Sirolimus for Advanced Age-Related Macular Degeneration

Objective: Age-related macular degeneration (AMD), the leading cause of blindness in people
over age 65 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 subsequently lead 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 serial sirolimus intravitreal injections in participants with bilateral
GA.

Study Population: Six participants with bilateral GA associated with AMD will be enrolled
Initially, 10 participants with bilateral GA associated with AMD were to be enrolled.
However, only six will be enrolled, as sirolimus intravitreal injections will no longer be
administered to participants.

Design: In this single-center, prospective, controlled, unmasked, Phase I/II study, one eye
of eligible participants was initially randomized to investigational product (intravitreal
sirolimus) while the fellow eye was observed. Participants initially received a 20 (micro)L
(440 (microg) intravitreal injection sirolimus in the study eye at baseline and every two
months thereafter unless contraindicated. As of September 2012, sirolimus intravitreal
injections were no longer administered to participants. Both the study and fellow eyes will
be observed every two months until the study terminates. The study will not terminate until
all participants have been followed through Month 12.

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 photographs in the study eye and fellow eye
at Month 12 compared to baseline. Secondary outcomes will include changes in best-corrected
visual acuity (BCVA), changes in drusen area based on masked digital grading of fundus
photography, absolute and relative changes in area of GA measured using fundus photography
and autofluorescence imaging, and development of exudative AMD measured using optical
coherence tomography (OCT). Safety outcomes will include the number and severity of adverse
events (AEs). Ocular safety outcomes will be indicated by changes in visual acuity, ocular
surface changes, intraocular inflammation and any other ocular changes not consistent with
the natural progression of GA.

- INCLUSION CRITERIA:

- Participant must be 56 or older.

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

- Participant must have at least disc area (approximately 1 mm2) of GA compatible
with AMD present in each eye. GA is defined as one or more well-defined and often
circular patches of partial or complete depigmentation 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
depigmentation may be classified as early GA. The GA in each eye must be able to be
photographed in their entirety, and it must not be contiguous with any areas of
peripapillary atrophy, which can complicate area measurements.

- Participant must have at least one large druse (greater than or equal to 125 micro m)
in each eye.

- Participants must not have any evidence or history of exudative disease related to
AMD in either eye as determined by a recent fluorescein angiogram performed within 4
months of study enrollment.

- 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.

- Participant must have visual acuity of 20/400 or better in each eye.

- Female participants of childbearing potential and male participants able to father
children must have (or have a partner who has) had a hysterectomy or vasectomy, be
completely abstinent from intercourse, or agree to practice two acceptable methods of
contraception throughout the course of the study and four months after their last
study injection. Acceptable methods of contraception include:

- hormonal contraception (i.e., birth control pills, injected hormones, dermal
patch or vaginal ring),

- intrauterine device,

- barrier methods (diaphragm, condom) with spermicide, or

- surgical sterilization (hysterectomy or tubal ligation).

EXCLUSION CRITERIA:

- Participant is actively receiving study therapy in another investigational study.

- Participant is unable to comply with study procedures or follow-up visits.

- Participant has evidence of an 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).

- 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-VEGF agent
for wet/exudative AMD at any point, and d) received an intravitreal injection of any
other agent (not an anti-VEGF agent) within four months prior to study enrollment.
Participants currently taking or who have previously taken AREDS vitamin
supplementation are not excluded.

- Participant has had a vitrectomy.

- Participant is expected to need ocular surgery during the course of the trial.

- Participant has undergone lens removal in the last three months or YAG laser
capsulotomy within the last month.

- Participant is on chemotherapy.

- Participant is on immunosuppressive medication.

- Participant is on ocular or systemic medications known to be toxic to the lens,
retina or optic nerve.

- Participant has a history of ocular herpes simplex virus (HSV).

- Participant has 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).

- Participant has a history of cancer (other than a non-melanoma skin cancer) diagnosed
within the past five years.

- Participant has laboratory values outside normal limits and considered clinically
significant by the investigator.

- Participant is currently taking one of the following drugs: amprenavir, atazanvir,
clarithromycin, darunavir, delavirdine, erythromycin, fluconazole (at doses of 200mg
or greater), fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone,
nelfinavir, posaconazole, quinupristin, ritonavir, saquinavir, telithromycin,
troleandomycin, verapamil or voriconazole.

- Female participant is pregnant or breast-feeding.