Retinal and Retinal Pigment Epithelium (RPE) Autoimmunity in Age-related Macular Degeneration (AMD) - Correlation With Lucentis(R) Therapy

Up to 10% of patients with neovascular Age-Related Macular Degeneration (AMD) treated with
ranibizumab respond poorly or worsen despite therapy. The reason for this lack of response
is unclear. We have preliminary data that suggests abnormal autoimmune activity is apparent
in these patients. Previous studies have shown evidence of retinal autoimmunity in AMD
patients, but there is very little data describing any specific immunologic commonality that
correlates with disease and/or poor response. Perhaps just as significantly there is little
data regarding the immunologic activity of age-matched normals, making published data hard
to evaluate especially in this age group in which autoimmunity is known to increase. While
there are many known retinal antigens in autoimmune retinal disease, the role of these
antigens is not well established in AMD and not all the antigens have been identified.
Moreover, RPE-reactivities are only beginning to be understood in ocular disease. We intend
to address humoral responses in AMD by making a systematic comparison of the immunologic
activity of ranibizumab responders, anti-VEGF initial non-responders, and a comparable
population of age-sex-race matched normal controls. Data suggests that 4 groups of patients
are evident after 3 treatments with anti-VEGF: 1) rapid responders, 2) delayed responders
3) gradual responders and 4) non-responders. We hypothesize that non-responders and gradual
responders may in fact be patients with complicating underlying autoimmune activity
involving retinal and RPE antigens, which are exposed secondary to the breakdown of the
blood-retinal barrier during CNV development. We will study this humoral response (antibody
production) over the treatment period, as it likely is changing at different rates in the
patients with different responses. In addition we will correlate underlying genetic
phenotype in these patients.

For this study, we plan to look at 2 treatment groups and 2 control groups:

- Group 1: patients with neovascular "wet" Age Related Macular Degeneration (AMD) who
respond to ranibizumab treatment after 4 consecutive injections with ranibizumab

- Group 2: age-sex-race matched normal population controls (without AMD)

- Group 3: patients with neovascular AMD who are initial non-responders to anti-VEGF
treatment after 4 consecutive injections

- Group 4: age-sex-race matched "dry" AMD patients (AREDS category 2/3 ou) controls

This is an open-label study assessing antibody formation (anti-RPE and anti-retinal) in 3
groups. Group 1 (n=40) will include "wet" AMD patients treated with ranibizumab. Patients
will be included and receive ranibizumab 0.5mg intravitreally monthly x 4 months and then as
needed (PRN) monthly for 2 additional months. After the 4th ranibizumab injection, if a
Group 1 patient has not responded (persistent fluid on OCT), they will be moved into Group 3
(anti-VEGF initial non-responders). Group 2 (n=40) will be an age-sex-race matched normal
subjects from the population that does not have AMD. Group 3 (n=15) includes patients
treated with 4 injections of monthly anti-VEGF treatment without an initial response
(Initial non-response is defined as < 100 microns of improved (decreased) retinal thickening
by OCT and no visual gains after 4 consecutive injections). Patients will be included after
the 4th injection and followed for 2 more months in which they can receive ranibizumab 0.5
mg as needed for any fluid on OCT. Group 4 (n=40) will be age-sex-race matched patients
with "dry" AMD as controls for immune response before there is a neovascular or "wet"
response.

NOTE: Only 10% of Group 1 (approximately 4 patients) are expected to be non-responders,
therefore, 11 of the Group 3 subjects will be patients treated with anti-VEGF for 4
injections outside the study who are found to be non-responders by chart review. These
patients will then be enrolled at the Month 4 visit to supplement the subjects transferred
from Group 1 for a total of 15 patients in Group 3.

We will use Western blotting for global assessment of all autoantibodies against the full
complement of retinal proteins in both normal individuals (Group 2) and those treated for
exudative AMD (Group 1), those initial non-responders to ranibizumab (Group 3), and patients
with "dry" AMD (Group 4).

Genotyping (CFH and HTRA1) will be performed for AMD patients (Group 1,3, and 4) and the
Normal patients (Group 2). Approximately 25 ml (2 tablespoons) of blood will be sent to Dr.
Khang Zhang of the Shiley Eye Center at the University of California, San Diego and he will
perform the genetics analysis.

This study will investigate if antibody production differs between "wet" AMD patients (Group
1 and Group 3) and the normal population (Group 2), if it differs between ranibizumab
responders (Group 1) and initial non-responders (Group 3), and we will also see how patients
with "dry" AMD (Group 4) compare with the "wet" AMD groups (Group 1 and Group 3).

Inclusion Criteria:

- Group 1 (Ranibizumab Responders):

- Ability to provide written informed consent and comply with study assessments
for the full duration of the study

- Age > 50 years

- Patients with active neovascular "wet" AMD naïve to treatment

- Group 2 (Normal Controls):

- Age-sex-race matched to Group 1 patients

- Non-AMD

- Ability to provide written informed consent

- Group 3 (Anti-VEGF Initial Non-responders):

- "Wet" AMD patient treated with 4 or more monthly injections of anti-VEGF
treatment without an adequate response (persistent fluid on OCT)

- Ability to provide written informed consent and comply with study assessments
for the full duration of the study

- Age > 50 years

- Group 4 ("Dry" AMD):

- Age-sex-race matched to Group 1 patients

- "Dry" AMD, category 2 or 3 by AREDS (Age-Related Eye Disease Study) criteria

- Ability to provide written informed consent

Exclusion Criteria:

- Pregnancy (positive pregnancy test) or lactation

- Premenopausal women not using adequate contraception. The following are considered
effective means of contraception: surgical sterilization or use of oral
contraceptives, barrier contraception with either a condom or diaphragm in
conjunction with spermicidal gel, an IUD, or contraceptive hormone implant or patch.

- Any other condition that the investigator believes would pose a significant hazard to
the subject if the investigational therapy were initiated

- Participation in another simultaneous medical investigation or trial

- Concurrent eye disease in the study eye that could compromise visual acuity (e.g.,
diabetic retinopathy, advanced glaucoma)

- Previous AMD therapy

- Patients being treated for autoimmune or other disease with immunomodulatory drugs
(i.e., prednisone, infliximab, methotrexate)

- Patients with recent (less than 6 months) ocular or systemic surgery