Safety, Efficacy and Pharmacokinetics of GreenGene™ F to Previously Treated Patients With Severe Hemophilia A

Inclusion Criteria:

1. Male or female subjects age ≥ 12 years at the time of informed consent

2. Body weight ≥ 35 kg

3. Diagnosed with severe hemophilia A. All subjects must have severe hemophilia A with
baseline FVIII <1% activity; <0.01 IU/mL

4. Have ≥ 150 previous exposure days to FVIII concentrates, as documented in the
subject's medical records

5. Subjects included in the on-demand treatment cohort must have a verifiable record of
at least three bleeding episodes per month on average in the last 6 months prior to
enrollment

6. Negative assays for FVIII inhibitor at inclusion (<0.6BU Nijmegen assay)

7. Negative assays for FVIII inhibitor in subject files (<0.6BU Nijmegen assay) No
history of positive inhibitor is allowed

8. Normal liver and kidney function.

9. Platelet count ≥ 100,000 μL

10. Normal prothrombin time or International Normalized Ratio (INR) < 1.5

11. Subjects receiving therapy for human immunodeficiency virus (HIV) or hepatitis must
be on a stable treatment regimen

12. Subjects must be able to withhold FVIII infusions for approximately 72 h prior to
each FVIII activity and inhibitor assay (96 h if participating in the PK sub study)

13. Absolute CD4 lymphocyte cell count ≥ 200 μL

14. Signed the written informed consent form or informed consent was obtained from the
subject's legal guardian

15. Females must not be lactating or pregnant at Screening or Baseline (as documented by
a negative beta-human chorionic gonadotropin [ß hCG] test with a minimum sensitivity
of 25 IU/L or equivalent units of ß hCG). A separate baseline assessment is required
if a negative screening pregnancy test was obtained more than 72 hours before the
first dose of study drug

16. All females will be considered to be of childbearing potential unless they are
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate
age group and without other known or suspected cause) or have been sterilized
surgically (i.e. bilateral tubal ligation, total hysterectomy or bilateral
oophorectomy, all with surgery at least one month before dosing)

17. Willing and able to comply with all aspects of the protocol

Exclusion Criteria:

1. Presence at Screening of FVIII inhibitor ≥ 0.6 BU as tested with the Nijmegen
modification of the Bethesda assay in either central or local laboratory

2. History of FVIII inhibitor of ≥ 0.6 BU as measured using the Nijmegen modification of
the Bethesda assay

3. History of FVIII inhibitor ≥ 1.0 BU if the subject has been tested routinely using
the original Bethesda assay, or history of periods with low recovery and no response
to Factor VIII treatment

4. Demonstrated an inability to respond to conventional doses of FVIII therapy

5. History of incremental recovery of Factor VIII <1.35% per IU/kg infused

6. Hematological disorders or blood coagulation diseases (e.g., idiopathic
thrombocytopenic purpura, von Willebrand disease, etc.) other than hemophilia A

7. Laboratory or clinical evidence of portal vein hypertension including,(but not
limited to, an INR > 1.4, the presence of splenomegaly and/or spider angiomata on
physical examination and/or a history of esophageal hemorrhage or documented
esophageal varices

8. Uncontrolled hypertension (diastolic blood pressure >100 mm Hg)

9. Hemoglobin < 10 g.dL

10. HIV disease symptoms regardless of presence of HIV antibodies

11. Routine administration (or planned routine administration during the course of the
study), of immunosuppressive or immunomodulating drugs other than antiretroviral
therapy (e.g., steroids, beta-interferon)

12. Severe renal dysfunction (creatinine > 2x upper limit of normal [ULN], total
bilirubin > 2x the ULN)

13. Liver disease (alanine aminotransferase [ALT], aspartate aminotransferase [ AST] > 3x
the ULN)

14. History of diabetes or other metabolic disease

15. History of hypersensitivity or serious adverse reaction to recombinant or
plasma-derived FVIII concentrate

16. History of pretreatment prior to the administration of FVIII products (e.g., of
antihistamines)

17. Regular use of antifibrinolytics or medications affecting platelet function

18. Hypersensitivity to hamster-or mouse derived proteins

19. Blood transfusions within 30 days of enrollment into the study

20. Current participation in another investigational drug or device study, or
participated in a clinical study involving an investigational drug or device within
30 days of enrollment into the study

21. Unable or unwilling to cooperate with study procedures