Hemophilia B Gene Therapy With AAV8 Vector

Brief Title

Hemophilia B Gene Therapy With AAV8 Vector

Official Title

A Phase 1 Safety Study in Subjects With Severe Hemophilia B (Factor IX Deficiency) Using a Single-Stranded, Adeno-Associated Pseudotype 8 Viral Vector to Deliver the Gene for Human Factor IX

Brief Summary

      Hemophilia B is a bleeding disease in males due to very low levels of coagulation factor IX
      (FIX) in the blood. The current treatment is intravenous injection of FIX clotting factor
      concentrates, in response to bleeding. This study will focus on the severe, most common type
      of hemophilia B. This study plans to use a virus called adeno-associated virus (AAV), which
      in nature causes no disease, and can be engineered to deliver the human FIX gene (AAV8-hFIX19
      vector) to liver cells, where FIX is normally made. This study will use the AAV8-hFIX19
      vector.

Detailed Description

Hemophilia B is a bleeding disease in males due to very low levels of coagulation factor IX
(FIX) in the blood. The major effect on health is joint disease caused by repeated bleeds
into joints like the knee, hip, ankles and elbows. Rarely, the disease causes death due to
bleeding into the brain or other important organs. The current treatment is intravenous
injection of FIX clotting factor concentrates, in response to bleeding. This study will focus
on the severe, most common type of hemophilia B.

This study plans to use a virus called adeno-associated virus (AAV), which in nature causes
no disease, and can be engineered to deliver the human FIX gene (AAV8-hFIX19 vector) to liver
cells, where FIX is normally made. Medical researchers in the United States and England have
recently used an AAV vector similar to the one planned for this study, and found that after a
single intravenous injection of the vector, blood levels of FIX reached levels greater than
1%, high enough to change the course of disease from severe to moderate. This means that the
need to take FIX clotting factor concentrates has decreased, or even stopped. While these are
important results, it needs to be noted that two of the six subjects who received the vector
at higher doses developed inflammation of the liver. These subjects were treated with a
steroid medication called Prednisolone, which is commonly used for serious types of
inflammation. Prednisolone seemed to decrease the liver inflammation, as measured by a
decrease in blood levels of elevated liver enzymes, and stability of FIX levels at greater
than 1% of normal.

This study will use the AAV8-hFIX19 vector. The vector will be injected once into a
peripheral vein of each subject, while the subject is in the hospital. If everything is fine,
the subject will be discharged from the hospital the next day. Three doses of vector (low,
middle, and high) will be tested in up to 15 different subjects, depending on safety outcome
(as determined by blood and urine tests) and results of FIX levels. If some subjects develop
liver inflammation, a short, tapering course of corticosteroids will be used.

Study Phase

Phase 1

Study Type

Interventional

Primary Outcome

Number of subjects with adverse events related to investigational product

Secondary Outcome

 Circulating plasma factor IX levels

Condition

Hemophilia B

Intervention

AAV8-hFIX19

Study Arms / Comparison Groups

 Low dose

Description:  AAV8-hFIX19

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Biological

Estimated Enrollment

Start Date

October 2012

Completion Date

March 2016

Primary Completion Date

March 2016

Eligibility Criteria

        Inclusion Criteria:

          -  Willingness to adhere to the clinical protocol and 15-year long-term follow-up as
             evidenced by written informed consent

          -  Adult males at least 18 years of age

          -  A. Severe FIX deficiency (<1% normal circulating FIX) or B. Moderately severe FIX
             deficiency (1-2% normal circulating FIX, inclusive) and a severe bleeding phenotype as
             defined by at least one of the following: i. On prophylaxis for a history of bleeding
             or ii. On demand therapy with a current or past history of frequent bleeding [4 or
             more bleeding episodes in the last 12 months or chronic hemophilic arthropathy (pain,
             joint destruction, and loss of range of motion) in one or more joints]

          -  No history of inhibitor against FIX

          -  No history of an allergic reaction or anaphylaxis to FIX products

          -  Greater than 20 exposure days of treatment with FIX protein

          -  Anti-AAV8 neutralizing titer measured at < 1:5

          -  Acceptable laboratory values: hemoglobin ≥ 11% gm; WBC ≥ 3,500/μL; platelets ≥
             100,000/μL; AST, ALT, alkaline phosphatase ≤ 2x ULN; bilirubin ≤ 1.2 gm/dL; and
             creatinine ≤ 1.5 gm/dL

          -  Subject agrees to use barrier contraception until at least two consecutive semen
             samples after vector administration are negative for vector sequences (may be for up
             to several months)

        Exclusion Criteria:

          -  Subjects with active hepatitis B or C, and HBsAg or HCV RNA viral load positivity,
             respectively. Negative viral assays in two samples, collected at least six months
             apart, will be required to be considered negative. Both natural clearers and those who
             have cleared HCV on antiviral therapy are eligible.

          -  Subjects currently on antiviral therapy for hepatitis B or C

          -  Subjects with significant underlying liver disease, as defined by presence of portal
             hypertension, splenomegaly, varices, ascites, edema, gastrointestinal bleeding,
             encephalopathy, reduction below normal limits of serum albumin, or prior liver biopsy
             demonstrating significant fibrosis, specifically ≥ Metavir 3 fibrosis

          -  Subjects with serological evidence of HIV who have CD4 counts ≤ 200/mm3. Subjects who
             are HIV-positive and stable, with an adequate CD4 count (> 200/mm3) and undetectable
             viral load (< 50 gc/mL) measured twice in the six months prior to enrollment, on an
             antiretroviral drug regimen are eligible to enroll.

          -  History of inhibitor against FIX

          -  Anti-AAV8 antibody titers ≥ 1:5

          -  History of chronic infection or other chronic diseases which the investigators
             consider to constitute an unacceptable risk

          -  Subjects who have participated in a previous gene therapy research trial within one
             year of enrollment

          -  Subjects who have participated in a clinical study with an investigational drug within
             six months of enrollment

          -  Any other condition that would not allow the potential subject to complete follow-up
             examinations during the course of the study or, in the opinion of the investigator,
             makes the potential subject unsuitable for the study

Gender

Male

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Clinical Director, ,

Location Countries

Australia

Location Countries

Australia

Administrative Informations

NCT ID

NCT01620801

Organization ID

AAV8-hFIX19-101

Responsible Party

Sponsor

Study Sponsor

Spark Therapeutics

Collaborators

 Children's Hospital of Philadelphia

Study Sponsor

Clinical Director, Study Director, Spark Therapeutics

Verification Date

December 2018