Mechanism of Action Study for Psoriasis

Both methotrexate and adalimumab are FDA-approved drugs for the treatment of moderate to
severe psoriasis. The two treatments, methotrexate and adalimumab, both show efficacy for
psoriasis, however their profiles differ. In the CHAMPION Study, more adalimumab-treated,
moderate to severe psoriasis patients achieved a PASI 75 after 16 weeks compared to those
treated with methotrexate (80% vs. 36%). The reason for this difference is poorly
understood. No direct comparative mechanism of action studies in psoriasis patients between
methotrexate and adalimumab (or any tumor necrosis factor blocker) has been reported.

With etanercept, another tumor necrosis factor blocker, the in vivo mechanism has been
studied with some scientific rigor. These studies demonstrate that etanercept down regulates
multiple pro-inflammatory pathways (as shown in Table 1 of the protocol).

To date, there are no similar studies with adalimumab or methotrexate.

In order to understand the molecular and cellular basis for the differential clinical
efficacy of adalimumab and methotrexate, it is essential to compare their mechanisms of
action in psoriatic plaques. Biopsies will be performed, and we will study biomarkers in
this proposal with immunohistochemistry, real-time polymerase chain reaction, and gene
arrays.

Inclusion Criteria:

- Adults 18-85 years of age with moderate to severe psoriasis, in general good health
as determined by the PI based upon the results of medical history, laboratory
profile, and physical examination, and who are candidates for systemic or
phototherapy

- Presence of a psoriatic plaque of >2cm in an area which can be biopsied repeatedly.

- Men must agree to avoid impregnating a woman while on this study.

- Women are eligible to participate in the study if they meet one of the following
criteria:

- Women who are postmenopausal (>1 year), sterile, or hysterectomized

- Women of childbearing potential must undergo monthly pregnancy testing during
the study and agree to use two of the following methods of contraception
throughout and for 60 days after the last dose of study drug:

- Oral contraceptives

- Transdermal contraceptives

- Injectable or implantable methods

- Intrauterine devices

- Barrier methods (diaphragm or condom with spermicide)

- Abstinence and Tubal Ligation are also considered a form of Birth control

Exclusion Criteria:

- Patients <18 or >85 years old

- Absence of a psoriatic plaque >2cm in diameter

- Active guttate, erythrodermic, or pustular psoriasis at the time of the screening
visit

- Evidence of skin conditions at screening (e.g. eczema) that would interfere with
evaluations of the effect of study medication

- Inability to understand the consent process

- Receipt of any investigational drugs, psoralen+ultraviolet A or oral systemic
treatments within 4 weeks of study drug initiation

- Biologics within 3 months of study initiation

- Topical steroids, topical vitamin A or D analog preparations, Ultraviolet B therapy
or anthralin within 2 weeks of study drug initiation. (Exception-stable regimen of
class I-II topical steroids on scalp, axillae, and groin)

- Methotrexate within 6 weeks of study initiation

- History of treatment with adalimumab

- History of primary non-response to methotrexate, infliximab or etanercept

- History of discontinuation of methotrexate or tumor necrosis factor (TNF) blocker for
a safety-related reason that makes it unwise to restart either type of drug

- Any internal malignancy within 5 years (excluding fully excised cutaneous basal cell
or squamous cell carcinoma)

- Pregnancy, not practicing effective birth control, or inability to practice safe sex
during the length of the study

- Lactation

- Subjects who have known hypersensitivity to adalimumab or methotrexate or any of its
components or who is known to have antibodies to etanercept

- History of alcohol or drug abuse one year before and during the study

- Known HIV-positive status or any other immune-suppressing disease

- Presence of a grade 3 or 4 infection <30 days prior to the screening visit, between
the screening visit and the first day of treatment on study, or any time during the
study that in the opinion of the PI would preclude participation in the study

- Any grade 3 or 4 adverse event, or laboratory toxicity, at the time of the screening
visit or at any time during the study, which in the opinion of the PI would, preclude
participation in the study

- Serum creatinine >3.0 mg/dL (265 micromoles/L)

- Serum potassium <3.5 mmol/L or > 5.5 mmol/L

- Serum alanine aminotransferase or aspartate aminotransferase >3 times the upper
limit of normal for the lab

- Platelet count <100,000/mm3

- White blood cell count <3,000/mm3

- Hgb, Hct, or red blood cell outside 30% of the upper or lower limits of normal
for the Lab

- Receipt of live vaccines 1 month prior to or while on study

- History of tuberculosis, and/or a positive PPD skin test/chest x-ray at screening
without appropriate treatment-treatment of latent tuberculosis (for those with
positive PPD tests) must be initiated prior to therapy with adalimumab or
methotrexate

- Chronic hepatitis B or C infection, history of multiple sclerosis, transverse
myelitis, optic neuritis or epilepsy