Anecortave acetate

Hajir Dadgostar, MD and Peter K. Kaiser, MD

KEY FEATURES

Anecortave acetate is a member of a novel class of steroid analogues known as angiostatic cortisenes. It is similar in structure to cortisol and displays many of the antiangiogenic properties of glucocorticoids but lacks their anti-inflammatory and immunosuppressive effects. It also does not exhibit the common ocular side-effects associated with glucocorticoids, including cataract formation and intraocular pressure (IOP) elevation. It is administered as a posterior juxtascleral depot (PJD) adjacent to the macula using a specially designed, blunt-tipped cannula, and it is well tolerated systemically and from an ocular standpoint. Anecortave acetate has demonstrated efficacy in the treatment of exudative age-related macular degeneration (AMD) and is currently being evaluated as means of reducing the risk of progression in high-risk nonexduative AMD.

INTRODUCTION AND HISTORY

Glucocorticoids have been widely used in the treatment of retina disease because of their angiostatic properties.1 Although their beneficial effect on retinal edema is well recognized, the use of this class of agents has been limited by their known association with ocular complications such as elevated IOP and cataract formation.2 Other steroid compounds, including the estrogen derivative 2-methoxyestradiol, the progesterone derivative 17α-medroxyprogesterone, and squalamine, have also been found to have angiostatic activity in various systems,3–6 suggesting that the angiostatic properties of steroid compounds may be distinct from other activities characteristic of glucocorticoids. In 1985, Crum and colleagues demonstrated the angiostatic properties of a new class of steroids that lack conventional glucocorticoid activity but were able to inhibit neovascularization in the presence of cofactors such as heparin or cyclodextran.7

Based on such data, efforts were made to design a steroid derivative with good ocular bioavailability which lacked conventional glucocorticoid activity but retained angiostatic activity. After testing over 100 compounds in a chicken embryo model and further testing 15 compounds in a rabbit corneal neovascularization model, two compounds were found to have potent angiostatic activity.8 These molecules, anecortave acetate (Retaane, Alcon Laboratories, Fort Worth, TX) and anecortave desacetate define a novel class of angiostatic nonglucocorticoid steroid derivatives known as cortisenes.

As shown in Figure 31.1, both anecortave acetate and anecortave desacetate are derived from cortisol and both lack the 11β-hydroxyl group. Removal of hydroxyl group at this position is believed to eliminate glucocorticoid activity. Instead a double bond was introduced at the C9–11 position, and this conversion of a hydroxyl group to a double bond is reflected in the nomenclature of this class of molecules (cortisol versus cortisene). The only structural difference between anecortave desacetate and anecortave acetate is that the latter contains an additional 21-acetate group which is believed to enhance ocular penetration and prolong treatment duration when the drug is delivered as a local depot (see below).

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The initial screening tests for angiostatic activity were performed using the chick embryo chorioallantoic membrane (CAM) system, an extensively used model of angiogenesis.9,10 In this system, embryos are carefully removed from fertilized chicken eggs and grown in a sterile Petri dish for 3 days and then exposed to a lipid suspension containing 10 µl agarose pellets impregnated with the compound of interest. Growth of capillaries around the pellet site is scored after 2 days of further incubation. As mentioned above, after the screening of many steroid derivatives, the C9–11 cortisenes were found to be the most potent inhibitors of vascular growth in this assay.11

Anecortave acetate behaves similarly in a rabbit corneal neovascularization model. This model involves the implantation of bacterial lipopolysaccharide (LPS)-containing pellets in a stromal pocket near the limbus, after which the extent of neovascular growth into the cornea is measured. Anecortave acetate was shown to inhibit corneal neovascularization in this system when implanted in pellet form and also when administered as 0.1% and 1% topical suspensions (Figure 31.2).11,12 Studies using topical administration showed dose-dependent suppression of neovascular growth even when treatment was initiated several days after the implantation of LPS pellets.12

PHARMACOLOGY

Based on dose titration studies in various in vitro models, it was determined that the effective concentration of anecortave acetate required to achieve effective angiostasis in target tissues is above 0.01 µm.13 Thus, this concentration was used as the target for animal studies evaluating pharmacokinetics and delivery routes.

Topical and systemic administration in animals resulted in insufficient drug concentrations in the retina and choroid; however, intravitreal injections of a 5-mg dose as well as sub-Tenon’s injections of either a 10-mg or 50-mg dose resulted in adequate drug concentrations for about 6 months.13 In the case of sub-Tenon’s injections, adequate drug concentrations were maintained only when the depot was deposited directly in contact with the sclera, but this delivery route was still considered more appealing than the intravitreal route because of its more favorable safety profile. For this reason, a specially designed, curved, blunt-tipped posterior juxtascleral cannula was designed so that depot doses of anecortave acetate could be delivered directly adjacent to the sclera in the macular region. Briefly, the recommended injection procedure in humans, which is described in detail elsewhere,14,15 involves making a small radial conjunctival incision 8 mm posterior to the limbus in the superotemporal quadrant after application of topical anesthetic. As shown in Figure 31.3, a specially designed curved blunt cannula is then advanced through this incision within the sub-Tenon’s space and the drug is slowly delivered as a PJD. A counterpressure device is held over the conjunctiva with the cannula in place to minimize drug reflux and thus improve the reproducibility of the dose delivered.

Using this delivery method, human pharmacokinetic studies were performed as part of a randomized, multicenter, placebo-controlled phase II trial in subjects with exudative AMD.13 Subjects received one of three doses of PJD anecortave acetate (3, 15, or 30 mg) or placebo at

Diseases Retinal in Mechanisms and Drugs • 4 section

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