Pilot Study of the Evaluation of Subconjunctival Sirolimus in the Treatment of Bilateral GA Associated With AMD

Pilot Study of the Evaluation of Subconjunctival Sirolimus in the Treatment of Bilateral Geographic Atrophy Associated With Age-Related Macular Degeneration

This study will determine if a drug called sirolimus is safe to give to people with geographic atrophy GA and if it can help preserve vision in patients. GA is an advanced form of dry age-related macular degeneration (AMD). AMD affects the macula, the central part of the retina needed for sharp, clear vision. There are two types of AMD, wet and dry. In dry AMD, cells in the macula die.GA may at least partly be caused by inflammation. Sirolimus helps prevent inflammation and therefore may help treat GA.

People with GA in both eyes with visual acuity between 20/20 and 20/400 in each eye may be eligible for this study. Participants undergo the following tests and procedures:

• Sirolimus injections in the study eye at each 3-month clinic visit. The drug is injected under the outer layer of the eye after the patient receives antiseptic and numbing drops. Antibiotic drops are continued for 2 days after the injection.
• Eye examinations before the first injection, 1 month after the first injection, during each clinic visit (11 to 15 visits over 2 to 3 years) and 3 months after the final injection. The examination includes testing visual acuity, measuring eye pressure and checking eye movements. To examine the inside of the eye, the pupil is dilated with eye drops. Regular photographs of the inside of the eye and optical coherence tomography photographs, which allow measurement of the thickness of the retina, may be taken during the eye examination.
• Autofluorescence imaging. The patient sits in a chair with his or her head placed in a chin rest in front of a camera. A light in the camera is used to scan the eye.
• Blood tests. Blood is drawn at the first visit and at up to seven study visits to check blood chemistries, such as liver and kidney function.
• Urine pregnancy test for women who are able to become pregnant.

Objective: Age-related macular degeneration (AMD), the leading cause of blindness in people over age 55 in the United States, is a heterogeneous clinical entity in which retinal degeneration occurs predominantly in the macula in the context of aging and leads to impairment of central visual acuity. AMD occurs in two general forms, one of which involves choroidal neovascularization (CNV) with subsequent formation of a disciform scar. This is often referred to as the neovascular or "wet" form. A second form, the subject of this study, is termed "dry" or atrophic macular degeneration and involves a constellation of clinical features that can include drusen, pigment clumping and/or retinal pigment epithelium (RPE) dropout and geographic atrophy (GA). GA can begin as a thinning of the RPE with involvement of the underlying choriocapillaris and lead subsequently to an atrophic change in the macula. Inflammation may play a role in the pathogenesis of GA. Sirolimus inhibits the production, signaling and activity of many inflammatory factors relevant to the development of GA. Therefore, the objective of this study is to investigate the safety and possible efficacy of multiple sirolimus subconjunctival injections in participants with bilateral GA.

Study Population: Ten participants with bilateral GA associated with AMD, with the potential to replace up to five participants if some fail to reach one year of follow-up.

Design: In this controlled, unmasked, Phase I/II study, one eye of eligible participants will be randomized to treatment while the fellow eye will be observed. Participants will receive a 20 μL (440 μg) subconjunctival injection of sirolimus in the study eye at baseline and every three months thereafter. The study will be completed once all participants have received two years of study medication and follow-up.

Outcome Measures: The primary outcome is the rate of change in area of GA, based on masked grading by an external Reading Center, of fundus photography in the study eye and fellow eye at two years compared with baseline. Secondary outcomes will include worsening of best-corrected visual acuity (BCVA) of three or more lines (15 or more letters), changes in area of GA as measured on autofluorescence, changes in drusen volume as measured by optical coherence tomography, changes in photoreceptor outer segment (PROS) thickness as measured by optical coherence tomography, as well as changes in drusen area based on masked digital grading of fundus photographs. Safety outcomes will include the number and severity of systemic and ocular toxicities, adverse events and infections.

Inclusion Criteria

1. Participant must be older than 55 years of age.
2. Participant must understand and sign the protocol's informed consent document.
3. Participant must have at least ½ disc area (approximately 1 mm^2) of GA compatible with AMD present in each eye. GA is defined as one or more well-defined, usually more or less circular patches of partial or complete de-pigmentation of the RPE, typically with exposure of underlying choroidal blood vessels. Even if much of the RPE appears to be preserved and large choroidal vessels are not visible, a round patch of RPE partial de-pigmentation may still be classified as early GA. The GA in each eye must be able to be photographed in their entirety.
4. Participant must have at least one large druse (more than or equal to 125 μm) in each eye.
5. Participant must have a steady fixation in both eyes in the foveal or parafoveal area and media clear enough for good quality photographs. This will permit randomization.
6. Participant must have visual acuity between 20/20 and 20/400 in each eye.
7. Female participants must be considered post-menopausal and must not be breast-feeding. Female participants over age 55 who have not had a period for one year will be considered post-menopausal.

Exclusion Criteria

1. Participant is in another investigational study and actively receiving study therapy.
2. Participant is unable to comply with study procedures or follow-up visits.
3. Participant has evidence of ocular disease other than AMD in either eye that may confound the outcome of the study (e.g., diabetic retinopathy with 10 or more hemorrhages or microaneurysms, uveitis, pseudovitelliform macular degeneration moderate/severe myopia).
4. Participant has any of the following: a) a history of macular laser, b) a history of photodynamic therapy (PDT), c) received an intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent for wet/exudative AMD at any point, d) received an intravitreal injection of any other agent (not an anti-VEGF agent) within four months prior to study enrollment or e) received topical treatment of any agent for advanced AMD within one month prior to enrollment. Participants currently taking or who have previously taken AREDS vitamin supplementation are not excluded.
5. Participant has had a vitrectomy.
6. Participant is expected to need ocular surgery during the course of the trial.
7. Participant has undergone lens removal in the last three months or yttrium aluminum garnet (YAG) laser capsulotomy within the last month.
8. Participant is on chemotherapy.
9. Participant is on immunosuppressive medication.
10. Participant is on ocular or systemic medications known to be toxic to the lens, retina or optic nerve.
11. Participant with a history of ocular herpes simplex virus (HSV).
12. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control).
13. History of cancer (other than a non-melanoma skin cancer) diagnosed within the past five years.
14. Laboratory values outside normal limits and considered clinically significant by the investigator.
15. Participant is currently taking one of the following drugs: amprenavir, atazanavir, clarithromycin, darunavir, delavirdine, erythromycin, fluconazole (at doses of 200 mg or greater), fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, quinupristin, ritonavir, saquinavir, telithromycin, troleandomycin, verapamil or voriconazole.