PEER REVIEWED

The Coming Boom in Dry AMD Therapies

MICHAEL ENGELBERT, MD, PhD · JAMES M. KLANCNIK, JR., MD

In the face of an aging demographic, age-related macular degeneration (AMD) became the most prevalent pathology presenting in most retinal practices in the developed world. One might say that it helped generate the explosion of the subspecialty of retina, which elucidated the different subtypes (wet and dry), with their respective subforms (classified and graded in the international classification and grading system for AMD¹). But physicians had to watch helplessly as their patients worsened without any treatment at hand. The first treatments to be FDA-approved — photodynamic therapy for wet AMD² and nutritional supplementation with a complex mixture of nutraceuticals (AREDS)³ — showed only modest effect in slowing disease progression.

Efforts to tackle the neovascular complications of AMD surgically after the development of sophisticated vitreoretinal techniques had disappointing results.⁴ Not until the breakthrough of anti-VEGF therapy could many patients afflicted with AMD be offered the hope of improved vision.^5,6 While these patients used to account for 85% of severe vision loss cases, they represent only a minority of the entire AMD population, and there is no approved, evidence-based form of treatment for patients with dry AMD, aside from AREDS vitamins. A treatment for dry AMD is the Holy Grail for retinal physicians.

However, hope is on the horizon, in the form of a myriad of experimental drugs, spanning the spectrum from the traditional (eg, eyedrops) to the futuristic — implantable cell farms containing genetically engineered cell lines that produce neuroprotective factors. Over the past decades, our understanding of the molecular pathogenesis has evolved substantially and identified a multitude of potential therapeutic targets.

In the following article, we will briefly summarize the current pathogenic model of AMD and review the gold standard of treatment, as well as relevant past and present experimental approaches to the treatment of dry AMD.

CURRENT PATHOGENIC MODEL OF AMD

Oxidative damage may be the root cause of the genetically regulated "multiple hit" process we call aging. In the eye, both incoming light, focused on the macula by the cornea and lens, and the byproducts of cells with high oxygen consumption and energy demand, and exposure to systemic toxins circulating through the luxuriant blood supply of the choroid, contribute to this process. Both lipid peroxidation and protein misfolding in aging photoreceptors and RPE cells aggravates the compromised cellular metabolism and leads to the accumulation of lipofuscin and other detritus, further damaging the cells in charge of their removal. This stimulates an immune response, largely mediated by the complement system, further contributing to local damage and initiating a vicious cycle eventually leading either to "quiet" degenerative loss of RPE cells and photoreceptors or choroidal neovascularization (CNV) followed by its exudative and hemorrhagic complications, often resulting in severe and sometimes sudden and dramatic visual loss.

Geographic Atrophy in Dry AMD.

Several environmental and genetic factors appear to influence the threshold for development of AMD. In terms of environmental factors, which are frequently modifiable, increasing oxidative stress in general is likely detrimental, as smoking has been shown to increase the risk of advanced AMD in a dose-dependent fashion,⁷ whereas the association of diets rich in the antioxidants lutein and zeaxanthin (enriched in green leafy vegetables) and omega-3 fatty acids (enriched in fish) with reduced risk of AMD may be based on neutralization of free radicals.⁸ Other environmental factors implicated in the pathogenesis of AMD are alcohol use⁹ and sun exposure.¹⁰

A genetic contribution to AMD was always intuitive, based on the differential incidences in various ethnicities and concordant phenotypes in twins. Recently, this genetic basis has unraveled, with genes of the complement pathway most prominent, thus highlighting the contribution of the immune system to the pathogenesis of AMD. In particular, susceptibility alleles encoding variants of complement factor H (CFH)^11,12 and other components of the complement cascade, such as complement factor 2 (C2) and/or complement factor B (CFB),¹³ complement factor 3 (C3),¹⁴ and complement factor I (CFI),¹⁵ have been identified. Protective alleles, such as CFHR1 and CFHR3, convey a decreased susceptibility to AMD.^16,17

Another component of the innate immune response, Toll-like receptor 3, has been found to be specifically associated with the development of geographic atrophy.¹⁸

A specific mitochondrial DNA variant, A4917G, and a polymorphism in the 5’-upstream region of ERCC6, a gene important for DNA repair due to stress and aging, have been reported to increase risk,¹⁹ pointing to the importance of oxidative damage and genomic stability in the pathogenetic process.

A single point mutation in HTRA1, a regulator of extracellular matrix degradation and an inhibitor of transforming growth factor-ß, has also been shown to confer an increased risk of advanced AMD, possibly by facilitating permeation of Bruch's membrane by choroidal neovascular vessels²⁰ but also by promoting geographic atrophy.²¹

THE GOLD STANDARD: NUTRITIONAL SUPPLEMENTATION ACCORDING TO AREDS

In the absence of treatment options, prevention becomes paramount. AREDS, a multicenter, randomized clinical trial, showed that oral supplementation with high doses of antioxidant vitamins C and E, beta-carotene, zinc, and copper may slow progression of advanced AMD significantly.⁴ A sequel to AREDS, AREDS2, will examine the role of lutein, zeaxanthin, and/or omega-3 fatty acids in preventing advanced AMD (www.areds2.org).

LASER TREATMENT

Drusen are the earliest clinical sign of AMD, and since low-intensity laser treatment anecdotally led to resolution of drusen, the CAPT trial (Complications of Age-related macular degeneration Prevention Trial) was conceived. Over 2000 eyes with at least 10 large drusen (>125 μm) were enrolled and followed for at least 5 years. While demonstrating drusen reduction by greater than 50% in more than one-third of patients, confirming the anecdotal experience of many, and without any immediate complications of treatment, CAPT failed to demonstrate significant differences in visual results (BCVA, contrast threshold, critical print size) or the development of advanced AMD (GA or CNV).²²

VISUAL-CYCLE INHIBITION

It is now widely recognized that increased autofluorescence often precedes RPE cell and photoreceptor death in patients with AMD.²³ It is believed that this increased autofluorescence is a corollary of accumulation of lipofuscin and vitamin A metabolites, such as the retinal fluorophore A2E. A2E has been shown to be toxic in a variety of ways: by destabilizing membranes, interfering with phagolysosomal metabolism, blue-light mediated cellular and nuclear damage, subsequent apoptosis, and downstream complement activation.

Fenretinide (4-hydroxy(phenyl)retinamide) is a synthetic retinoid that competes with retinol for binding to retinol-binding protein and transthyretin, thus diminishing the amount of retinol available in the visual cycle and decreasing the amount of toxic fluorophores accumulating in the RPE cells. Developed by Sirion Therapeutics (Tampa, FL), fenretinide's tolerability and bioavailability is well characterized, and several phase 2 and 3 studies employing fenretinide in the treatment of various cancers have been published, further supporting the safety of this agent.

Currently, a double-masked, placebo-controlled phase 2 trial has started to study whether fenretinide may be beneficial in the treatment of dry AMD. Specifically, 2 doses (100 and 300 mg) of an oral fenretinide preparation are being tested against placebo in 245 patients with GA between 1 and 8 disc diameters in size, threatening the fovea, with a visual acuity between 20/25 and 20/100 in the study eye. Both anatomical data, specifically progression of geographic atrophy as measured by fundoscopy, fluorescein angiography, fundus autofluorescence, and OCT, and functional data, such as best corrected visual acuity, contrast sensitivity, and reading rate, are being collected through 24 months.

Another nonretinoid visual cycle modulator under phase 1 investigation is ACU-4429 (Acucela Inc., Bothell, WA). Data on safety and tolerability of ACU-4429 were presented at the ARVO conference in May 2009, indicating that this oral drug is well tolerated in healthy subjects. Preclinical data shows that ACU-4429 slows the rod visual cycle resulting in decreased lipofuscin and A2E. Electro-retinograms showed reduced rod function in these subjects, as predicted. This type of intervention may have applications with dry AMD, as well as other degenerative disorders related to accumulation of lipofuscin. Phase 2 trials are planned for later this year.

Although visual-cycle inhibition appears promising in slowing down the progression of geographic atrophy, a reversible but inevitable side effect is slowing rod recovery, leading to difficulties adjusting to changes in ambient illumination and increased light sensitivity. Consequently, patients are advised in the study consent to "be careful while doing anything that requires night vision, including operating a car or machinery." These side effects may be only slowly reversible (in the case of another compound, AC-3223, this may last several days), limiting clinical utility to a greater or lesser extent. It is interesting to note, though, that the proportion of patients complaining of night blindness and reduced acuity was similar in the fenretinide study mentioned above.

ANTIOXIDANTS

OT-551 (Othera Pharmaceuticals Inc., Exton, PA) is a small lipophilic precursor molecule that readily penetrates the cornea after topical application and then gets converted by ocular esterases into TEMPOL-H, the active, hydrophilic metabolite, a potent free-radical scavenger and inhibitor of lipid peroxidation. It also appears to inhibit NFkB gene transcription, thus working through another anti-inflammatory and antiangiogenic mechanism. Randomized, open-label pilot studies examined the effect of OT-551 on loss of visual acuity and progression of geographic atrophy in AMD, as well as Stargardt disease.

Currently, OMEGA (OT-551 Multicenter Evaluation of Geographic Atrophy), a phase 2, randomized, double-masked, dose-ranging, multicenter study is comparing the safety and efficacy of topical OT-551 over the course of 2 years in patients with geographic atrophy ranging in size from 0.5 to 7 disc diameters and a BCVA of at least 20/63. Mean outcome measures are change in the rate of GA area progression, conversion to neovascular AMD, and change in BCVA.

COMPLEMENT INHIBITION

As already mentioned, there exists ample evidence that the complement cascade plays an important role in the pathogenesis of AMD and probably at all stages, ie, from drusen formation to geographic atrophy or choroidal neovascularization and eventual cicatrization. This has lead to the development of a myriad of complement inhibitors that could potentially work for patients with early as well as advanced AMD. Whether it is advantageous to inhibit upstream or downstream in the complement cascade is up for debate since the current rationale for tackling complement at this point relies on strong epidemiological evidence, rather than a detailed understanding of the molecular mechanisms.

POT-4 (Potentia Pharmaceuticals Inc., Louisville, KY) is a cyclic 13 amino acid peptide, which interferes with the cleavage of C3, the component all 3 pathways of complement activation converge on. It was the first complement inhibitor to be be studied in patients with AMD. POT-4 forms an intravitreal gel deposit that functions as a depot for the drug. Preliminary phase 1 data suggest that it is safe and well tolerated at the doses studied.

Other compounds target the terminal complement component C5, which is critical for membrane attack complex formation and production of the highly proinflammatory molecule C5a. Eculizumab (Alexion Pharmaceuticals Inc., Cheshire, CT) is a humanized monoclonal antibody to C5. It is FDA approved for the treatment of paroxysmal nocturnal hemoglobinuria, and the COMPLETE (COMPLement inhibition with Eculizumab for the Treatment of non-Exudative age-related macular degeneration) study is randomizing patients with dry AMD to eculizumab or placebo, with the hope of reducing both the growth rate of geographic atrophy, as well as high-risk drusen area and volume.

Another agent targeting C5 is ARC-1905 (Ophthotech, Princeton, NJ), a pegylated aptamer that inhibits the complement component C5; phase 1 trials for dry AMD and CNV (in combination with an anti-VEGF agent) are currently underway. JPE1375 ( Jerini Ophthalmic Inc., New York, NY) is a peptidomimetic small molecule that targets the receptor for C5a on inflammatory cells. It is a biodegradable injectable designed to last for 6 months.

One concern that has been raised is that complement inhibition may decrease the eye's ability to fight iatrogenically induced pathogens, thus potentially increasing the incidence or aggravating the outcome of injection-related endophthalmitis. Complement, however, is present in the vitreous only in minute quantities compared to the levels in the choroidal circulation, and while important in the pathogenesis of age-related macular degeneration, it appears to only play a subordinate role in the defense against intraocular pathogens.²⁴

PROTECTIVE CYTOKINES

Ciliary neurotrophic factor (CNTF) has been shown to be able to rescue dying photoreceptors in several paradigms of neurodegeneration, and in several experimental animal species. It is produced and delivered continuously in situ through encapsulated cell technology. A semipermeable tube of about 6 mm length and 1 mm diameter contains human RPE derived cells genetically engineered to produce human CNTF, which diffuses through the 15-nm pores. A phase 1 study, sponsored by Neurotech USA (Lincoln, RI), demonstrated that this tube could safely be implanted into eyes with severely degenerated photoreceptors from retinitis pigmentosa.²⁵ Visual acuity appeared to improve both subjectively and objectively in this open-label study. This has motivated a phase 2 trial, which is currently underway.

SUMMARY

Recent research in the pathogenesis of AMD has identified multiple potential therapeutic targets. While the role of nutritional supplementation according to the AREDS protocol is well established, AREDS2 will hopefully yield an improved formulation, with higher efficacy for a broader group of patients. It is encouraging to observe multiple compounds, targeting multiple different pathways in the multifactorial pathogenic cascade, making it from bench to bedside. This review restricted itself to mention representative compounds that have advanced furthest through the consecutive trial phase process, but many more are in the R&D pipelines of established and startup companies. We believe that there is reason for optimism that pharmacological options will revolutionize the treatment of dry AMD just as anti-VEGF agents have shifted the treatment paradigm in wet AMD. RP

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