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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hemophilia B
• Intervention / Treatment: Genetic: AAV5-hFIXco-Padua; Biological: Factor IX (FIX)

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Leuven, Belgium, 3000
    • University Hospital Leuven
• Denmark
  • Copenhagen, Denmark, 2100
    • Righospitalet
• Germany
  • Berlin, Germany, 10249
    • Vivantes Klinikum im Friedrichshain
  • Frankfurt am main, Germany, 60590
    • Klinikum der Johann Wolfgang Goethe Universitat
• Ireland
  • Dublin, Ireland, D08 A978
    • National Coagulation Centre, St James's Hospital
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC - Locatie AMC
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus MC
  • Utrecht, Netherlands, 3508 GA
    • UMC Utrecht, Van Creveldkliniek
• Sweden
  • Malmö, Sweden, SE-205 02
    • Center for Thrombosis and Hemostasis Skåne University Hospital Malmö
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • The Cambridge Haemophilia and Thrombophilia Centre Camridge University Hospitals NHS Foundation Trust - Box 217 Addenbrooke's Hospital
  • London, United Kingdom, E1 2ES
    • The Royal London Hospital (Barts Health NHS Trust)
  • Southampton, United Kingdom, SO16 6YD
    • University Hospital Southampton NHS Foundation Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
    • Los Angeles, California, United States, 90007
      • Los Angeles Orthopedic Hospital
    • Sacramento, California, United States, 95817
      • University of California, Davis
    • San Diego, California, United States, 92161
      • University of California, San Diego
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center Hematology and Oncology
  • Florida
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New York
    • Buffalo, New York, United States, 14209
      • Hemophilia Center of Western New York
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina, Chapel Hill
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee Health Science Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center & Medical School
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98101
      • Washington Institute for Coagulation
    • Seattle, Washington, United States, 98104
      • Bloodworks Northwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male
2. Age ≥18 years
3. Subjects with congenital hemophilia B, classified as severe or moderately severe, and are currently on factor IX prophylaxis
4. >150 previous exposure days of treatment with factor IX protein

Exclusion Criteria:

1. History of factor IX inhibitors
2. Positive factor IX inhibitor test at screening
3. Select screening laboratory value >2 times upper limit of normal
4. Positive human immunodeficiency virus (HIV) test at screening, not controlled with anti-viral therapy
5. Active infection with hepatitis B or C virus at screening
6. History of Hepatitis B or C exposure, currently controlled by antiviral therapy at the end of the lead-in phase
7. Previous gene therapy treatment
8. Receipt of an experimental agent within 60 days prior to screening
9. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AMT-061; 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; Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061); Other Names: AMT-061; etranacogene dezaparvovec
Active Comparator: FIX replacement (Lead-in Period); 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); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: CSL Behring
• Investigators: Principal Investigator: Steven Pipe, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2018
• Primary Completion (Actual): September 22, 2021
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: June 14, 2018
• First Submitted That Met QC Criteria: June 14, 2018
• First Posted (Actual): June 26, 2018

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Bleeding; Gene therapy; hemophilia; FIX; factor IX; Viral vector; Padua; AAV (adeno-associated virus); serotype 5 AAV (adeno-associated virus); serotype 5
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: CSL222_3001 (CT-AMT-061-02)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No