Anakinra for Behcet s Disease

Autoinflammatory diseases are illnesses characterized by episodes of inflammation that,
unlike autoimmune disorders, lack the production of high titer autoantibodies or
antigen-specific T cells. There is growing genetic and clinical evidence that Interleukin-1
(IL-1) plays a pathogenic role in several of these diseases. This exploratory study aims to
examine the utility of anakinra in the treatment of adult subjects with Behcet s Disease
(BD), a disease which shows similarities to the known anakinra-responsive autoinflammatory
disorders, familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells Syndrome (MWS).
Anakinra is a recombinant form of the human interleukin-1 receptor antagonist that has been
studied in RA and the autoinflammatory disorders. It has a half life of 4 to 6 hours with a
FDA approved recommended dose of 100 mg/day subcutaneously for the treatment of rheumatoid
arthritis.

This pilot study is designed to address: 1) the utility of anakinra in the treatment of BD;
2) the effect of anakinra on laboratory biomarkers in BD; and 3) an exploratory assessment
of the safety of anakinra in individuals with Behcet s Disease.

Subjects with oral or genital ulcers will receive anakinra for three to six months. If five
of the initial seven patients have a positive response, up to 20 patients with oral or
genital ulcers will then be randomized to withdrawal or continuation of drug for six months
once placebo is available. Patients with eye disease will be treated with anakinra for a
total of twelve months without randomization to withdrawal. Clinical and biochemical
correlates of inflammation will be measured at appropriate intervals to assess response and
to further understand disease mechanisms.

- INCLUSION CRITERIA:

1. Male or female subjects with BD associated inflammatory disease greater than or
equal 18 years of age

2. Participation in NIH study #03-AR-0173 ( Studies of the Natural History,
Pathogenesis, and Outcome of Autoinflammatory Diseases )

3. Diagnosis of Behcet s disease as determined by the International Study Group
Criteria [17] or by complete Japanese Criteria [18].

4. Active mucocutaneous disease as defined by at least one oral or genital ulcer
within the past month.

5. Stable dose of steroids, NSAIDs, DMARDs, or colchicine for four weeks prior to
enrollment visit.

6. For patients with ocular disease, no active intermediate or posterior disease at
enrolment but history of an ocular flare (greater than or equal to 3 in the last
6 months) in the presence of any systemic anti-inflammatory therapy such as
prednisone, azathioprine, Mycophenolate, methotrexate, cyclosporine, a TNF
inhibitor, or a combination of these medications. Patients must have developed
active disease in the presence of at treatment with at least one of the
following medications for at least six months: azathioprine, cyclosporine, or a
TNF inhibitor.

7. Females of childbearing potential (young women who have had at least one
menstrual period regardless of age) must have a negative urine pregnancy test at
screening and a negative serum pregnancy test at baseline prior to performance
of any radiologic procedure or administration of study medication. Female
patients will be screened for pregnancy at all NIH visits.

8. Women of childbearing age and men able to father a child, who are sexually
active, who agree to use a form of effective birth control, including
abstinence.

9. Either (1) a negative PPD test using 5 T.U. intradermal testing per CDC
guidelines and no evidence of active TB on chest X-ray at the time of enrollment
or (2) a positive PPD with no evidence of active TB by history or on chest X-ray
at the time of enrollment and either past or present treatment with adequate
therapy for at least one month prior to first dose of study medication. Full
prophylaxis regimens will be completed. Subjects who have been BCG-vaccinated
will also be skin-tested.

10. Able to understand, and complete study-related questionnaires.

11. Able and willing to give informed consent and abide with the study procedures.

EXCLUSION CRITERIA:

1. Treatment with a live virus vaccine during 3 months prior to baseline visit. No live
vaccines will be allowed throughout the course of this study.

2. Patients with ocular disease who received local treatments other than eye drops (i.e.
periocular or intraocular steroids, implants or other anti-inflammatory agents within
4 weeks prior to enrolment)

3. Current treatment with TNF inhibitors or discontinuation of TNF inhibitors within 8
weeks.

4. Presence of active infections or a history of pulmonary TB infection. Patients with a
history of exposure to TB (positive PPD) who have not been treated with a TB
prophylaxis regimen for at least one month.

5. Chest x-ray read by a radiologist with pleural scarring and/or calcified granuloma
consistent with prior TB.

6. Positive test for or prior history of HIV, Hepatitis B or C.

7. History or concomitant diagnosis of congestive heart failure.

8. History of malignancy. Subjects deemed cured of superficial malignancies such as
cutaneous basal or squamous cell carcinomas, or in situ cervical cancer may be
enrolled.

9. Known hypersensitivity to CHO cell derived biologicals or any components of anakinra.

10. Presence of any additional rheumatic disease or significant systemic disease. For
example, major chronic infectious/ inflammatory/ immunologic disease (such as
inflammatory bowel disease, psoriatic arthritis, spondyloarthropathy, SLE in addition
to autoinflammatory disease).

11. Presence of any of the following laboratory abnormalities at enrollment visit:
creatinine > 1.5 times the ULN, WBC < 3.6 times10(9)/mm(3); platelet count < 75,000
mm(3); ALT or AST > 2.0 times the ULN

12. Lactating females or pregnant females.

13. Subjects with asthma not adequately controlled on current inhaled therapy for at
least four weeks.

14. Enrollment in any other investigational treatment study or use of an investigational
agent, or has not yet completed at least 4 weeks or 5 half-lives, whichever is
longer, since ending another investigational device or drug trial.

15. Subjects for whom there is concern about compliance with the protocol procedures.

16. Presence of other severe acute or chronic medical or psychiatric condition, or
significant laboratory abnormality requiring further investigation that may cause
undue risk for the subject s safety, inhibit protocol participation, or interfere
with interpretation of study results, and in the judgment of the investigator would
make the subject inappropriate for entry into this study.

17. Treatment within the past 12 months with canakinumab

18. Active neurologic disease which would require cyclophosphamide treatment. Active
neurologic disease is defined as either new evidence of parenchymal
(meningoencephalitis) or non-parenchymal (vascular complications including
thrombosis) disease.

19. Subjects who experience an end organ flare after discontinuation of a TNF inhibitor
as part of this study.