Use of Etanercept in the Treatment of Moderate to Severe Lichen Planus

Lichen planus affects up to 1% of the worldwide population. Recent estimates suggest
approximately 0.44% of the US population suffers from this disease. Oral or genital
involvement occurs in 60-70% of patients, and it may be the sole manifestation of disease in
20-30% of patients.

Lichen planus is a mucocutaneous disorder that can involve the skin, oral or genital mucosa,
conjunctiva, and nails. On the skin, the disease presents as multiple papules, which can be
localized or generalized, that are often extremely itchy. Mucosal disease can consist of
either asymptomatic plaques or extremely painful erosive lesions. The disease course is
unpredictable and typically lasts 1-2 years but can follow a chronic, relapsing course.
Erosive mucosal disease is important to aggressively treat for many reasons: First, the
associated pain can be debilitating for the patient. Patients with severe oral lichen planus
can become malnourished due to pain associated with eating. Vulvar disease can cause
dyspareunia, burning pain, and discharge; second, the disease tends to be chronic, with
little chance for self-resolution; third, erosive disease is associated with an increased
risk of squamous cell carcinoma in the affected areas. These cancers occur in up to 1% of
patients over a 3-year period, and they can be aggressive and even-life threatening for the
patient if not recognized and treated early.

Several lines of evidence suggest that TNF-alpha plays a role in the pathogenesis of lichen
planus. It has been shown that there are increased levels of TNF-alpha in the serum of these
patients. In addition, skin and mucosal biopsies show increased TNF-alpha produced by the
infiltrating lymphocytes as well as the basal keratinocytes. It has been suggested that the
expression of TNF-alpha receptor on the basal keratinocytes may contribute to apoptosis.
Also, TNFR1 (a TNF-alpha receptor) is expressed by the infiltrating mononuclear cells as well
as the keratinocytes. Increased levels of soluble TNF receptors are also found in the serum
of patients with lichen planus. A recent report also has shown that polymorphisms in the
TNF-alpha gene are associated with both oral and cutaneous lichen planus. Finally,
thalidomide, which partly functions as a potent inhibitor of TNF-alpha transcription, has
been shown to be effective (in small case series and reports) in selected patients for the
treatment of oral and genital lichen planus. However, thalidomide is a potent teratogen and
cannot be used in women of childbearing potential. In addition, thalidomide usage not
uncommonly results in neurotoxicity, which can be permanent, and thus limits use of this
drug. Despite the evidence for a role of TNF-alpha in LP there are no reports of any TNF
inhibitors being used for this disease.

This is a double-blind, placebo-controlled pilot study to observe the safety and efficacy of
etanercept in patients with lichen planus.

This study will consist of 3 periods: first, a double-blind period (weeks 0-12) in which
subjects will be randomized to etanercept 50 mg twice weekly or placebo; second, an
open-label period (weeks 12-24) in which subjects who were randomized to placebo treatment,
who have not achieved a complete remission, will be rolled over to use etanercept at 50 mg
twice weekly. Subjects who previously received etanercept during weeks 0-12, who have not
achieved a complete remission, will be continued on etanercept at a lower dosage of 25 mg
twice weekly for weeks 12-24; third, an 8 week follow-up period for all subjects.

Inclusion Criteria:

- At least 18 years old.

- Must carry a diagnosis of lichen planus as determined by biopsy

- Patients must have a score of 3 or greater on the physician global assessment (PGA).

- Patient must be considered appropriate for systemic therapy based upon fulfilling one
of the following criteria:

1. inability to maintain weight due to pain with eating, chewing, or swallowing;

2. dyspareunia or dysuria due to genital lesions;

3. itch/pain of sufficient severity that activities of daily living are
significantly affected

- Must be off systemic lichen planus treatment for 4 weeks prior to starting etanercept

- If using topical corticosteroid to the affected areas, the dose and frequency must be
unchanged for 2 weeks prior to beginning the study agent and during the course of the
study.

- Must be off topical cyclosporine, tacrolimus, or pimecrolimus for 2 weeks prior to
starting the study drug and for the entire duration of the study.

- Must be able and willing to give written informed consent and comply with the
requirements of the study protocol and must authorize release and use of protected
health information.

- Women of childbearing potential must have a negative pregnancy test at the time of
entry into the study and must be practicing successful contraception for at least 3
months prior to the study.

- Subject or designee must have the ability to self-inject investigational product.

- Screening laboratory results are within the following parameters:

- Hemoglobin > 10 g/dL

- White blood cells > 3.5 x 10^9/L

- Neutrophils > 1.5 x 10^9/L

- Platelets > 100 x 10^9/L

- Lymphocytes > 0.5 x 10^9/L

- Serum creatinine < 1.5 mg/dL

- Hepatitis C serology - nonreactive

- AST and ALT < 2X upper limit of normal (ULN)

Exclusion Criteria:

- Subject is currently enrolled in another investigational device or drug trial(s), or
subject has received investigational agent(s) within 90 days of baseline visit.

- Known HIV-positive status, any other immuno-suppressive disease, or inability to
practice safe sex during the length of the study

- Subject has been diagnosed with a malignancy within the past 5 years

- Subject has signs or symptoms of a lymphoproliferative disease.

- Other skin or mucosal disease that might interfere with lichen planus assessments.

- Lichen planus variants including hypertrophic, atrophic, follicular (including lichen
planopilaris), and bullous cutaneous forms.

- Patients with lichen sclerosis et atrophicus (LS&A)

- Clinical history and lesion distribution suspicious for a lichenoid drug eruption

- Severe co-morbidities

- History of tuberculosis (TB) or positive PPD at screening. Known history of active
hepatitis B or C, or lupus, SLE, history of multiple sclerosis or prior episode of
central nervous system demyelination, transverse myelitis, optic neuritis, epilepsy,
psychiatric condition, or other chronic serious medical illnesses.

- Subject has a diagnosis of congestive heart failure (CHF) of any severity

- Use of a live vaccine 90 days prior to, or during this study.

- Previous exposure and/or known sensitivity to etanercept

- Concurrent use, or failure of, any TNF-inhibitor

- Previous exposure to alefacept or efalizumab within 6 weeks of administration of study
drug

- Concurrent sulfasalazine therapy

- Prior or concurrent cyclophosphamide therapy

- Active severe infections, or prior infection requiring hospitalization or
oral/intravenous antibiotics within 4 weeks before screening visit, or between the
screening and baseline visits.

- Active inflammatory bowel disease or peptic ulcer disease

- Drug or alcohol abuse within 12 months of screening visit.

- History of non-compliance with other therapies

- Pregnant or lactating

- Documented presence of any of the following:

- Proteinuria > 1+ by dipstick screening

- 24 Hour protein excretion > 0.5 g

- Symptomatic liver disease with serum albumin < 3 G/DL

- PT or PTT > ULN, or

- Chronic liver disease

- Documented forced vital capacity < 50% of predicted