Laurie Barclay, MD

Almost all blindness in the United States results from common eye diseases, according to Research to Prevent Blindness, Inc., and 80 million Americans suffer from potentially blinding eye diseases. In the developed world, the leading causes of blindness are age-related macular degeneration (AMD) and diabetic retinopathy (DR). Currently available treatments for AMD and DR are of limited efficacy and may not arrest progression in many patients. Glaucoma, another common eye condition causing visual loss, may be more amenable to pharmacotherapy.

Macular degeneration results from a partial breakdown of the retinal pigment epithelium (RPE) in the macula, or central part of the retina, causing decreased visual acuity and possible loss of central vision. One third of Americans over age 50, or about 20 million, are at risk of developing AMD; 10 million suffer visual loss from AMD, and 104,000 are legally blind from AMD. By age 75, nearly 15% of individuals have AMD. In addition to advancing age, smoking, family history, hypertension, hypercholesterolemia and female sex may increase risk of AMD.

In the "dry" phase of macular degeneration, breakdown of the RPE causes thinning of the retina. Although there is no specific treatment for this phase, zinc supplementation may slow its progression. Subsequent release of harmful elements from the RPE, with excess production of vascular endothelial growth factor (VEGF), may also promote new choroidal blood vessel formation, leakage, and edema. This is referred to as the "wet" phase of macular degeneration, which often leads to significant vision loss.

In the early stages, "wet" AMD may respond to laser photocoagulation of leaking choroidal blood vessels. Alternatively, photodynamic therapy involves intravenous injection of a light-sensitive medication called Visudyne (verteporfin). Shining a non-thermal laser into the eyes activates Visudyne to produce a chemical reaction that destroys abnormal blood vessels.

Among diabetics, 14 million are at risk for blinding retinal disease, 1.8 million have severe visual impairment from DR, and 65,000 diabetics develop proliferative retinopathy annually. In non-proliferative DR, which occurs earlier and is less severe, existing blood vessels leak fluid into the retina, causing blurred vision. In proliferative DR, growth of new blood vessels within the eye in response to VEGF leads to hemorrhage, loss of vision and scarring. Laser surgery to coagulate leaking vessels or vitrectomy to evacuate hemorrhage and repair retinal detachment may be needed.

Glaucoma, or increased intraocular pressure (IOP) which can injure the retina, affects two million Americans with visual impairment and 120,000 with blindness. Primary open angle glaucoma, the most common form, results from obstruction within drainage canals in the eye, with few symptoms or early warning signs. If not diagnosed and treated promptly, it can cause gradual vision loss, but typically it responds to pharmacotherapy. Angle closure glaucoma (acute glaucoma or narrow angle glaucoma) is much more rare and results in sudden increase in IOP, which usually is amenable to surgery.

Other eye disorders targeted by pharmaceutical research are rhegmatogenous retinal detachment (RRD), keratoconjunctivitis sicca, and bacterial conjunctivitis.

RRD is the most common form of retinal detachment, caused by retinal tears allowing vitreous fluid to accumulate between the retina and the RPE. In the U.S., there are approximately 50,000 cases of RRD each year. Retinal reattachment is usually attempted surgically, but post-surgical complications may include decreased visual acuity, loss of ocular range of motion, misaligned eyes, prolonged convalescence, and post-operative pain.

Keratoconjunctivitis sicca, or dry eye syndrome, results from decreased tear gland function leading to a thickened cornea and decreased visual acuity. It is typically related to aging but may be a manifestation of autoimmune disease.

CenterWatch has identified 20 drugs in various stages of development for AMD, DR, glaucoma, and other eye conditions.

Miravant Medical Technologies has submitted a new drug application (NDA) for SnET2(tin ethyl etiopurpurin), a form of investigational photodynamic therapy for wet AMD. Based on the results of two phase III, placebo-controlled, double-masked clinical trials with this light activated drug, the Food and Drug Administration (FDA) has granted SnET2 Priority Review Designation.

More than 900 patients enrolled at 60 U.S. ophthalmology centers received an initial single treatment of PhotoPoint SnET2 or placebo followed by a low power light treatment and were followed for two years for safety and efficacy evaluation, with retreatments if required. Patients who received the minimum exposure to the SnET2 treatment regimen had significantly reduced risk of vision loss compared with those who received placebo.

Pfizer has also submitted an NDA for Xalcom, a combination of latanoprost ophthalmic solution (Xalatan) and the beta blocker timolol, for use in glaucoma. Most physicians surveyed are enthusiastic about using this drug if it is approved, citing the hope that it would improve compliance over a two-drug regimen. Optometrists surveyed indicated that they would switch more than 70% of their monotherapy patients to this combination, and doctors also estimate that about 83% of patients newly diagnosed with glaucoma who need both a prostaglandin and a beta blocker would be started on Xalcom rather than on two drugs.

Eyetech Pharmaceuticals and Pfizer have also submitted an NDA for Macugen (pegaptanib, formerly EYE-001). This VEGF inhibitor targets abnormal vascular growth in AMD, and it is also in Phase II testing for diabetic macular edema.

Another VEGF inhibitor is Lucentis (ranibizumab), in Phase III testing for wet AMD by Genentec. This therapeutic antibody fragment to VEGF is designed to bind VEGF and thereby inhibit angiogenesis. Phase III randomized trials are ongoing in collaboration with Novartis Ophthalmics, both in minimally classic/occult patient populations and in predominately classic patients.

A novel approach to AMD is AdPEDF, in Phase I testing by GenVec. Using an adenovector to deliver pigment epithelium-derived factor (PEDF) gene to the eye, AdPEDF allows on-site production of PEDF, the most potent known natural inhibitor of angiogenesis in the eye. Preclinical data suggest that administration of AdPEDF results in substantial inhibition of new vessel formation in an animal model. These vectors can be administered multiple times to cause the repeat production of protein from the delivered gene, and they are well tolerated.

Acuity Pharmaceuticals is pursuing a similar genetic approach to wet AMD and DR with Cand5, a small interfering RNA (siRNA) which shuts down VEGF genes promoting angiogenesis. In August, Acuity filed an Investigational New Drug application (IND) with the FDA to initiate Phase I clinical trials, based on encouraging results in primates and rodents.

For bacterial conjunctivitis, InSite Vision is in Phase III testing of AzaSite(ISV-401). This formulation of azithromycin, a broad-spectrum antibiotic not currently used in ophthalmology, is formulated with DuraSite, InSite's patented drug-delivery vehicle. In a Phase II clinical study, ISV-401 was both safe and effective, achieving clinical resolution and bacterial eradication of both gram-positive and gram-negative strains of acute bacterial conjunctivitis.

Although currently available ophthalmic antibiotics must be administered every two hours on the first day and four times daily for the remainder of treatment, up to fourteen days, ISV-401 may allow reduced dosing frequency and improved compliance.

InSite Vision has also completed Phase II testing of ISV-205, a DuraSite-based formulation of diclofenac for use in glaucoma. Diclofenac has been shown to inhibit the production of the TIGR protein which accumulates in the drainage system of the eye, interfering with equalization of intraocular pressure and thereby causing glaucoma. Unlike currently available drugs, ISV-205 therefore treats the root cause of glaucoma rather than the symptoms.

Cambridge Antibody Technology is in Phase II/III development of lerdelimumab(CAT-152), a human monoclonal antibody designed to reduce scarring after glaucoma and cataract surgery. This anti-TGFb2 antibody specifically neutralizes the cytokine TGFb2, overactivity of which is thought to cause scarring in and around the eye.

In a Phase II clinical trial, 56 patients who were undergoing combined glaucoma and cataract surgery were randomized to receive either CAT-152 (n = 36) or placebo (n = 20) administered as a series of four subconjunctival injections given immediately pre- and post-operatively, on the day after surgery, and one week after surgery.

CAT-152 was safe and well tolerated without serious drug-related adverse events, severe injection site reactions, or evidence of increased inflammation in the anterior chamber of the eye. Although both patient groups had successful lowering of intraocular pressure (IOP) by glaucoma surgery, long-term results were better with CAT-152. At 12 months after surgery, mean IOP was 14.4 mmHg in CAT-152 treated patients and 16.9 mmHg in the placebo group (P = .03). The proportion of patients with IOP below 22 mmHg was 100% for CAT-152 and 85% for placebo (P = .04).

Patients receiving CAT-152 also fared better in terms of the proportion of patients who required topical medication to manage IOP (11% vs. 20%) and need for repeat glaucoma surgery (0 vs. 1). Intervention after operation with antimetabolite injections of 5-fluorouracil) was similar in both groups (28% vs. 30%).

For macular edema, Oculex (Allergan) has completed Phase II testing of Posurdex, a micro-sized intraocular drug delivery system for dexamethasone. This bioerodable, extended release implant delivers dexamethasone directly to the retina.

In a prospective, multicenter study, 306 patients with macular edema secondary to diabetes, retinal vein occlusion, uveitis, or cataract surgery were randomized to receive a single Posurdex® implant containing a 350µg dose of dexamethasone, a single Posurdex® implant containing 700µg of dexamethasone, or observation without drug therapy.

Compared with the observation group, patients receiving Posurdex had significant improvement in signs and symptoms of macular edema, and a significant increase in the percentage of patients achieving at least a three-line improvement in visual acuity. If Phase III trials are successful, Allergan is hoping for FDA approval for Posurdex by late 2006 or 2007.

An alternate approach to AMD is squalamine(MSI-1246), in Phase II testing by Genaera. This aminosterol compound isolated from dogfish shark reduces angiogenesis by inhibiting salt and acid regulating pumps on endothelial cells, thereby blocking the action of VEGF and other angiogenic growth factors. Early trials in AMD have shown shrinkage or stabilization of choroidal neovascularization lesions, and improvement or stabilization of vision. Because squalamine is administered intravenously rather than injected into the globe, it has lower risks of eye infection or injury.

For rhegmatogenous retinal detachment, Inspire Pharmaceuticals is in Phase II development of INS37217 ophthalmic (denufosol tetrasodium), a second generation P2Y2 receptor agonist. In experimental models, this compound stimulates retinal re-attachment by reabsorbing extraneous sub-retinal fluid across the RPE.

Inspire hopes that INS37217 Ophthalmic may become the first FDA-approved product to be administered as first-line therapy for retinal reattachment in some RRD patients without the need for surgery. Because it stimulates fluid reabsorption across the RPE, it may also be useful for diabetic and non-diabetic macular edema. A Phase I/II trial showed that intravitreal injection of INS37217 Ophthalmic was well tolerated, with improvement in extent of retinal re-attachment compared with placebo. Results from a Phase II study in RRD are expected in mid-2005.

For keratoconjunctivitis sicca, Sucampo Pharmaceuticals is in Phase II testing of FK-506 (tacrolimus), a potent immunosuppressive agent. An ongoing multicenter, safety and efficacy study has randomized approximately 160 patients with documented keratoconjunctivitis sicca to three treatment groups.

Many of the new pharmaceuticals in the pipeline for eye disorders are targeting VEGF, given the importance of angiogenesis to the pathophysiology of both AMD and DR. These new drugs are approaching VEGF from multiple angles, including an antibody directly interfering with its mechanism of action, or genetic regulation via adenovectors or interfering RNA. Thanks to novel drug delivery systems, localized delivery and specific targets should hopefully allow high degrees of efficacy with few systemic effects.