between retinol and RBP, and prevents the transport of retinol to the RPE, thus down-regulating photoreceptor metabolism. In 2005, investigators discovered that fenretinide effectively halted the formation of A2E and related ßuorophores in an animal model of Stargardt disease [20]. Fenretinide is currently being investigated by Sirion Therapeutics (Tampa, FL, USA) for the treatment of GA. In 2007, Sirion initiated a doublemasked, placebo-controlled, dose-ranging (100 and 300 mg/day) phase II study to evaluate fenretinide efÞcacy in patients with GA. Interim (18-month) data showed a slowing effect on the enlargement rate of GA: a 45% reduction in median lesion growth was observed in patients receiving the 300 mg dose compared to the placebo group. Slower lesion growth was also observed in the 100 mg group among patients who had lesions smaller than the median baseline at entry (approximately three disc areas), suggesting that early intervention may improve outcomes. The phase II study investigating fenretinide for the treatment of GA is fully enrolled and the outcomes for the second year of follow-up have not yet been released [17].

ACU-4429

ACU-4429 (Acucela, Inc., Bothell, WA) is an orally administered small non-retinoid molecule that inhibits conversion of all-trans-retinyl ester to 11-cis-retinol via inhibition of the isomerase known as RPE65. ACU4429 functions as an enzyme inhibitor rather than by reducing the availability of a precursor, so its effects should be longer-lasting than fenretinide and require less frequent dosing. However, there may be greater risk of side effects, such as nyctalopia. By modulating isomerization, ACU-4429 slows the visual cycle in rod photoreceptors and decreases the accumulation of A2E. The ongoing phase I study has shown that the drug was safe and well tolerated as a single dose in healthy volunteers. The drug was well tolerated up to a dose of 75 mg and appeared to have an effect on ocular retinoid metabolism as evidenced by electroretinography [21]. Dose-related side effects included dyschromatopsia and delayed dark adaptation. A phase II study for treatment of dry AMD is currently recruiting patients.

17.4.2.4 Other

RN6G (PF-4382923, Pfizer)

This novel therapeutic strategy for the preservation of photoreceptors and the RPE is borrowed from the treatments under development for AlzheimerÕs disease

since amyloid § is present in both diseases. RN6G is a humanized monoclonal antibody that targets the C-termini of amyloid §-40 and amyloid §-42. Intravenous treatment with RN6G is intended to prevent the accumulation of amyloid §-40 and amyloid §-42 and to prevent their cytotoxic effects [22]. In a mouse model of AMD, systemic treatment with RN6G decreased the amount of amyloid b in the eye and prevented damage to the retina in a mouse model of AMD [23]. A phase I clinical trial has been completed successfully, and a phase II trial is underway for treatment of subjects with advanced non-exudative AMD.

17.4.3Drugs to Prevent Injury from Oxidative Stress and Micronutrient Depletion

Oxidative stress has been implicated in many agerelated diseases and in ageing itself. Molecules such as free radicals, which result from oxidative stress and damaged tissues, are referred to as a reactive oxygen species. The retina is particularly susceptible to oxidative stress because of its high oxygen consumption, high concentration of polyunsaturated fatty acids (docosahexanoic acid (DHA)), and exposure to light in conjunction with inadequate levels of naturally occurring antioxidants. A growing body of evidence suggests that cumulative oxidative damage may be responsible for AMD; however a causative link has not been proven [24]. These exposures and deÞcits result in the accumulation of cellular debris including oxidized lipids, which promote inßammation and may be directly toxic to the macular tissues and result in the clinical manifestations known as AMD. This paradigm is supported by epidemiologic studies showing that diets rich in antioxidants decrease the risk of AMD, while smoking was associated with an increased risk of AMD [25].

Support for this nutrient-based paradigm was provided by the AREDS trial. This multicenter, NEIsponsored study evaluated the effect of pharmacological doses of zinc and/or a formulation containing micronutrients with antioxidant properties (vitamin C, vitamin E, and beta-carotene) on the rate of progression to advanced AMD and on visual acuity. The use of these vitamins and micronutrients reduced the risk of developing advanced AMD by about 25% and the overall risk of moderate vision loss was reduced by 19% at 5 years [4]. The AREDS2 trial is a randomized multicenter clinical trial designed to assess:

ÐThe role of lutein (10 mg)/zeaxanthin (2 mg) and omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA)) in preventing of development of GA or CNV.

ÐThe possible elimination of beta-carotene and lowering the daily zinc oxide dose from 80 to 25 mg. These micronutrients are believed to function not

only as antioxidants, but also as anti-inßammatory and antiangiogenic agents, according to epidemiologic and laboratory studies (Table 17.2).

17.4.3.1 OT-551

OT-551 (Othera Pharmaceuticals, Exton, PA), also known as 4-cyclopropanoyloxy-1-hydroxyl-2,2,6,6- tetramethylpiperidine HCl, is a small lipophilic molecule that readily penetrates the cornea when applied as a topical medication. OT-551 is converted by ocular esterases to TEMPOL-H (TP-H), the active metabolite that is a potent free-radical scavenger and antioxidant that does not penetrate the cornea. In animal studies, topical therapy has resulted in excellent ocular bioavailability, with signiÞcant levels of TP-H achieved in the retina. The drug OT-551 was shown to possess anti-inßammatory and antiangiogenic properties as well as antioxidant properties. OT-551 also was shown to protect against oxidative damage in vitro, to protect against light damage in vivo, to suppress photoreceptor cell death in animal models, and to block angiogenesis stimulated by growth factors [26].

Based on these preclinical data, OT-551 was investigated as a therapy for GA in AMD. A 2-year, phase II trial, known as the OMEGA (OT-551 Multicenter Evaluation of Geographic Atrophy) Study investigated concentrations of OT-551 up to 0.45%, which appeared to be safe when dosed four times a day for up to 2 years. However, OT-551 did not appear to reduce the

progression of the area of GA in subjects with AMD, and the study was terminated early at month 18 of follow-up.

Another clinical trial using OT-551 reported that the drug was well tolerated with no apparent serious adverse effects. However, in this second study, the preliminary efÞcacy measurements indicate a possible beneÞt in maintaining visual acuity in treated eyes. However, the absence of signiÞcant effects on the rate of GA lesion enlargement indicated the need for further study involving the efÞcacy of OT-551 as a treatment for GA in AMD [27, 28].

17.4.4 Drugs to Suppress Inflammation

17.4.4.1 Complement Inhibition at C3

Genetic association studies using different populations have shown that inßammation appears to be the driving force behind AMD [29]. In 2005, four groups identiÞed a genetic polymorphism in complement factor H (CFH) which was associated with an increased risk of developing AMD. The documented risk-conferring singlenucleotide polymorphism (SNP) was a thymine (T) to cytosine (C) substitution at nucleotide 1277 in exon 9, which results in a tyrosine-to-histidine change at amino acid position 402 (Y402H) of the CFH protein. Since the initial association studies with CFH, two independent studies reported the association of AMD with two other loci that encode complement proteins: the complement component 3 (C3) gene and the complement factor B (CFB)/complement component 2 (C2) locus. An association between the complement factor 1 gene and AMD has been reported as well. Less robust associations have been reported between AMD and SERPING1, which regulates the complement component 1 (C1), and between AMD and the complement component 7 (C7)

Fig. 17.1 The complement pathway and drugs that modulate complement activation. A number of strategies for modulating the complement system are now being explored for the treatment of age-related macular degeneration. These include, in general, approaches that block various effector molecules, such as C3, C5, factor B, and factor D and an approach that reestablishes control and homeostasis of the system by augmentating the pathway with the protective form of complement factor H. This Þgure depicts 5 potential targets within the complement pathway that are being considered for therapeutic intervention:

TA 106, which inhibits factor B; FCFD4514S, which inhibits factor D; POT-4/AL-78898A, which inhibits the system at the level of C3; SOLIRIS and ARC1905, which inhibits the system at the level of C5. All these inhibitors should prevent formation of the membrane attack complex (MAC) and C5a. The target protein for each drug is encircled. Drugs and manufacture are listed in boxes with a dashed line connecting between the drug and its target protein in the complement cascade. MAC membrane attack complex, MBL mannose-binding lectin, MASPs MBL-associated serine proteases

and mannose-binding lectin 2 (MBL2) loci. Protective alleles associated with the complement pathway have also been reported. Two of the Þve CFH-related genes (CFHR1-5), which lie within the regulators of complement activation (RCA) locus on chromosome 1q32, known as CFHR1 and CFHR3, are considered to be protective against AMD. These genetic association studies conÞrmed previous histopathological studies that implicated complement proteins in the pathogenesis of AMD [30, 31]. Since complement is a system of serum proteins that comprise an important arm of the innate immune system, association studies have deÞnitively linked AMD to the immune system, particularly the alternate pathway [32]. These genetic association studies and histopathological studies would suggest that inhibition of complement activation would be a reasonable strategy for the treatment of AMD (Fig. 17.1).

One way to investigate whether complement activation affects the enlargement rate of GA would be to see if lesions with faster enlargement rates are associated

with the at-risk alleles within the complement loci. Recent publications have reported that variants at CFH and C3 confer signiÞcant risks for GA and AMD, but there was no association between progression rates of GA and these at-risk alleles [33, 34].While these data may suggest that other factors are probably responsible for modulating the rate of disease progression, these data certainly donÕt preclude the use of complement inhibition as a viable treatment strategy for GA in dry AMD.

POT-4

POT-4 (Potentia Pharmaceuticals, Louisville, KY/ Alcon Research Ltd., Fort Worth, TX) is a cyclic peptide comprised of 13 amino acids derived from compstatin. POT-4 binds reversibly to complement component 3 (C3) and prevents its proteolytic activation to C3a and C3b as well as the subsequent release of all downstream anaphylatoxins, and prevents the formation of terminal membrane attack complex. As a C3 inhibitor, POT-4 inhibits all three major pathways of