Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B

A Phase 1/2 Open-Label, Single Ascending Dose Trial of a Self-Complementing Optimized Adeno-associated Virus Serotype 8 Factor IX Gene Therapy (AskBio009) in Adults With Hemophilia B

The purpose of this study is to evaluate the safety of single ascending IV doses of a Factor IX (FIX) Gene Therapy in up to 16 Adults with Hemophilia B.

Study Overview

• Status: Active, not recruiting
• Conditions: Hemophilia B
• Intervention / Treatment: Biological: AskBio009

Detailed Description

Hemophilia B is a genetic X-linked bleeding disorder caused by a deficiency in blood-clotting Factor IX (FIX) activity. FIX is synthesized in the liver and circulates in the blood as a proenzyme. Current treatment for hemophilia B is based on replacement of the deficient FIX with IV injections of recombinant FIX protein prophylactically or as needed to treat bleeding episodes. This clinical program will test a gene transfer approach involving the use of a gene delivery vector carrying a FIX gene. This first-in-humans study is intended to evaluate the safety, kinetics, and if possible, the dose of AskBio009 required to achieve stable plasma FIX activity between 10% and 40% of normal activity.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90007
      • Orthopaedic Hemophilia Treatment Center
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Diego, California, United States, 92103-8651
      • University of California at San Diego Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • U of Colorado School of Medicine, Hemophilia & Thrombosis Treatment Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 022105
      • Children's Hospital of Boston
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, Masonic Clinical Research Unit, Clinical and Translational Science Institute
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • The Hemophilia Center, Oregon Health and Science University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • Gulf States Hemophilia and Thrombosis Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Bloodworks Northwest
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • BloodCenter of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males age 18-75 years, inclusive
• Established hemophilia B with ≥3 hemorrhages per year requiring treatment with exogenous FIX OR use of FIX prophylaxis because of history of frequent bleeding episodes
• Plasma FIX activity ≤2% (<1% for first cohort; then per protocol)
• Negative for active Hepatitis C virus (HCV), defined as Hepatitis C virus antibody negative and negative (undetectable) PCR test for plasma Hepatitis C virus ribonucleic acid (RNA) OR if Hepatitis C virus antibody positive must have ≥2 consecutive negative (undetectable) PCR tests for plasma HCV RNA at least 3 months apart, and negative at screening

Exclusion Criteria:

• Family history of inhibitor to FIX protein or personal laboratory evidence of having developed inhibitors to FIX protein at any time (>0.6 Bethesda Units on any single test)
• Documented prior allergic reaction to any FIX product
• Detectable AAV8 neutralizing antibodies

• Markers of hepatic inflammation or overt or occult cirrhosis as evidenced by one or more of the following:

  • Platelet count <175,000/μL
  • Albumin ≤3.5 g/dL
  • Total bilirubin >1.5 x ULN and direct bilirubin ≥0.5 mg/dL
  • Alkaline phosphatase >2.0 x ULN
  • ALT or AST >2.0 x ULN (except for subjects who are HIV infected)
  • Liver biopsy in the past indicating moderate or severe fibrosis (Metavir staging of 2 or greater)
  • History of ascites, varices, variceal hemorrhage or hepatic encephalopathy

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: AskBio009 Dose Escalation; Single Dose of a Self-Complementing Optimized Adeno-associated Virus (AAV) Serotype 8 Factor IX Gene Therapy	Biological: AskBio009; Single dose IV injection; Other Names: BAX 335

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of patients experiencing treatment-related adverse events by dose group	Infusion to Week 3 and Infusion to end of study
Change from baseline in clinical laboratory evaluations	Change from baseline at week 3 and change from baseline at the end of study

Secondary Outcome Measures

Outcome Measure	Time Frame
Changes from Baseline in FIX activity levels, FIX protein levels, and Bleeding Episode Severity & Frequency	At multiple timepoints from pre-dose through up to 5 years post-dose
Immune Response to AskBio009	At multiple timepoints from pre-dose through up to 5 years post-dose
Detection of AskBio009 genomes in blood, saliva, urine, stool, and semen	At multiple timepoints from pre-dose through up to 1 years post-dose

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire
• Investigators: Study Director: Study Director, Shire

Publications and helpful links

General Publications

• Konkle BA, Walsh CE, Escobar MA, Josephson NC, Young G, von Drygalski A, McPhee SWJ, Samulski RJ, Bilic I, de la Rosa M, Reipert BM, Rottensteiner H, Scheiflinger F, Chapin JC, Ewenstein B, Monahan PE. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood. 2021 Feb 11;137(6):763-774. doi: 10.1182/blood.2019004625.
• Weber A, Engelmaier A, Voelkel D, Pachlinger R, Scheiflinger F, Monahan PE, Rottensteiner H. Development of Methods for the Selective Measurement of the Single Amino Acid Exchange Variant Coagulation Factor IX Padua. Mol Ther Methods Clin Dev. 2018 Jun 28;10:29-37. doi: 10.1016/j.omtm.2018.05.004. eCollection 2018 Sep 21.

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2013
• Primary Completion (Estimated): January 17, 2030
• Study Completion (Estimated): January 17, 2030

Study Registration Dates

• First Submitted: August 27, 2012
• First Submitted That Met QC Criteria: September 14, 2012
• First Posted (Estimated): September 19, 2012

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Hemophilia B; gene therapy; factor IX deficiency
• 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: AskBio009-101; 231401 (Other Identifier: Sponsor)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No