Dose Confirmation Trial of AAV5-hFIXco-Padua

Phase IIb, Open-label, Single-dose, Single-arm, Multi-center Trial to Confirm the Factor IX Activity Level of the 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, single-arm, multi-center trial, with a screening, a treatment + post-treatment follow-up phase, and a long-term follow-up phase.

The IMP 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 IMP is identified as AAV5-hFIXco-Padua (AMT- 061). The pharmaceutical form of AMT-061 is a solution for intravenous infusion.

The administered dose of AMT-061 will be 2 x 10^13 gc/kg.

Study Overview

• Status: Completed
• Conditions: Hemophilia B
• Intervention / Treatment: Genetic: AAV5-hFIXco-Padua (AMT-061)

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • California
    • Sacramento, California, United States, 95817
      • University of California, Davis
    • San Diego, California, United States, 92122
      • University of California, San Diego
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

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
4. >20 previous exposure days of treatment with FIX protein

Exclusion Criteria:

1. History of FIX inhibitors
2. Positive FIX inhibitor test at screening
3. Select screening laboratory values > 2 times upper normal limit:
4. Positive human immunodeficiency virus (HIV) 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single infusion of AMT-061; Subjects will receive a single infusion of AAV5-hFIXco-Padua (AMT- 061) at baseline. After IMP administration (post IMP), subjects will be monitored for tolerance to the IMP and detection of potential immediate AEs at the clinical trial site for 24 hours (overnight stay).	Genetic: AAV5-hFIXco-Padua (AMT-061); Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Factor IX Activity Levels	To confirm that a single dose of 2x10^13 gc/kg AMT-061 (CSL222) resulted in factor IX activity levels of ≥5% at 6 weeks after dosing measured by the one-stage (activated partial thromboplastin [aPTT]-based) assay.	6 weeks post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Exogenous Factor IX Usage	Annualized use was calculated as the normalized amount of therapy administered per baseline weight, extrapolated where necessary from any time period less or greater than 1 year. Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included.	52 weeks post-dose
Annualized Bleeding Rate (ABR)	ABR was calculated as the ratio of the number of bleeds to the number of days in the time interval multiplied by 365.25.	5 years post-dose
Factor IX Activity Levels	Measured by the one-stage (aPTT-based) assay.	52 weeks post-dose
Number of Participants Remaining Free of Continuous Prophylaxis	Participants with no usage of continuous factor IX prophylaxis after AMT-061 (CSL222) treatment were considered free from continuous factor IX prophylaxis use.	1 year post-dose
Annualized Exogenous Factor IX Usage Post-Continuous Prophylaxis	The post-continuous-prophylaxis period began on the day after the end of continuous (routine) prophylaxis.Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included.	Up to 5 years post-dose
Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs		Up to 5 years post-dose
Number of Participants With Clinically Meaningful Findings in Hematology and Serum Chemistry Parameters	Clinically meaningful findings were defined as values which were outside the standard normal reference ranges for hematology and serum chemistry parameters.	Up to 5 years post-dose
Number of Participants With Newly Occurring or Worsening Potentially Clinically Significant Changes in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels	Post-baseline newly occurring or worsening potentially clinically significant ALT and AST levels were defined as values greater than twice the baseline value.	From baseline and up to 5 years post-dose
Number of Participants Receiving Corticosteroids for AST and ALT Elevations		Up to 5 years post-dose
Number of Participants Positive With AAV5 and Factor IX Neutralising Antibodies in Serum		Baseline and at 5 years post-dose
Number of Participants With AAV5 Capsid-specific T Cell Response		Up to Week 52
Number of Participants With Inflammatory Marker Levels Outside Normal Ranges	Inflammatory markers included interleukin (IL)-1β, IL-2, IL-6, interferon gamma (IFNγ), and monocyte chemotactic protein-1 (MCP-1). Only those biomarkers for which the data were higher than the normal range at the specified timepoints have been presented.	Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 26, 31, 36, 40, 44, 48 and 52
Time to First Negative Results for Vector Deoxyribonucleic Acid (DNA) From Semen and Blood	Time in weeks until the first negative result confirmed by negative result in 3 consecutive timepoints. A participant was considered to no longer be shedding vector DNA if they had a negative laboratory result for 3 or more consecutive timepoints.	Up to 5 years post-dose
Number of Participants With Abnormal Values in Alpha-fetoprotein (AFP) Levels	Participants who were outside the normal limit range were to be reported.	Up to 5 years post-dose
Number of Participants With Abnormal Results in Abdominal Ultrasound	Ultrasounds were evaluated by qualified personnel and abnormalities were assessed by the Investigator.	At Months 36, 42, 48, 54, and 60 post-dose

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Von Drygalski A, Giermasz A, Castaman G, Key NS, Lattimore S, Leebeek FWG, Miesbach W, Recht M, Long A, Gut R, Sawyer EK, Pipe SW. Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv. 2019 Nov 12;3(21):3241-3247. doi: 10.1182/bloodadvances.2019000811. Erratum In: Blood Adv. 2020 Aug 11;4(15):3668. doi: 10.1182/bloodadvances.2020002987.

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2018
• Primary Completion (Actual): October 30, 2018
• Study Completion (Actual): September 21, 2023

Study Registration Dates

• First Submitted: March 19, 2018
• First Submitted That Met QC Criteria: April 3, 2018
• First Posted (Actual): April 5, 2018

Study Record Updates

• Last Update Posted (Actual): June 28, 2024
• Last Update Submitted That Met QC Criteria: June 3, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Gene Therapy; Bleeding; FIX; Padua; Hemophilia,; Factor IX; viral vector
• 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_2001 (CT-AMT-061-01)

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