An Open-Label, Multicenter Evaluation of the Long-Term Safety and Efficacy of Recombinant, Human Coagulation Factor IX Fusion Protein (rFIXFc) in the Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects With Hemophilia B.

Hemophilia B, or Christmas disease, is a deficiency in the clotting Factor IX
(FIX)and is a recessively inherited coagulation disorder due to an X-chromosome
mutation carried by females and expressed mainly in males, affecting
approximately 80,000 people worldwide. A deficiency of FIX in subjects results
in bleeding into joints, soft tissue, and muscle that can be associated with
trauma or can occur in the absence of trauma (spontaneous bleeding). Depending
on the severity of the bleeding it can also pose a life-threatening situation
(e.g. intracranial hemorrhage, other internal bleeding) for a subject if not
treated appropriately. FIX, a serine protease, and factor VIII, a cofactor for
FIX, work in concert to activate Factor X, a central step in the clotting
cascade. The coagulation cascade has 2 pathways, the Contact Activation Pathway
(Intrinsic Pathway) and the Tissue Factor Pathway (Extrinsic Pathway). The
plasma factors are activated in the form of a cascade one after the other until
the soluble plasma protein fibrinogen is transformed into a fibrinous clot.

There is no available cure for hemophilia B, so treatment focuses on the
replacement of FIX with the intravenous (IV) administration of FIX-containing
coagulation products to promote clotting. The goal of treatment with
FIX-containing coagulation products is to raise the circulating level of FIX to
the lowest effective dose to achieve either resolution of bleeding (on-demand
treatment) or prevention of bleeding (prophylaxis treatment) The frequency of
administration of FIX products differs among subjects and is usually tailored
to the subject*s clinical status, taking into consideration the type of
bleeding episode, frequency of bleeding, and goal of treatment for the subject.
The dose of FIX required also varies and has been based on observations over
the years and guidelines established by organizations such as the National
Hemophilia Foundation of the United States and the WFH.
The use of FIX-containing, plasma-derived coagulation products, available for
almost 40 years, has led to vast improvements in the care of hemophilia B,
subject life expectancy, and quality of life for people with hemophilia. Risks
of plasma-derived products include subject infection with serious blood-borne
pathogens, including human immunodeficiency virus (HIV) and hepatitis B and C,
as well as thrombosis. Recombinant coagulation products with no animal- or
human-plasma-derived proteins, developed more recently have a safety advantage
in that the risk of disease transmission is minimal.

Identified priorities for hemophilia B therapy include the development of more
convenient dosing options and investigation into modified FIX agents with a
longer half-life to decrease injection frequency. Current therapy is focused on
home therapies, which, taken prophylactically or administered at the onset of a
bleeding episode, reduce short-term disability and long-term joint damage and
improve subjects* overall quality of life and functional independence.

rFIXFc (BIIB029) is a recombinant coagulation Fc fusion protein, which
comprises FIX covalently attached to the Fc domain of human IgG and is in
development as a long-acting version of rFIX for the treatment of hemophilia B.
rFIXFc has been tested in 14 subjects with severe, previously treated
hemophilia B in a Phase 1/2a study and is currently under investigation in a
preceding study in subjects aged 12 years and older. Preclinical and clinical
experience to date has shown an extended half-life of FIX activity compared
with commercially available recombinant FIX product. This extended half-life
may reduce the frequency of IV injections required for prevention of bleeding
and treatment for bleeding episodes in hemophilia B subjects. A therapy with
these characteristics may also improve treatment compliance and quality of
life.

Primary:
The primary objective of the study is to evaluate the long-term safety of
rFIXFc in subjects with hemophilia B.

Secondary:
The secondary objective of this study is to evaluate the efficacy of rFIXFc in
the prevention and treatment of bleeding episodes.

This is an open-label, multi-center, long-term study of intravenous (IV)
administration of rFIXFc in previously treated patients (PTPs) with hemophilia
B who have completed the B-LONG study (998HB102), the pediatric study
(9HB02PED), or any other study with rFIXFc. This is a global study and will
include those countries participating in these studies.

Based on estimated sample sizes from these studies, approximately 100 subjects
from the ongoing B-LONG study and approximately 20 subjects from the pediatric
study may be eligible to enroll in this extension study. The End of Treatment
(EOT) Visit of the previous study may serve as the screening visit of the
extension study. Assessments performed at this visit will be used to confirm
eligibility for participation in the extension study.

Study visits are scheduled at 6-month (±2 weeks) intervals following completion
of Visit 1. Unscheduled visits may occur as deemed necessary by the
Investigator. For subjects from the pediatric study (9HB02PED) who undergo
surgery and enter the extension study before completing their Last
Post-Operative Visit, the Last Post-Operative Visit assessments will be
performed when the subjects switch from their post-surgery dosing regimen to a
regimen outlined in Section 5.3.2 of the protocol. Inhibitor testing will be
performed at the time subjects reach 10-15 and 50-75 EDs, and after 100 EDs, as
applicable. The number of exposure days for inhibitor testing is comprised of
the number of exposure days from the parent study and this extension study,
combined. If the timing for inhibitor testing does not coincide with a
scheduled visit, an unscheduled visit may be conducted.

For subjects undergoing surgery, post-operative clinic visits may be more
frequent and, for subjects undergoing major surgery, a visit is required 1-2
weeks after surgery (Visit 3) and when subjects return to a regular rFIXFc
regimen (Visit 4). Scheduled visits will include safety and efficacy
assessments, and FIX activity measurements to assess trough and peak
(recovery). In addition, the site will contact study subjects and/or caregivers
by telephone on a bimonthly basis to review adverse events, treatment
compliance, use of concomitant medications and therapies, and other issues.

Treatment will be self-administered as prophylaxis or as an on-demand regimen.
Subjects will be able to switch from one regimen to another at scheduled or
unscheduled visits during the study, per Investigator discretion.

To ensure accuracy of trough/peak (recovery) and inhibitor testing, subjects
following a prophylaxis regimen should schedule clinic visits 72 hours after
the previous dose of rFIXFc, whenever possible.

Subjects are expected to be followed through at least 100 exposure days (EDs)
to rFIXFc and may continue in this study for up to 4 years or until rFIXFc is
commercially available in the applicable participating country.

rFIXFc will be administered over several minutes by slow intravenous (IV)
injection. The rate of administration should be determined by the subject*s
comfort level. Any missed doses should be taken as soon as possible or per the
instructions of the Investigator.
Subjects will follow either a prophylaxis or on-demand regimen based on the
subject*s clinical profile and by PK profiles and dosing levels from the prior
rFIX Fc study.
Subjects will be allowed to change from prophylaxis to on-demand, and from
on-demand to prophylaxis during this study. All treatment regimen changes will
be discussed between the Investigator and the subject (and parent/guardian, as
applicable).

The prophylaxis regimen may comprise doses of rFIXFc 20 IU/kg to 100 IU/kg once
weekly, or a tailored prophylaxis regimen taken at individualized intervals.
Individualized doses and dosing intervals can be based on PK profiles and
dosing levels from the preceding rFIXFc studies or FIX trough and/or peak
(recovery) levels obtained during this extension study.
Prophylaxis treatment options may include weekly prophylaxis, individualized
dosing intervals, or personalized prophylaxis.

The individual dose of rFIXFc to treat bleeding episodes will be based on the
subject*s clinical condition and the type and severity of the bleeding event.

For subjects who require emergent or elective surgery during the study period,
the dose and regimen of rFIXFc shall be that deemed appropriate for the type of
surgery to be performed.
All surgeries must take place in a center that can provide study treatment,
trained study personnel, post-operative assessments, and hematological consult
by the Investigator or Co-Investigator. If the surgery does not occur in such a
setting, the subject will be withdrawn from the study.
In addition, subjects who require major surgery may receive rFIXFc if
1. The surgery occurs within the contracted Institution for the trial and/or a
separate agreement has been executed, permitting the use of study drug and
Biogen Idec*s rights to data generated in the trial at an alternative
Institution deemed appropriate by the Principal Investigator.
2. The Investigator and/or appropriate qualified/licensed delegate is available
to
a. Administer all rFIXFc doses required during surgery and during
post-operative rehabilitation (if applicable).
b. Provide medical oversight and guidance throughout the duration of the
pre-operative and the intra-operative periods.

Surgeries, elective or emergent, will be classified as major or minor, as
follows: Major surgery is defined as any surgical procedure (elective or
emergent) that usually, but not always, involves general anesthesia and/or
respiratory assistance, in which a major body cavity is penetrated and exposed,
or a substantial impairment of physical or physiological functions is produced
(e.g., laparotomy, thoracotomy, craniotomy, joint replacement, or limb
amputation). Minor surgery is defined as any surgical procedure (elective or
emergent) that does not involve general anesthesia and/or respiratory
assistance (e.g., minor dental extractions, incision, and drainage of abscess,
joint or other injections, or simple excisions).
Inhibitor testing should be performed 2 to 4 weeks prior to the scheduled
surgery, pre-operatively on the day of surgery, 1-2 weeks post-surgery, and at
the last post-operative visit (for minor surgery, testing is not performed at
the last 2 timepoints). On the day of surgery, subjects will be given a
pre-operative loading dose of rFIXFc as a bolus, and, in the case of emergency
surgery, as soon as possible prior to the procedure. Pre-dose FIX activity
levels will be sampled followed by FIX peak (recovery) samples 30 ±5 minutes
post-dosing.

A repeat sample will be taken approximately 6 to 9 hours after this dose, but
may alternatively follow the local standard of care for determination of
subsequent rFIXFc dosing. During the subject*s hospitalization, FIX activity
will be measured daily at the local laboratory, and a plasma aliquot will be
prepared for each blood sample drawn so that subsequent analysis at the central
laboratory can be performed.
Doses higher than 100 IU/kg may be used in the context of surgery to achieve
the required FIX levels to prevent bleeding. However, the maximum number of
daily or every-other-day doses will not exceed the predicted accumulated Cmax
of approximately 150% of normal (normal ranges are 50% to 150% FIX activity).
All surgical dosing plans will be discussed with and approved by the Sponsor
Medical Monitor before surgery.

The use of a prophylaxis regimen in young children with hemophilia improves
their long-term clinical outcome by preventing joint bleeding in the early
years of life and subsequent hemophilic arthropathy. At 6 years of age,
children on a prophylaxis regimen had significantly less joint damage than
children treated with an on-demand regime.
This trial gives the opportunity for less frequent administration regime.

Side effects that have been reported in previous rFIXFc studies or with other
FIX products.

Possible serious side effects
• Allergic reaction (including anaphylaxis).
• Abnormal formation of blood clots.
•Nephrotic syndrome. A disorder of the kidneys has been reported in hemophilia
B patients who have had a history of allergic reactions to FIX and who have
received large, frequent doses of FIX to stop these allergic reactions and to
help them to respond better to it.