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

• ClinicalTrials.gov Identifier: NCT01687608
• Recruitment Status: Active, not recruiting
• First Posted: September 19, 2012
• Last Update Posted: September 30, 2022
• Sponsor: Baxalta now part of Shire
• Information provided by (Responsible Party): Takeda ( Baxalta now part of Shire )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia B	Biological: AskBio009	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 11, 2013
• Estimated Primary Completion Date: October 28, 2030
• Estimated Study Completion Date: October 28, 2030

Arms and Interventions

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 Name: BAX 335

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

Orthopaedic Hemophilia Treatment Center

Los Angeles, California, United States, 90007

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

University of California Davis Medical Center

Sacramento, California, United States, 95817

University of California at San Diego Medical Center

San Diego, California, United States, 92103-8651

United States, Colorado

U of Colorado School of Medicine, Hemophilia & Thrombosis Treatment Center

Aurora, Colorado, United States, 80045

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Massachusetts

Children's Hospital of Boston

Boston, Massachusetts, United States, 022105

United States, Minnesota

University of Minnesota, Masonic Clinical Research Unit, Clinical and Translational Science Institute

Minneapolis, Minnesota, United States, 55455

United States, New York

Mount Sinai Medical Center

New York, New York, United States, 10029

United States, Oregon

The Hemophilia Center, Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Texas

Gulf States Hemophilia and Thrombosis Center

Houston, Texas, United States, 77030

United States, Washington

Bloodworks Northwest

Seattle, Washington, United States, 98104

United States, Wisconsin

BloodCenter of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Baxalta now part of Shire

Investigators

• Study Director: Study Director; Shire

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT01687608
• Other Study ID Numbers: AskBio009-101; 231401 ( Other Identifier: Sponsor )
• First Posted: September 19, 2012
• Last Update Posted: September 30, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• 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.
• URL: https://vivli.org/ourmember/takeda/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Baxalta now part of Shire ):

Hemophilia B; factor IX deficiency; gene therapy

Additional relevant MeSH terms:

Hemophilia A; Hemophilia B; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked