Alefacept in Patients With Severe Scalp Alopecia Areata

Alopecia areata (AA) is an autoimmune condition characterised by a T-cell mediated attack on
the hair follicle. The inciting antigenic stimulus is unknown. A dense peribulbar lymphocytic
infiltrate and reproducible immunologic abnormalities are hallmark features of the condition.
The cellular infiltrate primarily consists of activated T-lymphocytes and antigen-presenting
Langerhans cells. T-lymphocytes play a critical role in the pathogenesis of disease. The
observance of hair regrowth in those with alopecia areata who are treated with cyclosporine,
a known inhibitor of T-cell function, further confirms the central role of the T-lymphocytes
in the development of the disease.

Activation of T-cells is initiated by interaction of the T-cell receptor with the
antigen/major histocompatibility complex on the antigen-presenting cells. Co-stimulatory
interactions occur secondarily, including binding of the T-cell CD2 receptor to the
antigen-presenting cell ligand LFA-3 (lymphocyte function-associated antigen-3 CD58).
Induction of a molecular signaling cascade with resultant T-cell activation and proliferation
ensues. Abrogation of this activation may result in diminished or aborted expression of
disease, and thus suggests a potential therapeutic role for alefacept in the treatment of
alopecia areata. Alefacept is a bioengineered LFA-3/Immunoglobulin fusion protein that binds
to the CD2 T-cell receptor and interferes with the ligation of LFA-3. Binding of the
immunoglobulin portion of the fusion protein to the FCy receptor on antigen-presenting cells
potentiates apoptosis of CD-2 T-cells to thereby reduce the population of activated T-cells.

Psoriasis is a T-cell mediated disorder that shares many immunologic features with alopecia
areata. Accordingly, treatments that are effective in psoriasis often prove to be beneficial
in alopecia areata. Anthralin, topical and intralesional steroids and cyclosporine are among
several therapeutic agents that have efficacy in both disorders. Based on the impressive
therapeutic responses seen in those with psoriasis treated with alefacept, a similarly
beneficial outcome is tentatively anticipated with treatment of those with alopecia areata.

Inclusion Criteria:

- Subjects must give written informed consent and candidates in the US must authorize
the release and use of protected health information (PHI)

- Subjects must be between the ages of 18 and 65 inclusive at the time of informed
consent

- Must have a diagnosis of scalp alopecia areata as determined by the study investigator

- Must have 50-95% patchy scalp hair loss due to alopecia areata of at least one year
duration

- Must have CD4+ T-lymphocyte counts at or above the lower limit of normal as determined
by a local laboratory.

Exclusion Criteria:

- History of systemic or cutaneous malignancy other than treated basal cell carcinomas
or 3 or less squamous cell carcinomas.

- Nevi or cutaneous lesions currently undiagnosed but suspicious for malignancy.

- Evidence of immunocompromise.

- Advanced or poorly controlled diabetes.

- Unstable cardiovascular disease.

- Clinically significant medical or psychiatric disease as determined by the
investigator.

- History of alcohol or drug abuse within 2 years of assessment for study enrollment.

- Serious local infection (e.g. cellulitis, abscess) or systemic infection (e.g.
pneumonia, septicemia) within 3 months prior to the first dose of investigational
drug.

- Positive PPD history of incompletely treated or untreated tuberculosis.

- Abnormal T-lymphocyte count, and/or liver function tests.

- If female, serum hemoglobin level greater than 1 unit below accepted limit for normal
or otherwise abnormal.

- Male subjects with an abnormal serum hemoglobin.

- Known positivity for hepatitis C antigen or hepatitis B surface antigen.

- Known positivity for HIV antibody.

- Diagnosis of diffuse alopecia areata.

- Coexistent androgenetic alopecia which, in males is Norwood-Hamilton stage VI or
greater, or in females, Ludwig stage III.

- Prior treatment with alefacept.

- Treatment with another investigational drug within 4 weeks prior to anticipated first
treatment dose.

- Unable to practice effective contraception for the duration of the study.

- Females who are nursing, pregnant or planning to become pregnant while in the study.

- Those who have donated blood within a month of date of screening evaluation.

- Concomitant enrollment in other investigational drug study.

- Unwilling to maintain a consistent hair style and to eschew shaving of scalp hair
throughout the course of the study.

- Unable to comply with the protocol.

- Other unspecified reasons that contraindicate enrollment in the study, as determined
by the study investigator.