Infliximab, Sirolimus and Daclizumab to Treat Age-Related Macular Degeneration

There has been much interest in the possible role of the immune system in AMD. Experimental
models and patient material have, to date, suggested a role for macrophages and complement.
This study hypothesized that the underlying mechanism that leads to choroidal
neovascularization (CNV) is similar to those at play in atherosclerosis. If this is the
case, the investigators believed that CNV treatment should be amenable to new
immunomodulatory agents directed against specific parts of the immune system.

After therapy with anti-angiogenic agents not leading to a persistent remission of CNV due
to AMD, participants were treated with one of three immunomodulatory agents or were observed
in conjunction with their continued anti-angiogenic therapy. Thus the participant continued
with the anti-angiogenic therapy they received after randomization. The investigators
hypothesized that this combination therapy would inhibit progression of CNV associated with
AMD.

This was an open-label, phase II, randomized, single center clinical trial of 18 study
participants randomized to receive one of three immunomodulatory agents or was observed in
conjunction with their anti-angiogenic therapy.

INCLUSION CRITERIA:

1. Understand and sign the institutional review board (IRB)-approved informed consent
document for the study.

2. Age greater than 55 years.

3. In the study eye, diagnosis of AMD defined by the presence of drusen larger than 63
microns.

4. Any anti-angiogenic therapy in the study eye within 7 days of beginning
immunosuppressive therapy.

5. In the study eye, the participant's study eye vision is between 20/20 and 20/400.

6. In the study eye, the presence of CNV under the fovea determined by the investigators
and defined as any one of the following fluorescein angiographic (FA) features:

1. Early stippled hyperfluorescence of flat retinal pigment epithelium (RPE)and
little or mild leakage in the late frames of the fluorescein (occult).

2. Irregular elevation of the RPE that does not exhibit discrete or bright
hyperfluorescence in the early transit phase of the angiogram. Stippled
hyperfluorescence may be present. Late frames may show persistent fluorescein
staining or leakage within a sensory retinal detachment overlying this area
(occult).

3. Late-phase leakage of undetermined source with leakage at the level of the RPE
in the late-phase frames of the angiogram in which the source of the late
leakage cannot be determined from earlier-phase frames of the angiogram
(occult).

4. A well-demarcated area of bright hyperfluorescence in the early phase of the
angiogram with leakage through the mid- and late-phase frames which obscures the
boundaries of the area (classic).

7. For all CNV lesions considered to have occult CNV with no classic CNV, one of the
following criteria must be met:

1. A documented loss of visual acuity (5 or more letters of best-corrected visual
acuity if both measurements are made using an Early Treatment for Diabetic
Retinopathy Study (ETDRS) chart or, a doubling of the visual angle if Snellen
acuities are available from either an outside referral center or within the
participating center (e.g., 20/80 to 20/160) a doubling of the visual angle is
required because of the measurement variability of Snellen acuities).

OR

2. Documented FA evidence of a 10% increase in the lesion greatest linear dimension
over the 3 months prior to enrollment.

OR

3. Documented blood associated with CNV.

8. The greatest linear dimension of the entire lesion (classic CNV, occult CNV and any
features that could obscure the identification of classic or occult CNV) has to be
less than or equal to 5400 microns in greatest linear dimension on the retina as
measured by the treating ophthalmologist.

9. Retinal photographs and angiography of sufficient quality, allowing assessment of the
macular area according to standard clinical practice, can be obtained.

10. Women of childbearing potential must not be pregnant or lactating, must have a
negative pregnancy test at screening and must be practicing an adequate method of
birth control. Acceptable methods of birth control include intrauterine device (IUD);
oral, dermal, implanted or injected contraceptives; tubal ligation; and barrier
methods with spermicide.

11. Willingness to comply with the protocol.

EXCLUSION CRITERIA:

1. CNV, in the study eye, associated with other ocular diseases such as pathologic
myopia, ocular histoplasmosis or posterior uveitis, etc.

2. Presence of geographic atrophy under the fovea in the study eye.

3. Evidence of retinal angiomatous proliferation as suspected by the presence of
intraretinal hemorrhage, intraretinal leakage, adjoining serous pigment epithelial
detachment (PED) or the presence of a connecting retinal vessel.

4. The presence of a chorio-retinal anastomosis.

5. Decreased vision, in the study eye, due to retinal disease not attributable to CNV,
such as nonexudative forms of AMD, geographic atrophy, inherited retinal dystrophy,
uveitis or epiretinal membrane. Participants who have any additional ocular diseases
that have irreversibly compromised or, during follow-up, could likely compromise the
visual acuity (VA) of the study eye including amblyopia, anterior ischemic optic
neuropathy, clinically significant diabetic macular edema, severe non-proliferative
diabetic retinopathy, or proliferative diabetic retinopathy.

6. Decreased vision, in the study eye, due to significant media opacity such as corneal
disease or cataract, or opacity precluding photography of the retina; a tear (rip) of
the RPE; a vitelliform-like lesion of the outer retina (e.g., as in pattern
dystrophies or basal laminar drusen), idiopathic parafoveal telangiectasis, or
central serous retinopathy.

7. Presence of fibrosis, hemorrhage, pigment epithelial detachments and other
hypofluorescent lesions obscuring greater than 50% of the CNV lesion.

8. History of other systemic antiangiogenic treatment or treatment for CNV (not
including photodynamic therapy and pegaptanib sodium injections) in the study eye
with transpupillary thermotherapy or other local treatment (such as submacular
surgery). Previous laser photocoagulation therapy is acceptable, provided it was not
subfoveal.

9. Participant with a known underlying systemic disease with evidence of serious or
potentially lethal uncontrolled active disease in one or more extraocular organ
systems for which a defined effective medical regimen is indicated.

10. Participant with a corneal melting, necrotizing keratitis, or impending vision loss.

11. Participants with history of allergy to/or exposure to mouse protein.

12. Participant with scleritis of infectious etiology.

13. Participant receiving any other investigational therapy or another anti-tumor
necrosis factor (TNF) agent that would interfere with the ability to evaluate the
safety or efficacy of infliximab.

14. Participant has significant active infection requiring hospitalization.

15. Participant with multiple sclerosis.

16. Participant has severe (class 3/4) congestive heart failure.

17. Participant has a history of cancer within the past 5 years other than basal or
squamous cell carcinoma.

18. Participant is pregnant or lactating.

19. Participant with posterior scleritis.

20. Participant has evidence of liver disease (any etiology). History of moderate to
severe abnormal liver function, unless documented evidence of normal liver enzymes is
provided.

21. Participant has positive PPD (tuberculosis test) unless cleared by Internal Medicine.

22. Participant has positive Chest X-ray showing acute pulmonary disease.

23. Participant has unexplained hematuria.

24. Participant has a history of alkylating therapy use.

25. Current exam evidence of ocular toxoplasmosis; pseudoexfoliation; external ocular
infection, including conjunctivitis; chalazion; significant blepharitis; or aphakia
in the study eye (pseudophakic participants are eligible).

26. Intraocular surgery (including lens replacement surgery) within 6 weeks prior to
randomization.

27. Recent history of (within the last 6 months), or current acute ocular or periocular
infection (including any history of ocular herpes zoster or simplex).

28. Known hypersensitivity/allergy to verteporfin, porfimer sodium, or other porphyrins,
porphyria or other porphyrin sensitivity, or hypersensitivity to sunlight or bright
artificial light. Participation in any other clinical study or are receiving, or have
received any experimental systemic treatment for AMD (e.g., retinoic acid,
thalidomide). Local therapy for AMD is permitted.

29. Medical problems that make consistent follow-up over the treatment period unlikely
(e.g., stroke, severe myocardial infarction (MI), end stage malignancy), any
contraindications to performing the necessary diagnostic studies (i.e., known allergy
to fluorescein dyes etc.), or in general a poor medical risk because of other
systemic diseases or active uncontrolled infections.

30. Participant has a history of moderate to severe abnormal liver function, unless
documented evidence of normal liver enzymes is provided.

31. Participant has a history of active pulmonary tuberculosis.

32. Participant has a history of active viral hepatitis.

33. Participant has chronic continued Ketoconazole use.