Daclizumab to Treat Non-Infectious Sight-Threatening Uveitis

Uveitis refers to intraocular inflammatory diseases that are an important cause of visual
loss. Standard systemic immunosuppressive medications used for uveitis can cause significant
toxic side effects, especially with prolonged use. Consequently, an effective treatment with
a safer side effect profile is highly desirable. Daclizumab is a humanized monoclonal
antibody directed against the high affinity IL-2 receptor CD25 or Tac subunit. The IL-2
receptor system plays a central role in mediating immune responses. Blocking this system
impedes immune responses and can inhibit local inflammatory responses, including uveitis.
Pilot studies using intravenous or subcutaneous daclizumab treatments suggest that
daclizumab treatments at 1 mg/kg every 2-4 weeks for quiescent uveitis may effectively
replace the other immunosuppressive medications in a majority of cases.

Because we have little experience using daclizumab for active uveitis, this feasibility
study will enroll five study participants that would normally be treated with systemic,
high-dose corticosteroids or other cytotoxic, systemic immunosuppressive medications. Since
daclizumab for other indications can be tolerated with repeated dosing at 8-10 mg/kg, we
will administer daclizumab to reach high serum levels with a pair doses at 8 mg/kg and 4
mg/kg two weeks apart. The primary objective of this study is to collect preliminary
information on the utility of acute daclizumab therapy on active ocular inflammation. The
primary outcome is resolution of active disease defined as the reduction of vitreous haze by
at least 2 steps (from 2+ to Trace, or 1+ to none) and is assessed at 21 days after the
initial daclizumab injection. Secondary outcomes will include fluorescein retinal vascular
leakage, CME, anterior chamber cells, and visual acuity. In addition all adverse events will
be collected regardless of possible relation to daclizumab. Participants who show a 2 step
reduction in vitreous haze at day 21 will be permitted to continue SC daclizumab maintenance
treatments beginning at Day 28 at 2 mg/kg every 4 weeks for a year. At any time during the
followup period, if a participant loses greater than 3 lines of visual acuity from baseline
study treatments will be discontinued.

- INCLUSION CRITERIA:

Volunteers will be considered eligible participants for this study provided they meet all
of the following inclusion criteria:

1. Participant has a diagnosis of active, non-infectious intermediate or posterior
uveitis, which may include but is not restricted to the following conditions known to
cause intermediate or posterior uveitis: panuveitis, intermediate uveitis of the pars
planitis subtype, sarcoidosis, the Vogt-Koyanagi-Harada (VKH) syndrome, birdshot
retinochoroidopathy, retinal vasculitis and sympathetic ophthalmia;

2. Participant has active uveitis with greater than or equal to Grade 1 (1+) vitreous
haze in at least one eye including evidence of retinal vascular leakage using
fluorescein angiography or the presence of cystoid macular edema (CME) at enrollment;

3. Participant's uveitis is currently treated or untreated at the time of enrollment;

4. Participant has best-corrected distance visual acuity (BCVA) in the worst eye of
20/400 or better (ETDRS logMAR less than 1.34);

5. Participant does not plan to undergo elective ocular surgery (e.g., cataract
extraction) during the study period;

6. Participant, male or female, with reproductive potential and who is sexually active
agrees to use double-barrier contraception methods throughout the course of the study
(minimum of 52 weeks) and for 6 additional weeks after completion of the protocol
treatment period.

EXCLUSION CRITERIA:

A volunteer will not be permitted to enroll if they meet any one of the following
exclusion criteria:

1. Participant is under 18 years of age;

2. Participant has received previous treatment with an IL-2 or IL-2R directed therapy
within the past 90 days;

3. Participant has lens opacities or obscured anterior ocular media upon enrollment such
that reliable evaluation and grading of posterior segment cannot be performed (except
that anterior chamber cells due to inflammation is not an exclusion);

4. Participant has a history of an active herpes zoster or varicella infection within 6
weeks before enrollment, or chicken pox exposure within 21 days before enrollment.

5. Participant has a known history of HIV infection;

6. Participant is currently enrolled in another investigational or interventional
therapeutic trial, or is using a therapy for a non-uveitis condition that would
likely affect immune responses or interfere with trial logistics, or has received any
investigational therapy within the 30 days prior to enrollment;

7. Participant has a history or diagnosis of Behcet's disease (since subsequent tapering
or withdrawal of concomitant immunosuppressive medications is not a standard-of-care
for Behcet's patients) or a primary diagnosis of anterior uveitis (e.g., HLA-B27
associated uveitis, or ocular conditions usually treated with local and not systemic
medications);

8. Participant has a significant local or systemic infection requiring medical treatment
at the time of enrollment;

9. Participant is currently pregnant or lactating;

10. Participant has a history of cancer (other than a non-melanoma skin cancer or in situ
cervical cancer) diagnosed within the past 5 years;

11. Participant has a non-ocular, medically significant co-morbid condition that impairs
normal activities, requires immunosuppression, or has a condition with a prognosis
that indicates a significant risk of disability or death if the condition were to
continue or be exacerbated during the study period, or a medical condition that would
likely have an impact on the participant's ability to comply with the visit schedule.
Such conditions may include, for example, recent heart attack, significant COPD,
brittle diabetes, kidney disease, severe emphysema, organ transplant (requiring
corticosteroids or other immunosuppressive medications), hepatitis or other liver
disease, or uncontrolled psychiatric illnesses.