DRUG EFFECTS IN RETINAL DISEASES

PRECLINICaL STUDIES

Retinopathy of prematurity

ROP is the leading cause of blindness associated with premature birth. Its incidence is correlated with birth weight and gestational age, with 84% of those born at <28 weeks’ gestational age being affected. The majority of cases are mild and regress spontane­

ously; however, threshold ROP occurs in 7–8% of infants with a birth weight of <1251 g.19,20 The pathogenesis of this disease is believed to

be related to incomplete peripheral retinal vascularization combined with exposure to high oxygen levels in the neonatal intensive care unit setting. Upon return to normal oxygen concentrations, the avascular peripheral retina becomes ischemic, giving rise to a neovascular response with devastating potential consequences, including vitreous hemorrhage and tractional partial or total retinal detachment. The current standard of care in the treatment of pre­ threshold to threshold ROP is laser photocoagulation delivered to all avascular areas of the retina in order to induce regression of neovascularization.

Anecortave acetate has been evaluated in two animal models of ROP. One of these is a rat model in which retinal neovascularization is induced in newborn rats exposed to alternating oxygen concentrations of 10% and 50% shortly after birth and then returned to room air 14 days later. Intravitreal anecortave acetate injected at various timepoints inhibited pathologic retinal neovascularization in this model by 50% or more compared to vehicle.17 In another model of ROP, newborn kittens were exposed to 80% oxygen for 80 hours and then returned to room air.21 In this model, intravitreal anecortave desacetate dose-dependently reduced pathologic neovascularization with a 50% reduction at the highest dose (reviewed in Clark11).

Intraocular tumors

Uveal melanoma and retinoblastoma are the most common primary intraocular malignancies in adults and children, respectively, and both can display aggressive spread with life-threatening complications. A fundamental principle in the pathophysiology of most malignant tumors is the fact that as a tumor outgrows its blood supply; it must elaborate growth factors to induce further angiogenesis in order to sustain its growth.22,23

Anecortave acetate has been used to target tumor angiogenesis in two ocular tumor models. When 99E3 uveal melanoma cells are transplanted into the eyes of nude mice, they grow rapidly and become highly vascularized. Topical application of 1% anecortave acetate at various timepoints posttransplantation significantly inhibited­ tumor growth by 40–70% compared to vehicle.24 Since there was no effect on the in vitro growth of tumor cells, it was presumed that the inhibitory effect in vivo was a result of reduced angiogenesis, although this was not directly demonstrated. In a mouse retinoblastoma model developed by transgenic expression of SV40 T-antigen under a retina-specific promoter, subconjunctival anecortave acetate was able to inhibit tumor growth and vascularity in a dose-dependent fashion.25

Choroidal neovascularization

When defects in Bruch’s membrane allow a network of choroidal vessels to grow beneath the retinal pigment epithelium (RPE) and/ or retina, vision loss can occur as a result of exudation, hemorrhage, or fibrosis. Although the most common cause of choroidal neova­ scularization (CNV) among the elderly is AMD,26 there is a large list of other diagnoses where CNV can occur, including presumed ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, choroidal rupture, trauma, and a variety of inflammatory chorioretinopathies.

It is believed that angiogenic growth factors are needed to sustain the growth of CNV, and a rabbit model of CNV has been developed by implanting a sustained-release depot of basic fibroblast growth factor (FGF) in the subretinal space.27 In this model, a single posterior juxtascleral administration of 0.5 mg anecortave acetate immediately after FGF depot implantation resulted in no detectable leakage on fluorescein angiography at 8 weeks in 6/8 animals compared to 2/10 animals receiving vehicle after FGF implant (P < 0.025). In a mouse model using laser damage to disrupt Bruch’s membrane and induce CNV, intravitreal anecortave acetate resulted in a 58% inhibition of CNV (P < 0.001; reviewed in Clark11).

CLINICAL STUDIES

Exudative AMD

Until recently, the only available treatments for exudative AMD, the leading cause of blindness among the aging population in developed countries, were laser photocoagulation and verteporfin PDT.26 In recent years a number of pharmacotherapeutic agents targeting various steps in the angiogenesis pathway have been and are being investigated as treatments for exudative AMD.28 Among these are the VEGF inhibitors pegaptanib (Macugen, OSI-Eyetech, New York, NY), ranibizumab (Lucentis, Genentech, South San Francisco, CA), and bevacizumab (Avastin, Genentech, South San Francisco, CA), which have shown great promise in this context (discussed elsewhere). Because the broad mechanism of anecortave acetate is believed to target multiple points in the neovascularization process, possibly including VEGF-independent­ pathways as well (see above), and because the PJD delivery route requires less frequent dosing and is less invasive than intravitreal administration, anecortave acetate has been evaluated in clinical trials for the treatment of exudative AMD (Table 31.1).

The Anecortave Acetate Clinical Study Group reported the 12-month results of a randomized, placebo-controlled clinical safety and efficacy trial comparing three different doses of anecortave acetate (3, 15, and 30 mg) with placebo.29 This monotherapy trial enrolled 128 subjects with subfoveal CNV, 80% of which were predominantly classic lesions at baseline. Subjects were randomized to either placebo treatment or one of the three doses of anecortave acetate delivered using the specially designed PJD cannula at 6-month intervals. As shown in Figure 31.7, the most beneficial effect was derived from the intermediate (15-mg) dose, which resulted in significantly better visual acuity at 12 months than placebo (visual acuity difference of 1.8 logMAR lines; P = 0.0131). The percentage of subjects losing <3 lines of visual acuity at 12 months was 79% in the 15-mg anecortave acetate group compared to 53% in the placebo group (P = 0.0323). Severe vision loss (6 lines) occurred in 1/33 eyes (3%) in the 15-mg group compared to 7/30 eyes (23%) in the placebo group (P = 0.0224). A subgroup analysis of the patients with predominantly classic CNV revealed similar data, with 84% in the 15-mg group losing <3 lines compared to 50% in the placebo group (P = 0.01) and none with severe vision loss in the 15-mg group compared to 23% in the placebo group (P = 0.0299). Thus, anecortave acetate was shown to be superior to placebo for the stabilization of visual acuity in the setting of subfoveal CNV in this clinical trial.

A separate combination treatment trial randomized 136 subjects to PDT followed within 8 days by a single dose of anecortave acetate (either 15 or 30 mg) or vehicle (reviewed in Russell et al.30). In this 6-month study, subjects in the PDT-only group lost 1.5 lines of visual acuity, whereas subjects in the PDT–anecortave acetate 15-mg group lost 1 line of visual acuity. Overall, there was a trend toward less vision loss in the combination groups; however, these differences were not statistically significant.

In a pivotal phase III trial, the efficacy of anecortave acetate was compared directly to that of PDT.31 This was a noninferiority study enrolling 530 subjects with predominantly classic subfoveal CNV who were randomized to anecortave acetate 15 mg after sham PDT or stan-

Diseases Retinal in Mechanisms and Drugs • 4 section

Acetate chaptecortave• 31 An