Abatacept vs Placebo in RA Patients With Hepatitis B on Entecavir Background

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder affecting 1% of the
world's population. If not adequately controlled, it may lead to disability in up to 30% of
patients within the first three years of disease onset [1] and can be associated with
premature death. Recent research has suggested that the first event in the pathogenesis of RA
is an antigen dependent activation of T-cells in an immunogenetically susceptible host.
T-cells require two signals for activation, one involving the trimolecular complex (class II
Major Histocompatibility Complex (MHC), antigen, T-cell receptor), and the other being
co-stimulation of the CD28 (Cluster of Differentiation 28) molecule on T-cells by the B7
molecules (CD80 and CD86) on antigen presenting cells.

Hepatitis B virus (HBV) can cause chronic disease in 5% of immunocompetent adults and has a
prevalence of over 350 million worldwide. It is a leading cause of chronic hepatitis,
cirrhosis and hepatocellular cancer and accounts for one million deaths annually. In patients
with chronic hepatitis B and RA, treatment options are limited. Traditional disease modifying
anti-rheumatic drugs (DMARDs) are associated with hepatotoxicity and are contraindicated in
chronic hepatitis. A recent retrospective analysis suggests that successful use of anti-tumor
necrosis factor alpha (anti-TNF) agents may be possible in these patients but the authors do
warn that these patients should be closely monitored and that fatal reactivation of hepatitis
B is possible. Treatment with rituximab, a chimeric monoclonal antibody against B-cell
protein CD20, is another option; however, the use of this medication in RA patients with
chronic hepatitis B may also cause reactivation.

When RA patients with chronic hepatitis B were started on a Tumor Necrosis Factor (TNF)
inhibitor or methotrexate (MTX), 2 of 5 HBsAg+ patients reactivated their hepatitis B,
indicating a possible high rate of activation in these patients when not on hepatitis B
treatment. Reactivation in this and another study occurred after 9-19 months of antirheumatic
therapy. In RA patients with chronic Hepatitis B, entecavir appears to be effective at
preventing reactivation.

There are no studies on the safety of abatacept in patients with RA and HBV. Adequate T-cell
function is important to help cure or contain HBV infection. Our site has conducted a
retrospective study that shows preliminary safety of abatacept in patients with RA and
chronic Hepatitis B on antiviral therapy. The purpose of this study is to assess the safety
and efficacy of abatacept in RA patients with chronic Hepatitis B in a pilot study in a
randomized, controlled fashion.

Inclusion Criteria:

1. Diagnosis of RA.

2. Baseline CDAI >10 with TJC (Tender Joint Count) > 4 and SJC (Swollen Joint Count) > 2.

3. Chronic Hepatitis B as defined by a history of patients with a HBsAg positive for at
least 6 months with undetectable HBV DNA; or a history of patients with negative HBsAg
and positive HBcAb or HBsAb, with undetectable HBV DNA.

4. No evidence of hepatocellular carcinoma (HCC) based upon alpha-fetoprotein (AFP) ≤20
ng/mL at screening,) negative liver imaging as shown by ultrasound, computerized
tomography or magnetic resonance imaging within 24 weeks of screening. Participants
with AFP >20 ng/mL must be evaluated clinically with additional imaging and shown not
to have HCC on CT or MRI before they can be enrolled.

5. Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) and NSAIDs
(Non-Steroidal Anti-inflammatory Drugs) are permitted if the patient is on a stable
dose regimen for ≥ 2 weeks prior to and including at baseline.

6. Men and women, >= 18 years of age.

Exclusion Criteria:

1. Women who are pregnant or breastfeeding. Sexually active fertile men not using
effective birth control if their partners are WOCBP (Women of Child Bearing
Potential).

2. Target Disease Exceptions

a) Rheumatic autoimmune disease other than RA; fibromyalgia or
keratoconjunctivitis/xerostomia are allowed, as long as these will not confound the
CLINICAL EFFICACY OUTCOMES.

3. Medical History and Concurrent Diseases

1. Subjects who are impaired, incapacitated, or incapable of completing
study-related assessments.

2. Subjects who underwent previous MCP (metacarpophalangeal) arthroplasty, have such
a procedure scheduled, or anticipate the need for such a procedure during the
study.

3. Major surgery (including joint surgery) within 8 weeks prior to screening

4. Subjects with active vasculitis of a major organ system, with the exception of
rheumatoid nodules or minor rheumatoid vasculitis lesions of the skin

5. Subjects with current uncontrolled symptoms of severe, progressive, or
uncontrolled renal, hepatic hematologic, gastrointestinal, pulmonary, cardiac,
neurologic, or cerebral disease, including Cirrhosis with Child-Pugh Class >=2 or
COPD (chronic obstructive pulmonary disease) with FEV1 (forced expiratory volume
in 1 second) /FVC (forced vital capacity) < 0.6

6. Female subjects who have had a recent breast cancer screening that is suspicious
for malignancy and where the diagnosis is not excluded.

h) Subjects who currently abuse drugs or alcohol. i) Subjects with evidence of active
or latent bacterial or viral infections at the time of potential enrollment, including
HIV.

j) Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2
months before the informed consent document was signed.

k) Subjects who have received any live vaccines within 3 months of the anticipated
first dose of study medication.

l) Subjects with any serious bacterial infection within the last 3 months, unless
treated and resolved with antibiotics, or any chronic bacterial infection.

m) Subjects at risk for tuberculosis (TB) or not treated for latent TB is tested
positive.

n) Subjects who are positive for hepatitis C antibody if the presence of hepatitis C
virus was also shown with polymerase chain reaction or recombinant immunoblot assay.

o) Subjects who have abnormal laboratory values

4. Prohibited Treatments and/or Therapies

1. Subjects who have at any time received treatment with any investigational drug
within 28 days (or less than 5 terminal half-lives of elimination) of the Day 1
dose.

2. Any concomitant biologic DMARD, such as anakinra.

3. Previous treatment with cell-depleting therapies, including investigational
agents, including but not limited to CAMPATH, anti-CD4 (cluster of
differentiation 4), anti-CD5, anti-CD3, and anti-CD19.

4. Anti-CD20 treatment within the last 6 months (OK to include if they were dosed >
6 months ago).

5. Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine,
mycophenolate mofetil, within <= 4 weeks prior to baseline.

6. Treatment with etanercept within 2 weeks,
infliximab/certolizumab/golimumab/adalimumab with <=8 weeks, anakinra within <=1
week prior to baseline.

7. Previous abatacept use.

8. Treatment with sulfasalazine within < 4 weeks prior to baseline