Study of the Safety, Pharmacodynamics and Efficacy of ANB-002 in Patients With Hemophilia B (SAFRAN)

Study Overview
=================
Brief Summary
-----------------
The goal of this multicenter, two-stage, open-label study is to investigate the safety, immunogenicity, and efficacy of ANB-002 in subjects with hemophilia В. The study will have a dose-escalation design with elements of phase I/II seamless adaptive design.

Detailed Description
-----------------
The study design includes ANB-002 dose escalation in at least two cohorts. In Cohort 1, the subject treated with a single dose of ANB-002 administered as an intravenous infusion. Follow-up for the assessment of dose-limiting toxicity (DLT) will be carried out for 28 days. If no DLT events are observed in the subject of Cohort 1, the following subjects will be included in Cohort 1. The decision to continue enrolling in Cohort 1 or dosing in Cohort 2 subjects will be made at the Independent Data Monitoring Committee (IDMC) meeting. After the IDMC makes a decision regarding the dosing in Cohort 2 subjects, further enrolment to the cohort will be carried out according to the following principles described above. Based on the data from the follow-up period of subjects included in Сohorts 1 and 2, a potential therapeutic dose for further study will be determined. The total duration of participation of one subjects in the study will be 5 years.

Official Title
-----------------
An Open-label, Non-comparative, Single Dose-Escalation Study of the Safety, Pharmacodynamics and Efficacy of ANB-002 in Patients With Hemophilia B

Conditions
-----------------
Hemophilia B

Intervention / Treatment
-----------------
* Genetic: ANB-002, dose 1
* Genetic: ANB-002, dose 2


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male with hemophilia B. Age ≥18 years. FIX activity at screening ≤2% without FIX inhibitor. ≥150 previous exposure days of treatment with FIX concentrates. Exclusion Criteria: Previous gene therapy. Other blood or hematopoietic disorders. Positive Anti-AAV5 antibodies. Diagnosed HIV-infection, not controlled with anti-viral therapy. Hepatitis B, acute or chronic hepatitis C. Any active systemic infections or recurrent infections requiring systemic therapy at screening. Any other disorders associated with severe immunodeficiency. Significant hepatic disorders (liver cirrhosis, liver fibrosis, etc). Malignancies with remission <5 years.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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-002 at a dose 1. Follow-up for the assessment of dose-limiting toxicity (DLT) will be carried out for 28 days. If no DLT events are observed in the subject of Cohort 1, the following subjects will be included in Cohort 1. | Genetic: ANB-002, dose 1<br>* Adeno-associated viral vector carrying the FIX gene single infusion at dose 1.<br>|
| Experimental: Cohort 2<br>Subjects in Cohort 2 will receive ANB-002 at a dose 2. The decision to continue enrolling in Cohort 1 or dosing in Cohort 2 subjects will be made at the IDMC meeting. After the IDMC makes a decision regarding the dosing in Cohort 2 subjects, the next subject will be included in Cohort 2. If no DLT events are observed in the subject of Cohort 2, the following subjects will be included in Cohort 2. | Genetic: ANB-002, dose 2<br>* Adeno-associated viral vector carrying the FIX gene single infusion at dose 2.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FVIII activity from baseline |  | 12 months; final assessment - 5 years | 
| Proportion of subjects with adverse reactions |  | 12 months; final assessment - 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in FIX activity |  | 5 years | 
| Annualized use of FIX concentrates |  | 5 years | 
| Annualized bleeding rate |  | 5 years | 
| Annualized rate of bleedings requiring therapy with FIX concentrates |  | 5 years | 
| Changes in Haemo-A-QoL (Hemophilia-Specific Quality of Life) scores from baseline | Haemo-A-QoL is a quality of life (QoL) assessment instrument for patients with haemophilia, including the domains of consequences of bleeding, emotional impact, physical functioning, role functioning, treatment concern, and worry. Using scale overall score ranges from 0 to 100.The high score represent low quality of life. | 5 years | 
| Changes in EuroQol-5D-3L (European Quality of Life Questionnaire) scores from baseline | The EQ-5D-5L descriptive system of health-related QoL states consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). The EQ-5D-5L VAS overall score ranges from 0 to 100. A higher score is considered to be more favorable. | 5 years | 
| Changes in SF-36 (Short Form-36) scores from baseline | SF-36 is a questionnaire for evaluating health-related QoL (Quality of Life). The 36 questions are meant to reflect 8 domains of health, including physical functioning, physical role, pain, general health, vitality, social function, emotional role, and mental health. SF-3 overall score ranges from 0 to 100. The lower the score the more disability. | 5 years | 
| Response duration based on FIX activity |  | 5 years | 
| Evaluation of the condition of joints based on the Hemophilia Joint Health Score (HJHS) | Hemophilia Joint Health Score (HJHS) is the assessment system of joints in patients with haemophilia. Each joint (knee, elbow and ankle) receives a numeric score, which can be compared to itself over time to determine whether a joint is showing degeneration. The maximum score for an individual index joint is 20. Gait is scored 0 to 4. The maximum HJHS total score is 124, with a higher score indicating worse joint health. | 5 years |