Anakinra for Inflammatory Pustular Skin Diseases

Background:

- Inflammatory disorders that present with neutrophilic pustular skin lesions, including
generalized pustular psoriasis, are characterized by severe cutaneous manifestations,
generalized inflammation and significant morbidity.

- Recent studies in patients with phenotypically similar pustular diseases have identified
two monogenic forms of neutrophilic pustular psoriasis implicating interleukin (IL)-1 in
disease pathogenesis.

- Deficiency of the IL-1 receptor antagonist (IL1RN, DIRA) is an autosomal recessive
condition characterized by severe generalized pustular eruptions in the neonatal
period, osteopenia, lytic bone lesions, joint pain, respiratory insufficiency,
thrombosis, elevated acute phase reactants and significant mortality. Patients with
this condition have responded rapidly to IL-1 receptor antagonist, anakinra.

- Deficiency of IL-36 receptor antagonist (IL-36RN/IL1F5, DITRA) is an autosomal
recessive condition with episodic widespread pustular skin lesions, fevers and
systemic inflammation defined by marked leukocytosis and elevated creactive
protein.

- Both IL1RN and IL36RN/IL1F5 are highly expressed in epidermal keratinocytes, suggesting
a role for keratinocytes in initiating innate immunity-mediated inflammatory skin
diseases, and ultimately manifesting in a pustular phenotype.

- Patients with inflammatory pustular diseases often respond poorly to conventional
treatment with methotrexate, cyclosporine and anti-TNF agents.

- Two recent case reports describe patients with pustular psoriasis unresponsive to TNF
inhibition who responded to anti-IL-1 receptor therapy with anakinra. We hypothesize
that monogenic and polygenic inflammatory pustular skin diseases share common pathogenic
mechanisms mediated by IL-1.

- We propose a phase 2 study that will utilize a collaborative bench-to-bedside approach,
applying targeted anti-IL-1 therapy, novel imaging modalities, and laboratory techniques
including immunohistochemistry, gene expression and cytokine studies, and in vitro
manipulations of skin to dissect and validate pathways in these complex diseases.

Objectives:

-To characterize the clinical efficacy, optimal dosing and safety of anakinra in patients
with pustular dermatoses.

Eligibility:

- Age greater than or equal to 18 years.

- Active macroscopic noninfectious pustular skin lesions involving greater than or equal
to 5% of the total body surface area, or palmoplantar involvement.

- Histopathologic confirmation of epidermal neutrophilic pustulosis.

- Patients must have maintained a stable dose of immunosuppressant therapy, retinoids or
anti-neutrophil therapy for 2 weeks prior to study initiation with resultant stable or
worsening skin disease.

- Use of biologic agents requires a washout period of at least 3 half-lives prior to study
initiation.

- Patients must have organ and marrow function as defined below:

- leukocytes >3,000/mcL

- absolute neutrophil count >1,500/mcL

- platelets >100,000/mcL

- creatinine within normal institutional limits OR creatinine clearance >60
mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

Design:

- A 16-week, open-label phase 2 study.

- Patients will initially receive treatment with anakinra 100 mg/day by self-administered
subcutaneous injection.

- Disease response will be assessed every 4 weeks, and determination of dose escalation
will be made based on clinical assessment. Dose escalation can increase up to 200
mg/day, and for patients >75 kg up to 300 mg/day at the end of week 8.

- If a response is achieved with anakinra, other immunosuppressants administered for the
purpose of treatment of pustular skin disease may be tapered per physician discretion.

- Clinical assessment, and laboratory and subjective data will be collected in-person
every 4 weeks to determine disease response. Telephone assessments will be performed
weekly.

- Twenty-five evaluable patients will be enrolled onto this trial. The accrual ceiling for
this study will be set to 30.

- INCLUSION CRITERIA

1.1 Females and males, aged greater than or equal to 18.

1.2 Patients must demonstrate active noninfectious inflammatory pustular skin lesions
resembling pustular psoriasis and involving greater than or equal to 5% total body surface
area, or palmoplantar involvement. Conditions may include, but are not be limited to,
pustular psoriasis, Sneddon-Wilkinson disease, subcorneal pustular dermatosis, reactive
arthritis, palmoplantar pustulosis, acrodermatitis continua of Hallopeau and palmoplantar
pustular psoriasis.

1.3 Patients must have histopathologic confirmation of epidermal neutrophilic pustular skin
disease.

1.4 If taking immunosuppressants, retinoids or anti-neutrophil therapy, participants must
maintain stable doses of these medications during the 2 weeks prior to study initiation.

1.5 Patients must have stable topical medication regimen for 2 weeks prior to study
initiation.

1.6 Patients must have normal organ and marrow function as defined below:

leukocytes greater than or equal to 3,000/mcL

absolute neutrophil count greater than or equal to1,500/mcL

platelets greater than or equal to 100,000/mcL

creatinine within normal institutional limits OR creatinine clearance greater than or equal
to 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

1.7 Quantiferon TB Gold must be performed for screening for mycobacterium tuberculosis
infection. However, a tuberculin skin test may be placed if the Quantiferon TB gold test is
indeterminate. Patients must have a negative Quantiferon TB Gold (or tuberculin skin test)
or evidence of appropriate treatment prior to study entry.

1.8 Patients must be able to understand and sign a written informed consent document and
complete study-related procedures and questionnaires.

EXCLUSION CRITERIA

2.1 Enrollment in any other investigational treatment study or use of an investigational
agent, or has not yet completed at least 3 half-lives since ending another investigational
device or drug trial.

2.2 History of treatment with canakinumab within the 12 months prior to study initiation.

2.3 History of anakinra use.

2.4 History of phototherapy within 2 weeks prior to study initiation.

2.5 Patients may NOT concurrently be on biologic therapy such as etanercept, adalimumab,
alefacept, infliximab, rituximab or rilonacept. If there is a history of use of biologic
agents, there must be a washout period of at least 3 half-lives prior to study initiation.

2.6 Subjects who experience a significant flare after discontinuation of a TNF inhibitor as
part of this study that requires urgent medical management or hospitalization, or in the
estimation of the principal investigator poses excessive risk to the patient to enter the
study.

2.7 Other defined dermatologic conditions which may include pustules as part of the
clinical presentation, but which clinically and/or histologically do not resemble pustular
psoriasis. Examples include, but are not limited to acute generalized exanthematous
pustulosis (AGEP, a drug-induced pustular dermatosis typically caused by beta-lactam
antibiotics, tetracyclines, oral antifungals and other drugs), bacterial or fungal
folliculitis, cutaneous candidiasis, tinea pedis, tinea corporis, neutrophilic eccrine
hidradenitis or eosinophilic pustular folliculitis (Ofuji syndrome).

2.8 Known diagnosis of DIRA.

2.9 History of allergic reactions attributed to compounds of similar chemical or biologic
composition to anakinra or other agents used in study. Known hypersensitivity to CHO-cell
derived biologics or any components of anakinra.

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

2.11 Patients with active or untreated malignancy-- with the exception of cutaneous basal
or squamous cell carcinomas, or in situ cervical carcinoma-- are ineligible because of the
immunomodulating effects of anakinra. The risk of recurrent malignancy secondary to this
drug is unknown.

2.12 Presence of active infection. History of exposure to TB (positive PPD or Quantiferon
TB gold) who have not been treated with a TB prophylaxis regimen for at least one month.

2.13 Chest x-ray demonstrating pleural scarring and/or calcified granuloma consistent with
prior or current untreated TB.

2.14 History of chronic or recurrent infection including but not limited to HIV, hepatitis
B or hepatitis C.

2.15 Individuals with severe or uncontrolled recurrent cutaneous infections who are
considered at elevated risk for serious infection on anakinra therapy will be excluded per
physician discretion.

2.16 Presence of other known significant autoimmune or inflammatory disease. Examples
include major chronic infectious/inflammatory/immunologic diseases such as systemic lupus
erythematosus, rheumatoid arthritis, Sjogren s syndrome and periodic fever syndromes.

2.17 Other immunoregulatory or immunodeficiency diseases, such as multiple sclerosis.

2.18 Individuals with life-threatening or disabling inflammation of the eyes, gut or joints
requiring urgent or immediate medical attention, or at the physician s discretion.

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

2.20 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, uncontrolled or unmonitored psychiatric illness/social situations, or history of
congestive heart failure, unstable angina pectoris or medically significant cardiac
arrhythmia that would limit compliance with study requirements.

2.21 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 enrollment inappropriate.

2.22 The effects of anakinra on the developing human fetus are unknown. Women of
childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control or abstinence) prior to study entry and for the duration of
study participation. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately. Females of childbearing potential must have a negative serum pregnancy test at
screening. Females must also have a negative serum pregnancy test at baseline and prior to
performance of any radiologic procedure or administration of study medication and during
each NIH visit. Lactating mothers will discontinue breastfeeding prior to study enrollment.

2.23 Pregnant or lactating females. Women of non-childbearing potential is defined as women
who are postmenopausal (no menses for > one year) or who have had a hysterectomy and will
not require B-HCG testing