | Genetic: ANB-010, dose 3<br>* Adeno-associated viral vector carrying the FVIII gene single infusion at dose 3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FVIII activity from baseline to Week 52 |  | 12 months | 
| Assessment of ANB-010 safety | Proportion and characteristics of adverse events | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FVIII activity from baseline to scheduled assessment visits | FVIII activity will be assessed at every scheduled visits and compared to baseline | 12 months | 
| Proportion of subjects achieving clinical response | Clinical response is formulated as FVIII activity of 5-150% | 12 months | 
| Proportion of subjects who achieved normalized response | Normalized response is formulated as FVIII activity of 50-150% | 12 months | 
| Annualized consumption of FVIII concentrates by a subject |  | 12 months | 
| Annualized bleeding rate |  | 12 months | 
| Annualized rate of bleeding requiring therapy with FVIII concentrates |  | 12 months | 
| Duration of response based on activity FVIII |  | 12 months |