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

Condition(s) targeted: Age Related Macular Degeneration

Intervention: ranibizumab (Lucentis(R)) (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Lawrence S. Morse, MD

Official(s) and/or principal investigator(s):
Lawrence S Morse, MD, PhD, Principal Investigator, Affiliation: University of California, Davis

Overall contact:
Lawrence S Morse, MD, PhD, Phone: 916-734-6074, Email: lsmorse@ucdavis.edu

The investigators hope to determine if "wet" AMD patients differ from patients with "dry" AMD or normal eyes in the production of anti-retinal pigment epithelium (anti-RPE) or anti-retinal antibody formation. To explain: the immune system can make antibodies that attack our own cells, specifically the RPE and the retina. Normally the RPE and retinal cells are ignored by the immune system, but when disease occurs, immune reactions can occur, making an autoantibody that can attack the patient's own cells and make things worse. This production of autoantibodies that react with our own RPE and retinal cells is what the investigators want to test in this proposal to see if they may contribute to, or are responsible for, a poor response to treatment.

The investigators also want to know how those patients who initially respond to the standard-of-care treatment, ranibizumab injections, differ in the production of anti-RPE or anti-retinal antibody formation, from those patients who do not respond initially after 4 consecutive injections.

Official title: Retinal and RPE Autoimmunity in AMD: Assessment of Correlation With Degree of Response to Ranibizumab Therapy

Study design: Allocation: Non-Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To determine if "wet" AMD patients (Group 1 and Group 3) differ from population normals (Group 2) in the production of anti-Retinal Pigment Epithelium (RPE) or anti-retinal antibody formation.

Secondary outcome: To determine mean change in visual acuity (VA) and ocular coherence tomography (OCCT) from baseline to month 6

Detailed description: 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).

Minimum age: 50 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Lawrence S Morse, MD, PhD, Phone: 916-734-6074, Email: lsmorse@ucdavis.edu

University of California, Davis, Sacramento, California 95817, United States; Recruiting

Starting date: August 2009
Last updated: August 28, 2012