February 2013, Issue 54

Investigational Therapies for Dry AMD

Jaclyn L. Kovach, MD Assistant Professor of Clinical Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine

While therapy for neovascular age-related macular degeneration (AMD) has undergone revolutionary advancements during the past 10 years with the advent of anti-vascular endothelial growth factor (anti-VEGF) agents, treatment for dry AMD is lacking. Currently, the recommended therapy of AREDS vitamin supplementation with vitamins C and E, beta-carotene, zinc and copper can slow progression of AMD, but not arrest or reverse the condition.¹ The results from the AREDS2 Study, which is investigating the role of lutein, zeaxanthin, and omega-3 fatty acids in the prevention of advanced AMD, are expected later this year. There are numerous investigational treatments for dry AMD that are progressing through the clinical trials pipeline. These investigational treatment options are designed to disrupt the complex interplay of oxidant, inflammatory, and degenerative factors that cause dry AMD.

Increased lipid peroxidation secondary to oxidant exposure leads to compromised cellular metabolism in aging retinal pigment epithelial (RPE) cells and fosters the accumulation of photoreceptor byproducts including lipofuscin. One of the components of lipofuscin is the retinal fluorophore A2E, which is toxic to RPE cells and is pro-inflammatory. Fenretinide (4-hydroxy[phenyl]retinamide) (ReVision Therapeutics San Diego, CA) is a synthetic retinoid that competes with retinol for binding to retinol-binding protein and transthyretin, reducing the amount of retinol delivered to RPE cells and decreasing the number of toxic fluorophores in the RPE. In a phase 2 randomized, double-blind, placebo- controlled trial, 246 participants received either 300mg of fenretinide, only placebo, or 100mg of fenretinide and 2 placebo capsules. After 24 months, fenretinide reduced the risk of progression to wet AMD, but did not slow the growth of geographic atrophy (GA). Fenretinide was generally well tolerated, but was associated with some side effects, such as problems with dark adaptation and dry eye symptoms.

Acucela (ACU-4429) (Acucela Inc., Bothell, WA) is a non-retinoid visual cycle modulator that was designed to be selective for rod photoreceptors. ACU-4429 specifically inhibits isomerase/RPE65, preventing conversion of all-trans-retinol to 11-cis-retinol and reducing the amount of lipofuscin and A2E.² The phase 1 clinical trial was a single-center, randomized, double-masked, placebo-controlled, dose-escalation study in which ERG data demonstrated well-tolerated, dose-dependent modulation of the visual cycle. In January 2010 the phase 2 trial ENVISION (Evaluating a Novel VISION treatment for AMD) began enrollment. This is a randomized, double-masked, placebo-controlled study of 3 escalating oral dose levels and up to 2 additional dose levels. Participants are scheduled to receive either ACU-4429 or placebo daily for 3 months.

Inflammation, in the form of complement activation and macrophage recruitment, may promote progression of AMD to GA and VEGF-dependent choroidal neovascularization. Iluvien (Alimera Sciences, Alpharetta, GA) is a fluocinolone acetonide intravitreal insert currently in a phase 2 clinical trial investigating the effect of two daily elution doses of Iluvien in slowing GA enlargement.

Sirolimus (Rapamycin) (Macusight/Santen, Union City, CA) is a macrolide fungicide that has anti-inflammatory, antiangiogenic and antifibrotic activity. This drug is administered subconjuntivally and is currently being studied in phase 1 and 2 trials for the treatment of GA and wet AMD.

Unregulated complement activation may play a role in every stage of AMD pathogenesis. AL-78898A (previously known as POT-4) (Potentia Pharmaceuticals, Louisville, KY/Alcon Research, Fort Worth, TX) is a cyclic peptide that binds reversibly to complement component 3 (C3) inhibiting all three major complement pathways and preventing the formation of the membrane attack complex (MAC). Upon intravitreal injection, POT-4 forms a gel, which functions as a depot allowing slow and sustained drug release. The phase 1 dose-escalation study, Assessment of Safety of Intravitreal POT-4 Therapy for Patients with Neovascular AMD (ASaP), showed safety up to a dose of 1.05mg with evidence of depot formation. A phase 2 study (NCT01157065) has been completed to further investigate the anti-VEGF properties of POT-4 identified in the phase 1 study and to determine the appropriate dosing interval for future dry AMD trials. Another phase 2 study was recently initiated to evaluate the safety and efficacy of 12 monthly intravitreal injections of 0.400mcg of AL-78898A in slowing the rate of progression of GA (NCT01603043).

Eculizumab (SOLIRIS) (Alexion Pharmaceuticals Inc., Cheshire, CT) is a humanized monoclonal antibody to complement component 5 (C5) which prevents the formation of MAC and preserves the microbial opsonization properties of C3. It is FDA-approved for the intravenous treatment of paroxysmal nocturnal hemoglobinuria. A phase 2 clinical trial, the COMPLETE study, evaluated the safety and efficacy of an intravenous infusion of eculizumab for the treatment of dry AMD. In this study, 30 patients with GA and 30 patients with drusen were randomized 2:1 to receive intravenous eculizumab or a saline placebo. Half of the patients in the eculizumab group received a low dose and half received a higher dose. After 26 weeks of treatment, no differences were detected between the treatment and placebo groups. Eculizumab did not prevent the growth of GA and did not decrease the drusen volume in the two separate cohorts. One-year follow-up is currently underway.

ARC-1905 (Ophthotech, Princeton, NJ), an anti-C5 pegylated aptamer, is administered intravitreally and is currently being investigated in phase 1/2 trials for the treatment of dry AMD and wet AMD.

LFG316 (Novartis Pharmaceuticals, New Jersey) is an antibody directed against C5 and is administered intravitreally. The phase 1 study to assess safety and tolerability of intravitreal LFG316 in patients with advanced AMD, GA or CNV, has been completed and a phase 2 study to evaluate the efficacy of 6 successive monthly doses on the growth of GA is currently underway.

FCFD4514S (Genentech/Roche, South San Francisco, CA) is a recombinant humanized monoclonal antibody fragment directed against complement factor D, which is a rate-limiting enzyme in the alternative complement pathway. The phase 1 study results suggest that intravitreal administration is safe and well tolerated up to a 10mg dose. Phase 2 studies are underway.

Glatiramer acetate (Copaxone, Reva Pharmaceuticals; Kfar-Saba, Israel) is an immunomodulatory agent approved for the treatment of multiple sclerosis. It induces suppressor T cells and down-regulates inflammatory cytokines. A phase 1 study evaluating the safety and efficacy of weekly treatment over 12 weeks with subcutaneous glatirimer in patients with drusen has shown that it reduces drusen area. A phase 2/3 study is underway.

Photoreceptor and RPE cell death is a hallmark of AMD progression. One neuroprotective compound that helps to preserve photoreceptors is ciliary neurotrophic factor (CNTF). CNTF can be produced and delivered continuously in situ through encapsulated cell technology. A tube with a semipermeable membrane containing human RPE-derived cells engineered to produce human CNTF can diffuse through pores in the membrane after tube implantation. A phase 2 clinical trial showed that CNTF is associated with a dose dependent increase in retinal thickness, an expansion of the outer nuclear layer, and an excellent safety profile. High dose therapy showed greater vision stabilization in subjects with better baseline visual acuity. However, there were no statistically significant differences observed in the progression of GA at 12 months for either the high-dose or low-dose groups compared with the sham group.

Brimonidine tartrate (Allergan Inc., Irvine, CA) is believed to possess neuroprotective properties; however, the exact mechanism of action is unknown. An injectable, sustained release intravitreal brimonidine polymer is currently being evaluated in a randomized, double-blind, dose-response, and sham-controlled phase 2 study with regard to safety and its effect on the progression of GA.

AL-8309B (Tandospirone) (Alcon Research Ltd.;Ft. Worth, TX) is a selective serotonin 1A receptor agonist that has been shown to protect the retina from light damage in animal studies. A multicenter, randomized, double- masked, placebo-controlled phase 3 clinical trial known as the Geographic Atrophy Treatment Evaluation (GATE) trial was performed to investigate the effects of topical AL-8309B in patients with GA, but the results have not yet been released.³

Amyloid-beta may be involved in AMD progression. RN6G (Pfizer, New York, NY), a humanized monoclonal antibody targeting amyloid-beta, was found to be safe in patients with dry AMD and is being studied in a phase 2 clinical trial. GSK933776 (GlaxoSmithKline) is another humanized monoclonal antibody directed at amyloid-beta that is administered intravenously. A phase 2 multicenter, randomized, double-masked, placebo-controlled study in patients with GA is underway.

The ability to arrest the progression of dry AMD, regain normal macular structure and function, and prevent wet AMD may seem unattainable, but recently, many therapeutic targets in the pathogenesis of dry AMD have been identified and numerous therapies are currently progressing through clinical trials. A multimodal treatment approach including antioxidant, anti-inflammatory and neuroprotective combination therapy may yield the greatest benefit. As we await the results of the AREDS2 Study, with cautious optimism, we anticipate the addition of novel treatments to our limited armamentarium against the common and potentially devastating condition of dry AMD.

REFERENCES:
1. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.
2. Zarbin MA, Rosenfeld PJ. Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina. 2010 Oct;30(9):1350-67.
3. Mata NL, Vogel R. Pharmacologic treatment of atrophic age-related macular degeneration. Curr Opin Ophthalmol. 2010;21:190-96.