A Pilot Study Using Anakinra/Kineret for the Treatment of Patients With Severe Atopic Dermatitis

Severe refractory atopic dermatitis is a chronic inflammatory pruritic skin condition that
affects both children and adults. The disease is marked by periods of exacerbation and
remission. Symptoms of atopic dermatitis may resolve by adolescence; however, it is estimated
that the disease may persist in 50 percent of affected children well into adulthood.

Current possible treatments of atopic dermatitis include the use of topical corticosteroids,
calcineurin inhibitors, phototherapy, as well as systemic medications i.e., methotrexate,
cyclosporine, azathioprine, mycophenolate mofetil and interferon gamma. The difficulty with
long-term treatment of this disease lies in its chronic nature associated with severe
episodes. The combination of chronicity and severity of episodes of this diseases demands
more effective and better-tolerated therapeutic options than those that are currently
available. While the pathways of allergic inflammation are different than those of other
inflammatory conditions, certain elements may overlap, providing targets for immune
modulation. One of these targets is the interleukin-1 (IL-1) receptor.

The IL-1 receptor plays an important role in the development and maintenance of Th2
responses. Genetic, in vivo and in vitro data demonstrate a significant role for IL-1
signaling allergic and skin inflammatory conditions. This pilot study is therefore designed
to assess the safety and efficacy of IL-1ra, a natural inhibitor of the IL-1 receptor, in
disrupting atopic pathophysiologic pathways. Specifically, we will treat severe refractory
atopic dermatitis associated with evidence of multiple specific allergic sensitivities. Up to
8 patients ages 10-30 with severe refractory dermatitis will be enrolled. Patients will be
initially evaluated to establish the diagnosis of severe refractory AD as evidenced by SCORAD
score greater than 40, followed by a 2 month (8 week) run-in period, a 3 month (12 week)
treatment period of 3mg/kg/day anakinra given subcutaneously, followed by a 3 month (12 week)
post-treatment evaluation period. In order to be considered evaluable for response, patients
must have received a minimum of 67 out of 84 doses (80 percent) of anakinra. The primary
endpoint is lack of an increase in serious infections, the secondary endpoint is a reduction
of 30 percent or more in SCORAD score, and tertiary endpoints are cellular phenotypic and
cytokine responses to IL-1 receptor blockade in atopic patients.

- INCLUSION CRITERIA:

To be eligible for enrollment in this protocol, participants must fulfill all of the
following criteria:

1. Must be 10 years to 30 years of age

2. Patient or legal guardian must be able to give informed consent

3. Must have evidence of severe atopic dermatitis as determined by the investigators and
a SCORAD score >40 performed within 90 days of study entry

4. Must have report from primary physician documenting lack of sufficient response to
topical corticosteroids for > 6 months

5. Must have skin test or radioallergosorbent test (RAST) showing sensitivity to greater
than or equal to 3 food and/or airborne allergens

6. Must have a baseline CBC that demonstrates:

- White Blood Cell Count (WBC) greater than or equal to lower limit of normal for
age

- Absolute Neutrophil Count (ANC) greater than or equal to lower limit of normal
for age

c. Platelet Count greater than or equal to lower limit of normal for age

7. Must not be pregnant or breastfeeding

8. If subject is a female that has begun menstruation, and is sexually active, she must
agree to consistently use contraception throughout study participation. Acceptable
forms of contraception are:

- Condoms, male or female, with spermicide

- Diaphragm or cervical cap with spermicide

- Intrauterine device

- Contraceptive pills or patch, Norplant, Depo-Provera or other FDA-approved
contraceptive method

- Male partner has previously undergone a vasectomy for which there is
documentation of aspermatogenic sterility

- Abstinence

9. Must have a primary care physician

10. Must be willing to submit blood and skin tissue for storage

EXCLUSION CRITERIA:

A patient will be ineligible to participate in this protocol if any of the following
criteria are fulfilled:

1. Patient is taking oral or injectable immunomodulators (such as methotrexate, imuran,
and cyclosporine) or biologics (such as etanercept or omalizumab).

2. Patient requires systemic immunosuppression at any time during the study

3. Patient has known diseases of immunodysregulation or immunodeficiency.

4. Any chronic medical condition other than atopic dermatitis, allergy/asthma and
infection, such as heart disease, diabetes and autoimmunity that, in the investigator
s opinion, places the patient at undue risk by participating in the study.

5. History of anaphylactic reaction or hypersensitivity to anakinra.

6. The presence of certain types of acquired abnormalities of immunity such as human
immunodeficiency virus (HIV), cytotoxic chemotherapy for malignancy could be grounds
for possible exclusion if, in the opinion of the investigator, the presence of such
disease process interferes with evaluating a coexisting abnormality of immunity that
is a subject of study under this protocol.

7. The presence of any dermatologic diagnosis which, in the investigator's opinion, is
not consistent with atopic dermatitis and would impair the ability to assess drug
response.

8. Has a diagnosis of active tuberculosis with consistent findings from a PPD skin test,
computerized tomography (CT) scan or Chest x-ray. Those subjects found to have a
positive PPD will be referred back to their primary care physician for appropriate
management.

9. Has received a live vaccine within 4 weeks prior to therapy or potential need for a
live vaccine during the study.

10. Is unwilling to undergo testing or procedures associated with this protocol.

11. The patient or guardian is unable or unwilling to give daily injections.