HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients

Study Overview
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Brief Summary
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This is an open-label, single-dose, multi-center, multinational trial to demonstrate the efficacy of AMT-061 and to further describe its safety profile. The study drug is identified as AAV5-hFIXco-Padua (AMT- 061). AMT-061 is a recombinant adeno-associated viral vector of serotype 5 (AAV5) containing the Padua variant of a codon-optimized human FIX complementary deoxyribonucleic acid (cDNA) under the control of a liver-specific promoter. The pharmaceutical form of AMT-061 is a solution for intravenous infusion administered at a dose of 2 x 10^13 gc/kg.

Official Title
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Phase III, Open-label, Single-dose, Multi-center, Multinational Trial Investigating a Serotype 5 Adeno-associated Viral Vector Containing the Padua Variant of a Codon-optimized Human Factor IX Gene (AAV5-hFIXco-Padua, AMT-061) Administered to Adult Subjects With Severe or Moderately Severe Hemophilia B

Conditions
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Hemophilia B

Intervention / Treatment
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* Genetic: AAV5-hFIXco-Padua
* Biological: Factor IX (FIX)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Age ≥18 years Subjects with congenital hemophilia B, classified as severe or moderately severe, and are currently on factor IX prophylaxis >150 previous exposure days of treatment with factor IX protein Exclusion Criteria: History of factor IX inhibitors Positive factor IX inhibitor test at screening Select screening laboratory value >2 times upper limit of normal Positive human immunodeficiency virus (HIV) test at screening, not controlled with anti-viral therapy Active infection with hepatitis B or C virus at screening History of Hepatitis B or C exposure, currently controlled by antiviral therapy at the end of the lead-in phase Previous gene therapy treatment Receipt of an experimental agent within 60 days prior to screening Current participation or anticipated participation within one year after study drug administration in this trial in any other interventional clinical trial involving drugs or devices

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
Interventional Model Description: The reference therapy is prophylactic factor IX replacement therapy used during the lead-in phase prior to treatment with AAV5-hFIXco-Padua (AMT-061).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMT-061<br>Single infusion of AMT-061 Subjects will receive a single infusion of AAV5-hFIXco-Padua (AMT- 061) at baseline. After study drug administration (post study drug), subjects will be monitored for tolerance to the study drug and detection of potential immediate AEs at the clinical trial site for a few hours after dosing. | Genetic: AAV5-hFIXco-Padua<br>* Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)<br>* Other names: etranacogene dezaparvovec;|
| Active Comparator: FIX replacement (Lead-in Period)<br>During the lead-in phase, which lasted for a minimum of 26 weeks (i.e., ≥6 months), subjects recorded their use of FIX replacement therapy and bleeding episodes in their dedicated e-diary. | Biological: Factor IX (FIX)<br>* During the lead-in phase, which lasted for a minimum of 26 weeks (i.e., ≥6 months), subjects recorded their use of FIX replacement therapy and bleeding episodes in their dedicated e-diary.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Bleeding Rate (ABR) for All Bleeding Episodes | ABR was calculated as the ratio of the number of bleeds to the number of days in the time interval multiplied by 365.25. | Lead-in period and months 7-18 post-treatment of AMT-061 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Factor IX Activity Levels After AMT-061 Dosing |  | Baseline and 6,12, and 18 months after AMT-061 dosing | 
| Annualized Exogenous Factor IX Consumption |  | Lead-in period and months 0-6, 7-12, and 13-18 after AMT-061 dosing | 
| Adjusted Annualized Infusion Rate of FIX Replacement Therapy |  | Lead-in period and months 7-18 after AMT-061 dosing | 
| Percent of Subjects Who Discontinued FIX Prophylaxis and Remained Free of Routine FIX Prophylaxis After AMT-061 Dosing |  | Months 7-18 after AMT-061 dosing | 
| Percentage of Subjects With Trough FIX Activity <12% of Normal |  | Lead-in and 3, 12, and 18 months after AMT-061 dosing | 
| ABR for FIX-treated Bleeding Episodes |  | Lead-in and Months 7-18 after AMT-061 dosing | 
| Number of Spontaneous Bleeding Episodes |  | Lead-in period and months 7-18 after AMT-061 dosing | 
| Number of Joint Bleeding Episodes |  | Lead-in period and months 7-18 after AMT-061 dosing | 
| Mean FIX Activity (%) in Subjects With Pre-Existing Neutralizing Antibodies to AAV5 After AMT-061 Dosing |  | Baseline and 6,12, and 18 months after AMT-061 dosing | 
| Mean FIX Activity (%) in Subjects Without Pre-Existing Neutralizing Antibodies to AAV5 After AMT-061 Dosing |  | Baseline and 6,12, and 18 months after AMT-061 dosing | 
| Number of New Target Joints and the Number of New Target Joints Resolved. | A target joint was defined as 3 or more spontaneous bleeding episodes into a single joint within a consecutive 6-month period prior to the dosing visit and which was not resolved by the time of dosing. An identified target joint with ≤2 spontaneous bleeding episodes within a consecutive 12-month period was considered resolved. | Up to 18 months after AT-061 dosing | 
| Percent of Participants With Zero Bleeding Episodes During the 52 Weeks Following Stable FIX Expression (6 to 18 Months) After AMT-061 Dosing |  | Lead-in period and months 7-18 post-treatment of AMT-061 | 
| International Physical Activity Questionnaire (iPAQ) Overall Score | The iPAQ was designed to provide an evaluation of daily physical activities in metabolic equivalent of task (MET) minutes/week. To calculate MET minutes a week multiply the MET value given (walking = 3.3, moderate activity = 4, vigorous activity = 8) by the minutes the activity was carried out and again by the number of days that that activity was undertaken. A higher score is considered to be more favorable. | Lead-in period and up to 12 months after AT-01 dosing | 
| EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) VAS Overall Score | 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. | Lead-in period and up to 12 months after AMT-061 dosing | 
| Number of Adverse Events | Follow up and assess any adverse events reported for safety | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FIX, Gene therapy, factor IX, Bleeding, Viral vector, Padua, hemophilia, AAV (adeno-associated virus), serotype 5 AAV (adeno-associated virus), serotype 5