A Pilot Study of XOMA 052 in Familial Cold Autoinflammatory Syndrome / Muckle-Wells Syndrome and 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 the experimental drug candidate, XOMA 052 (XOMA (US), LLC) in the
treatment of adult subjects with the autoinflammatory disorders familial cold
autoinflammatory syndrome (FCAS) or Muckle-Wells Syndrome (MWS) associated with mutations in
cryopyrin-encoding CIAS1 and in adult subjects with Behcet's Disease (BD), a disease which
may be responsive to IL-1 blockade. XOMA 052 is a human recombinant IL-1beta antibody with
picomolar affinity for IL-1beta and a beta half-life of 22.4 days in humans. This agent is
currently in Phase 2 clinical studies for the treatment of Type 2 Diabetes and initial
studies have shown activity against clinical and biochemical indicators of inflammation.

This pilot study is designed to address: 1) the utility of XOMA 052 in the treatment of FCAS
/ MWS, in a disease known to respond to IL-1 blockade (FCAS / MWS) as shown by a response to
treatment with anakinra (Kineret(Registered Trademark), recombinant IL-1 receptor
antagonist), rilonacept (Arcalyst(Registered Trademark), IL-1 Trap, a fusion protein of the
IL-1 receptor and the Fc portion of IgG), and canakinumab (Ilaris(Registered Trademark),
IL-1beta blocking antibody); the latter two FDA approved for the treatment of this
condition; 2) the pharmacokinetics and dynamics of treatment with XOMA 052 in FCAS / MWS; 3)
the effect of XOMA 052 on laboratory biomarkers in BD; and 4) an exploratory assessment of
the utility of XOMA 052 in the treatment of BD.

For FCAS / MWS, biochemical and clinical correlates of autoinflammatory disease will be
measured at baseline following withdrawal of currently used IL-1 inhibitors. Subjects will
receive a course of therapy with XOMA 052 that is predicted to provide an estimated 4 weeks
of anti-inflammatory activity. If a favorable response is obtained, the continuation phase
will last twelve months. For BD, subjects will receive XOMA 052 for three to six months and
patients with a positive response will then be randomized to withdrawal or continuation of
drug for six months. Clinical and biochemical correlates of inflammation will be measured in
both patient groups at appropriate intervals to assess response and to further elucidate
disease mechanisms.

- INCLUSION CRITERIA:

FOR FCAS / MWS:

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

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

3. CIAS1 mutation positivity or FCAS / MWS based on clinical grounds with a history of a
complete response to IL-1 blocking medications.

4. Subjects presenting with active FCAS / MWS based on clinical signs/symptoms in
addition to elevated acute phase reactants (CRP, SAA or ESR). To meet established
clinical criteria for active disease, patients must have recurrent intermittent
episodes of fever and rash, an age of onset < 6 months of age, duration of most
attacks < 24 hours, and the presence of conjunctivitis with attacks. Active disease
will be defined as either the presence of classical features or a history of such
features that became quiescent in the setting of therapy with anakinra or rilonacept.
However, before a patient who has quiescent disease and is currently taking anakinra
or rilonacept can receive study drug, he/she must fulfill criteria for active disease
after anakinra or rilonacept has been discontinued. Subjects must be greater than 48
hours from their last dose of anakinra (half-life 4-6 hours) and 14 days from their
last dose of rilonacept (half-life 7.5 days) before beginning XOMA 052 therapy, and
will not take anakinra or rilonacept for the remainder of their enrollment in the
study.

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

6. 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.

7. 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.

8. Either (1) a negative PPD test using 5 T.U. intradermal testing per CDC guidelines
and no evidence of active TB by history on chest X-ray at the time of enrollment or
(2) a positive PPD with no evidence of active TB 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.

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

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

FOR BD:

1. Male or female subjects with BD associated inflammatory disease greater than or equal
to 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
or by complete Japanese Criteria

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:

For both study populations:

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 antinflammatory agents within 4
weeks prior to enrollment)

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 with or without
documented adequate therapy.

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 XOMA 052.

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< 3.6x10(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.