Rituximab for Autoimmune Retinopathy

Objective:

Autoimmune retinopathy (AIR) is an ophthalmic disorder in which autoantibodies damage the
retina and its components, causing progressive vision loss. AIR has no established treatment,
but systemic immunosuppression has shown favorable responses. Rituximab is an
immunosuppressive agent which binds specifically to B lymphocytes. The objective of this
study is to investigate the safety of rituximab as an effective treatment for AIR.

Study Population:

Five participants with AIR and visual acuity of 20/200 or better in at least one eye will
receive rituximab. AIR must be confirmed by immunohistochemical demonstration of serum
anti-retinal antibodies on normal, unfixed, frozen rhesus monkey or human retinas, as well as
visual field and electroretinography (ERG) changes. Up to seven participants may be enrolled,
in order to obtain the five participants to be included in the analysis if participants
withdraw prior to receiving rituximab.

Design:

The study duration is 18 months. Rituximab is administered as a cycle consisting of two
separate rituximab infusions of 1,000 mg each, two weeks apart. Participants will receive
their first rituximab cycle at baseline and evaluated for a second cycle six months later.
Treatment success is defined as experiencing a greater than a 25% improvement in ERG response
amplitudes or greater than a 3 decibel (dB) improvement in mean deviation on Humphrey Field
Analyzer [HFA (30-2)] or improvement in threshold values greater than 0.5 log in existing
scotomas or greater than 25% improvement in the area of scotomas on Goldmann Visual Field
(GVF) assessment as compared with baseline. As a result, participants could receive a maximum
of two cycles in this study. Participants will return to the clinic 6 weeks and 3 months
after their first infusion of each cycle for a safety visit. Study visits will continue every
three months for the study duration.

Outcome Measures:

The primary outcome is the number of participants who meet the definition of treatment
success within six months from baseline. Secondary efficacy outcomes include changes in
visual acuity, the number of treatment successes at 9 and 12 months, the number of partial
responders at 6, 9 and 12 months, changes in ERG or visual field as demonstrated by the HFA
(30-2) or GVF, changes in optical coherence tomography (OCT), changes in fluorescein
angiography (FA), changes in serum anti-retinal autoantibody or anti-retinal antibody
staining, changes in color vision, positive visual symptoms or nyctalopia and changes in the
participants quality-of-life as assessed by the NEI visual function questionnaire. For
participants with greater than or equal to 2 ERG measurements available prior to enrollment,
an attempt will be made to compare the rate of decline pre-study period to the rate of
decline post-enrollment period. Safety outcomes include the number and severity of systemic
and ocular toxicities, adverse events, and infections and the proportion of participants with
a loss of greater than or equal to 15 ETDRS letter score.

- INCLUSION CRITERIA:

Participant must be 18 years of age or older.

Participant must understand and sign the protocol s informed consent document.

Participant must be willing to comply with the study procedures and expected to be able to
return for all study visits.

Participant must have a diagnosis of AIR according to the features listed below.

Participants must have demonstrated evidence of anti-retinal antibodies as noted in
criterion a and one or more of the clinical manifestations listed in either criterion b or
c in order to be considered eligible.

1. Serologic or immunohistochemical demonstration of serum anti-retinal antibodies (on
normal, unfixed, frozen rhesus monkey or human retinas.

2. Visual field changes

i. Defects in visual fields [on HFA (30-2) or GVF]

ii. Enlarged blind spot

c. ERG changes

i. Abnormal amplitudes

ii. Prolonged implicit times.

Participant must have visual acuity of 20/200 or better in at least one eye.

Participant must have normal renal function, liver function and blood cell counts, OR has
mild abnormalities and is cleared for enrollment by internal medicine.

Participant must agree not to receive any live or live-attenuated vaccinations (e.g., nasal
flu vaccine [FluMist ] or Zostavax ) for the duration of the study.

Participant must have clear ocular media and adequate pupillary dilation to permit quality
imaging.

Participant must have a negative PPD screening test as defined by the Centers for Disease
Control (CDC) unless otherwise cleared by internal medicine (i.e., previously treated for a
positive PPD or a history of Bacillus of Calmette and Guerin (BCG) vaccination).

Female participants of childbearing potential must not be pregnant or breast-feeding, must
have a negative serum pregnancy test at screening and must be willing to undergo pregnancy
tests throughout the study.

Both female participants of childbearing potential* and male participants able to father a
child must agree to practice two** forms of adequate contraception throughout the course of
the study and for 12 months following the last administration of the investigational
product. Acceptable methods of contraception include hormonal contraception (i.e., birth
control pills, injected hormones, dermal patch or vaginal ring), intrauterine device,
barrier methods with spermicide (diaphragm with spermicide, condom with spermicide) or
surgical sterilization (hysterectomy, tubal ligation or vasectomy).

*Childbearing potential must be determined

**Participants with a hysterectomy or vasectomy (or who have a partner with a hysterectomy
or vasectomy) are exempt from using two methods of contraception. However, participants
with a tubal ligation (or male participants who have a female partner with a tubal
ligation) are not exempt, and are required to practice another acceptable method of
contraception.

EXCLUSION CRITERIA:

Participant received other biologic agents (e.g., infliximab, daclizumab or adalimumab)
within three months prior to study enrollment.

Participant is receiving more than two immunosuppressive agents or experienced a change in
his/her AIR immunosuppressive medication regimen within the two months prior to enrollment.

Participant received intraocular or periocular steroid injections within two months prior
to study enrollment.

Participant has a significant active infection (an infection requiring treatment as
determined by the medical team) or a history of chronic or recurrent infections.

Participant is HIV positive or has syphilis.

Participant has a history of cancer (other than a non-melanoma skin cancer or non-Hodgkin s
lymphoma [NHL]) diagnosed within the past five years.

Participant has or is a carrier of hepatitis B or C.

Participant has a known hypersensitivity to sodium fluorescein dye.

Participant has congestive heart failure, abnormal cardiac function or significant
pulmonary disease.

Participant is participating in another simultaneous investigational product treatment
trial.

Participant received a live or live-attenuated vaccine within the previous four weeks prior
to study enrollment

Participant had ocular surgery within 60 days prior to study enrollment or is anticipated
to require elective intraocular surgery.

Participant has inadequately controlled diabetes.

Participant has a condition that, in the opinion of the investigator, would pose a
significant hazard to the participant if the investigational product was initiated.

Participant has any other condition that would be contraindicated to treatment with
rituximab or their current immunosuppressive agent.