Rilonacept for Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)

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 specific
cytokine pathways are dysregulated. Monogenic defects in the IL-1 pathway cause cryopyrin
associated periodic syndromes (CAPS) and deficiency of the IL-1 receptor antagonist (DIRA),
the latter is caused by mutations affecting the IL-1-receptor antagonist gene (IL1RN). Both
disorders respond with complete resolution of the inflammatory response to treatment with the
short acting IL-1 blocking agent anakinra. This exploratory study aims to examine the utility
of the long acting IL-1 inhibitor rilonacept (rilonacept; Regeneron Pharmaceuticals, Inc.)

This pilot study is designed to address: 1) the utility and dosage of rilonacept needed to
achieve inflammatory remission in children with DIRA who have shown a response to treatment
with anakinra [Kineret[registered]]; and 2) to evaluate the safety and pharmacokinetics in
young children on rilonacept.

Rilonacept is a recombinant fusion protein with picomolar affinity for IL-1 and a half-life
of approximately 7.5 days in humans. It is approved by the Food and Drug Administration (FDA)
for the treatment of adults and children 12 years of age and older with Cryopyrin-Associated
Periodic Syndromes (CAPS), and was tested in the clinically milder forms of CAPS including
Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).

In this study, clinical, and laboratory parameters will initially be measured at baseline
following a withdrawal of anakinra for 24 hours. Subjects will receive a course of therapy
with rilonacept that is predicted to induce inflammatory remission. Clinical and laboratory
measures of inflammation will be assessed; rilonacept dose escalation will be implemented as
necessary to achieve clinical and laboratory remission. Subjects will remain on study for 12
months and primary end point will be evaluated at 6 months.

Those subjects who complete the 1-year treatment period and maintain improved clinical and
laboratory parameters compared to baseline values, may continue to receive study medication
at their current dose. Principal investigator will help to obtain insurance coverage for
rilonacept for their continued treatment, and will discuss with Regeneron Pharmaceuticals,
Inc. for additional supplies of rilonacept for these subjects.

- INCLUSION CRITERIA

1. Male or female pediatric and adult subjects with mutation positive IL1RN
indicating DIRA. For the first five patients enrolled, they must have been on a
stable dose of anakinra during the 2-week period prior to screening visit. If the
subject is on other medications such as NSAIDs, methotrexate and/or oral
steroids, it is a requirement that these doses have been stable during the 2-week
period prior to screening visit.

2. Subjects greater or equal to 3 months of age (however the first 5 patients
enrolled will be over 2 years of age). Subjects 3 months old or older will be
enrolled after SMC data review of the first 5 enrolled patients.

3. Participation in NIH study #03-AR-0173 ( Studies of the Natural History,
Pathogenesis and Outcome of Autoinflammatory Diseases (NOMID/CAPS, DIRA, CRMO,
Still s Disease, Behcet s Disease, and other Undifferentiated Autoinflammatory
Diseases )

4. Subjects currently treated with anakinra may be enrolled in this study even
though their DIRA may be quiescent. For these subjects, a history of active DIRA
prior to treatment with anakinra will be sufficient. Subjects will not take
anakinra 24 hours before initiation of drug treatment. Treatment naive patients
will also be enrolled after SMC data review of the first 5 enrolled patients.

5. Females of childbearing potential (young women who have had at least one
menstrual period regardless of age) must have a negative serum pregnancy test at
screening and a urine pregnancy test prior to administration of study medication.

6. Females of childbearing age and men able to father a child and who are sexually
active, who agree to use two forms of effective birth control, including
abstinence.

7. Negative Purified Protein Derivative (PPD) test using 5 T.U. intradermal testing
or the QuantiFERON(SqrRoot) - TB Gold test per the Centers for Disease Control
and Prevention (CDC) guidelines, and no evidence of active tuberculosis (TB) on
chest X-ray.

Subjects with latent TB (positive PPD or QuantiFERON - TB Gold test) currently
treated with adequate therapy for at least one month prior to first dose of study
medication may be included. Full prophylaxis regimens will be continued while on
the study.

Subjects who have had active TB in the past with documentation of adequate
treatment may be included with strict clinical and radiological follow-up as per
current guidelines.

The Infectious diseases service will be consulted regarding all patients with
evidence of TB infection (latent or active, current or history) prior to
enrollment, and as appropriate during the study.

Subjects who have been BCG-vaccinated will also be tested. Interpretation of PPD
and QuantiFERON - TB Gold test in BCG recipients will be the same as for subjects
who have not received BCG vaccine.

Guardian/parent able to understand, and complete study-related questionnaires.

Guardian/parent able and willing to give informed consent and abide with the
study procedures.

EXCLUSION CRITERIA

1. Treatment receiving a live virus vaccine (such as the measles, mumps, and rubella
vaccine) during the 3 months prior to baseline visit. No live vaccines will be
allowed throughout the course of this study.

2. Presence of active infections or a history of pulmonary TB infection without
documented adequate therapy. Subjects with current active TB, or recent close
exposure to an individual with active TB, are excluded from the study. Exceptions
include patients with latent TB treated with adequate therapy for at least one
month prior to the first dose of study medication, and patients with history of
TB with documentation of adequate treatment.

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

4. 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.

5. Known hypersensitivity to Chinese Hamster Ovary cell-derived biological or any
components of rilonacept.

6. 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).

7. Presence of any of the following laboratory abnormalities at enrollment visit:

creatinine greater than 1.5xULN

WBC less than 3.0x103/mm3

ANC less than 800 cells/mL

platelet count less than 150,000 mm3

ALT or AST greater than 2.0x ULN.

8. Lactating, breastfeeding or pregnant females.

9. 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.

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

11. 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.

12. Subjects who have received a DMARDs (except methotrexate) and or TNFblocking
agent within 4 half-lives prior to study entry.

13. Men able to father a child and who are sexually active, who do not agree to use 2
form of effective birth control, including abstinence during the duration of the
study an for at least 28 days following the last dose of rilonacept.

14. Females of childbearing potential (woman greater than 12 or who have had at least
1 menstrual period regardless of age) who are sexually active and who do not
agree to use 2 effective methods of birth control, including abstinence during
the duration of the study an for at least 28 days following the last dose of
rilonacept.