Evaluating Sirolimus to Treat Autoimmune Blistering Dermatosis Pemphigus

The purpose of this study is to explore a new medication for the skin disease termed
pemphigus. Our specific aim is to determine whether the use of sirolimus will allow for a
decrease in the dosage or possibly eliminate the need for corticosteroids, which so far is
the only type of drug that can control this disease.

Pemphigus is an autoimmune disease characterized by blistering, caused by autoantibodies
against certain cells in the skin. This disease most commonly occurs in individuals ages 50
and older, and it presents as painful shallow erosions and/or blisters in the mouth and/or
skin. Pemphigus is very painful and uncomfortable, associated with impaired quality of life
and significant morbidity. Severe or untreated cases of pemphigus can become fatal if the
involved surface area becomes large enough to cause dehydration and/or infection. The first
line of therapy, and the standard of care, for pemphigus remain to be systemic
corticosteroids. However, corticosteroids have many known side effects, especially when used
for a long time. Many cases of pemphigus are insufficiently controlled with corticosteroids
alone and require the addition of other immunosuppressive agents, such as azathioprine,
cyclophosphamide, mycophenolate mofetil, or a variety of other therapies used off-label. All
of these treatments are not always successful and have undesirable side effects, including
increased risk of malignancy and infections. Although these treatments can offer some relief
from the disease, they are also often the cause of many side effects.

Sirolimus (formerly known as rapamycin) is a drug commonly used after renal transplants to
prevent organ rejection. In this study, pemphigus subjects with active disease will begin
taking sirolimus in conjunction with corticosteroids, using a similar regimen used for organ
transplantation to treat pemphigus. While increasing sirolimus and decreasing the
corticosteroids, subjects will be monitored over a 12 month period to evaluate their disease
response. The purpose of this study is to observe data trends.

Our specific aim is to determine whether the use of sirolimus will allow for a decrease in
the dosage of the corticosteroid prednisone, which so far is the only type of drugs that can
control these diseases, without making the pemphigus worse.

Inclusion Criteria:

1. Subject must be 18 years of age or older.

2. Subject must have an established diagnosis of pemphigus disorder via biopsy and/or
serologic titer, as determined appropriate by the lead researcher.

3. Subject must have active disease at the time of enrollment, as defined by a positive
Nikolsky sign.

4. Subject must not be taking any immunosuppressive medication or therapy other than
corticosteroids.

5. Subject must be able to understand and follow directions.

6. If female, subject is not currently breast feeding and/or pregnant as confirmed via
negative pregnancy test, no potential for pregnancy, or if of child-bearing age,
agrees to using birth control for entire duration of study and 12 weeks after end of
study.

Exclusion Criteria:

1. Subject may not be under 18 years old.

2. Subject cannot understand or follow directions.

3. Subject may not have any condition that could, in the opinion of the investigator,
compromise the subject's ability to give written consent and/or comply with the study
procedures, such as a history of substance abuse or a psychiatric condition.

4. If female and of child bearing age, is pregnant or unwilling to use birth control
during the study period.

5. Subject may not have any of the following laboratory abnormalities at baseline:

- total white blood cell count < 2,000/mm3 or platelet count < 100,000/mm3

- creatinine >1.5mg/dL

- urine analysis protein of 2+ or greater

- fasting triglycerides > 400 mg/dL, fasting total cholesterol > 300 mg/dL, or
fasting LDLcholesterol > 160 mg/dL

- transaminases > 2 times the upper limit of normal

6. Subjects may not be using any of the following medications: systemic antifungals,
antiepileptics, HIV protease inhibitors, cimetidine, cisapride, clarithromycin,
danazol, diltiazem, erythromycin, metoclopramide, rifabutin, rifampin, rifapentine,
troleandomycin, or verapamil

7. Subject may not consume grapefruit juice and/or St. John's Wort (hypericum
perforatum) throughout the duration of the study.

8. Subject may not have other significant concurrent medical conditions, including

- Active malignancy, including evidence of cutaneous basal or squamous cell
carcinoma or melanoma, or history of cancer (other than fully resected and
surgically cured cutaneous basal cell and squamous cell carcinoma) within 5
years before the first 13 of 25 sirolimus dose. If malignancy occurred more than
5 years ago, documentation of disease-free state since treatment is required.

- Known immunodeficiency syndromes, including HIV

- Renal failure or insufficiency, as defined by laboratory parameters above

- Significant proteinuria, as defined by laboratory parameters above

- History of high cholesterol, lipids, or liver disease, as defined by laboratory
parameters above

- Uncontrolled hypertension, as defined by a blood pressure > 140/90 despite
optimal medical therapy, as prescribed by primary care doctor

- Any condition that, in the opinion of the investigator, might cause this study
to be detrimental to the subject

- Any active Common Terminology Criteria (CTC) grade 2 (localized infection;
requiring local intervention) or higher infection (including chronic or
localized infections) within 30 days prior to screening, at screening, or during
screening period prior to first dose of sirolimus