Clinical trial NCT01687608: Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hemophilia B
Keywords: Hemophilia B
factor IX deficiency
gene therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-09-19
Enrollment: 30
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Number of patients experiencing treatment-related adverse events by dose group
timeFrame: Infusion to Week 3 and Infusion to end of study
measure: Change from baseline in clinical laboratory evaluations
timeFrame: Change from baseline at week 3 and change from baseline at the end of study
Secondary outcomes:
measure: Changes from Baseline in FIX activity levels, FIX protein levels, and Bleeding Episode Severity & Frequency
timeFrame: At multiple timepoints from pre-dose through up to 5 years post-dose
measure: Immune Response to AskBio009
timeFrame: At multiple timepoints from pre-dose through up to 5 years post-dose
measure: Detection of AskBio009 genomes in blood, saliva, urine, stool, and semen
timeFrame: At multiple timepoints from pre-dose through up to 1 years post-dose
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Orthopaedic Hemophilia Treatment Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Diego
country: United States
facility: University of California at San Diego Medical Center
state: California
city: Aurora
country: United States
facility: U of Colorado School of Medicine, Hemophilia & Thrombosis Treatment Center
state: Colorado
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Boston
country: United States
facility: Children's Hospital of Boston
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota, Masonic Clinical Research Unit, Clinical and Translational Science Institute
state: Minnesota
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Portland
country: United States
facility: The Hemophilia Center, Oregon Health and Science University
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: Gulf States Hemophilia and Thrombosis Center
state: Texas
city: Seattle
country: United States
facility: Bloodworks Northwest
state: Washington
city: Milwaukee
country: United States
facility: BloodCenter of Wisconsin
state: Wisconsin
Study officials:
affiliation: Shire
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.