Multiple factors contribute to AMD, including oxidative stress to the RPE, reduced mitochondrial function,1 chronic low-grade inflammation of the retina,2 and endoplasmic reticulum stress-induced cell death triggered by the accumulation of unfolded proteins.3 Smoking is a major risk factor for AMD because it promotes oxidative stress and endoplasmic reticulum damage.4 It is also thought that epigenetic changes, defined as covalent DNA modifications that affect gene expression while preserving the DNA sequence, play an important role in linking aging and environmental exposures to AMD risk. This mechanism is supported by monozygotic twin studies, which have shown genome-wide differences in DNA methylation patterns as modulators of AMD.5 Current management is divided into anti-VEGF for treatment of wet AMD and medications targeted at treatment of dry AMD. This article reviews the outcomes of different trials directed at treatment of dry AMD using various oral and injectable agents and discusses recent promising trials for treatment of GA.
Several clinical trials are ongoing to prevent progression of dry AMD. The list of trials for this review were obtained from PubMed searches using the keywords “macular degeneration,” “randomized,” “placebo,” and “trial.” Additionally, the content of currently published articles on different clinical trials of AMD were reviewed for inclusion of relevant studies.6-9
Recent advances in etiology and genetics of GA have led to development of new treatments for this disease entity. Lampalizumab (FCFD4514S) is an antibody-binding fragment of a humanized monoclonal antibody that binds to complement factor D, which has been implicated in the pathogenesis of GA.10,11 While the complement pathway is an important component of the host-defense system, it must be tightly regulated to avoid inflammation and tissue damage. This finding is supported by the observation that polymorphisms in gene regulators of the alternative complement pathway are associated with increased risk of AMD.12
A phase 1a trial showed that administration of single-dose intravitreal lampalizumab was safe and well tolerated in patients with GA.13 Following this safety trial, the MAHALO phase 1b/2 trial (NCT01229215) enrolling 143 patients with GA showed that monthly treatment with lampalizumab reduces the rate of GA lesion progression by 20% at around month 18. CHROMA and SPECTRI are parallel phase 3 trials investigating lampalizumab for the treatment of GA in AMD. The identically designed, double-masked, randomized studies will compare a 10-mg dose of lampalizumab administered every 4 or 6 weeks by intravitreal injection to sham injections.14 In addition, a phase 3 trial is investigating the long-term safety of lampalizumab intravitreal injections in patients with AMD-associated GA (NCT02745119).
Brimonidine is a selective α-2 receptor adrenergic agonist that has IOP-lowering effects and carries neuroprotective properties thought to be linked to reduced accumulation of extracellular glutamate and blockade of N-methyl-D-aspartate receptors.15 Initial results from an Allergan phase 2 safety and efficacy trial of brimonidine tartrate intravitreal implant in treatment of dry AMD demonstrated that, compared with the sham arm, administration of low- (200 µg) and high-dose (400 µg) inserts of 22-gauge sustained-release brimonidine at baseline and at month 6 results in a statistically significant reduction (18% for low dose, 27% for high dose; n=113) of GA, starting at 3 months and continuing until 12 months after treatment. No significant adverse effects have been reported (NCT00658619). A second phase 2 trial is under way to investigate the efficacy and safety of a new 25-gauge brimonidine insert (400 µg) administered to study eyes on day 1 and every 3 months through month 21 (NCT02087085).
Stem cells can replace damaged cells and are widely explored as a treatment for neurodegenerative disorders.16 A recent study on 4 Asian patients with macular degeneration demonstrated that subretinal transplantation of human embryonic stem cell–derived RPE could improve or at least stabilize visual acuity in patients with dry AMD (n=2) and Stargardt macular dystrophy (n=2). In participants with dry AMD, 1 patient with initial BCVA of 1 letter maintained 2 letters read by the end of the 1-year visit, while the second patient with initial BCVA of 20/320 improved to 20/200 vision. Furthermore, the intensity of central scotoma tested by Goldmann perimetry diminished in the second patient. Enhanced subretinal pigmentation with localized black clumps, development of epiretinal membrane without macular puckering, corneal abrasion, elevated intraocular pressure, and subretinal hemorrhage were reported following the transplantation procedure. However, there was no evidence of adverse proliferation, cancer development, or ectopic tissue formation after 1 year of therapy.17 These results provide increasing hopes for AMD vision recovery following stem cell transplantation techniques. A clinical trial is under way to address the safety of umbilical-derived stem cells in patients with GA (NCT01226628).
CD59 complement factor is a naturally occurring membrane-bound inhibitor of membrane attack complex (MAC), an immune protein that mediates cell lysis by forming pores within the plasma membrane.18,19 There is increased abundance of MAC in the choriocapillaris of aging retina and AMD patients,20,21 prompting investigators to evaluate the role of CD59 in AMD. Indeed, intraocular delivery of an adeno-associated virus vector (AAV2) that expresses a soluble form of membrane-independent CD59 (sCD59) is shown to block MAC deposition and choroidal neovascularization, vascular leakage, and retinal ganglion cell death in a mouse model of diabetic retinopathy.22 Hemera Biosciences Inc. has recently obtained FDA approval to carry out a phase 1 gene therapy trial to evaluate the safety of MAC inhibition via AAV2/sCD59 vectors in participants with dry AMD.
Minocycline is a tetracycline derivative with caspase inhibitory properties that have been shown to have neuroprotective properties in animal models.23 An in vitro study also demonstrated that incubation of primary human RPE cells with minocycline provides protection against oxidative stress.24 A phase 2 trial is evaluating the effects of oral minocycline (100 mg, twice daily) in treatment of AMD-associated GA (NCT02564978). Likewise, another phase 2 trial is recruiting participants to investigate the efficacy of doxycycline (40 mg, daily) in the treatment of GA (NCT01782989).
The Age-Related Eye Disease Study (AREDS) is a randomized, controlled trial that has studied the effects of antioxidants in the progression of advanced AMD. This study investigated the protective effects of high-dose antioxidant vitamins, namely, vitamin C (500 mg), vitamin E (400 IU), and β-carotene (15 mg), as well as zinc (80 mg) and copper (2 mg) supplements. In the 5-year follow-up study, antioxidant vitamins plus zinc formulation reduced the risk of advanced AMD (by 25%) and associated vision loss (by 19%) in patients with at least moderate risk of AMD.25,26 Likewise, a follow-up study showed that AREDS formulation continues to protect against neovascular AMD after 10 years.27
The AREDS2 study investigated the risk of progression to advanced AMD with modifications such as the addition of dietary xanthophyll carotenoids (lutein and zeaxanthin) and omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), elimination of β-carotene, and lowering the dose of zinc supplement (25 mg).28,29 The antioxidants lutein and zeaxanthin, which provide pigment coloration to fruits and vegetables, are highly abundant in the macula.30 Likewise, synthesis of DHA from EPA in the retina is shown to protect photoreceptors from oxidative stress.31 Also, earlier studies suggested a decrease in risk of AMD progression from lutein/zeaxanthin or DHA/EPA dietary supplements, prompting investigators to test the effects of these dietary supplements in the AREDS2 study.32,33
The results of AREDS2 demonstrated that, except in patients with dietary deficiency of lutein and zeaxanthin, addition of lutein/zeaxanthin, DHA/EPA, or both does not decrease risk of AMD progression. Furthermore, no statistical significance exists between high- and low-dose zinc supplements. Finally, formulations that included β-carotene increased the risk of lung cancer in former smokers.28,29 The authors suggested that replacement of β-carotene with lutein/zeaxanthin may be a more appropriate formulation.34
Notably, recent genetic studies have shown that genetic polymorphism in complement factor H (CFH) and age-related maculopathy sensitivity 2 (ARMS2) influences AMD response to antioxidants and zinc supplements. In a study averaging over a period of 10.1 years, patients with CFH-risk alleles benefited from antioxidants alone while supplementation with zinc negated the beneficial effects of antioxidants.35 However, patients with ARMS2-risk alleles had maximum benefit from zinc-containing regimens and a deleterious response from antioxidants. Patients who were homozygous for both CFH- and ARMS2-risk alleles had no benefit from any category of AREDS.35 These results indicate that genetic polymorphism may play a crucial role in the outcome of AMD response to dietary supplements.
The Lutein Antioxidant Supplementation Trial (LAST), a randomized, controlled trial, investigated the effects of lutein (10 mg) on visual acuity of patients with atrophic AMD. Results demonstrated that lutein alone or combined with other antioxidants/minerals improves visual function of patients with atrophic AMD. Nevertheless, the sample size of this trial was relatively small (90 patients) and the authors recommended further studies with a larger population size to clarify the role of lutein in AMD.36 Subsequent studies show that supplementation of 10 mg of lutein increases macular pigment optical density, whereas the effects on BCVA were milder.37,38
Vitamin E is a strong antioxidant and, surprisingly, a randomized trial involving 39,876 participants aged 45 years or older did not find a large benefit from vitamin E supplementation (600 IU on alternate days) compared with the placebo group.39 However, supplementation of nonantioxidant vitamins folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day) significantly reduced the risk of AMD in a large cohort of women (5,442 participants aged 40 years or older) with a preexisting risk of cardiovascular disease.40 These results highlight that pathways other than oxidative stress also play an important role in the progression of AMD.
Zinc assists in the regulation of cell metabolism and plays an important role in oxidative defense.41 A randomized-placebo clinical trial of 40 participants showed that supplementation of zinc-monocysteine (25 mg, twice a day) for 6 months significantly improved visual acuity and contrast sensitivity.42
It has been suggested that statins may alter the pathologic pathway of AMD progression. A randomized, controlled study investigated the effects of simvastatin (40 mg/day) vs placebo on the progression of AMD in 114 patients with bilateral intermediate AMD or unilateral nonadvanced AMD with advanced AMD in the fellow eye. The selected participants had a normal lipid profile with BCVA ≥20/60 in at least 1 eye. Results demonstrated a significant reduction in the risk of AMD progression in patients with bilateral intermediate AMD.43 A similar study demonstrated that atorvastatin (80 mg/daily) in 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits results in regression of drusen deposits and associated vision gain,44 further supporting the protective role of statins in treatment of AMD.
Two previous randomized trials (20 and 99 participants) concluded that oral supplementation of ginkgo biloba for a 6-month duration improved visual acuity in treatment groups.45 Larger sample population size and longer durations of treatment are required to further solidify these findings.
A randomized clinical trial of 25 participants with early AMD showed that oral supplementation of saffron (20 mg/day) over 3 months increased focal electroretinogram (fERG) amplitude compared with the placebo group. Furthermore, fERG thresholds were decreased after saffron supplementation and retinal flicker sensitivity improved. Visual acuity also increased in 20 participants by 1 line, which is a statistically significant difference in comparison to placebo, which had no change in visual acuity.46 Given the small sample size, subsequent trials are required to confirm the clinical significance of saffron supplementation.
Trimetazidine (TMZ) is used in Europe as a second-line therapy for patients with stable angina. This medication is thought to conserve oxygen supply by shifting energy production toward glycolytic pathways, and it reduces cardiac fibrosis via decreased expression of connective tissue growth factor.47 Trimetazidine may help preserve the function of photoreceptors and prevent choroidal neovascularization by improving oxygen supply and choroidal circulation. A European multicenter, randomized, double-blind, placebo-controlled clinical trial studied the effects of oral placebo and oral TMZ (70 mg daily) on the rate of choroidal neovascularization or GA in 1,086 AMD patients. Results demonstrated that TMZ neither prevents choroidal neovascularization nor protects against the progression of GA.48
Emixustat hydrochloride (ACU-4429) is an oral medication that inhibits the RPE65 isomerase enzyme with consequent reduction in the accumulation of toxic vitamin A–based toxins, such as lipofuscin and A2E.51 In a randomized phase 2 clinical trial involving 54 emixustat and 18 placebo participants, 90 days of administration of ACU-4429 (2, 5, 7, or 10 mg once daily) in patients with GA resulted in a suppressed rod photoreceptor sensitivity in a dose-dependent manner. The suppressive effects of ACU-4429, however, were reversible within 7 to 14 days after cessation of the medication.52 Nevertheless, in a recent phase 2b/3 trial, emixustat treatment failed to reduce the rate of lesion growth in GA (NCT01002950). The compound is presently being studied for Stargardt disease. Table 1 summarizes clinical trials of oral medications for AMD.
|MEDICATION||MECHANISM OF ACTION||TRIAL SUBJECTS||OUTCOMES|
|AREDS25||Antioxidant (vitamin C, vitamin E, β-carotene, zinc, copper)||4,757 participants with AMD scales 1 to 4 based on drusen size/area, pigment abnormality, visual acuity, GA, and ocular laterality||25% reduction of progression of intermediate to advanced AMD and 19% reduction in moderate vision loss in a 5-year period; protection against neovascular AMD in a 10-year period|
|AREDS228||Antioxidant (1) AREDS formulation, (2) AREDS formulation minus β-carotene, (3) AREDS formulation with low-dose zinc, (4) AREDS formulation with low-dose zinc and no β-carotene randomized to placebo, lutein/zeaxanthin, DHA/EPA, or both lutein/zeaxanthin and DHA/EPA supplements||4,203 participants with AREDS AMD scales 1 to 4||Lowering zinc dose and eliminating β-carotene does not affect progression to advanced AMD; formulations that include β-carotene increase the risk of lung cancer in former smokers; lutein and zeaxanthin reduce the risk of AMD progression in patients with low dietary intake of these nutrients|
|Lutein38||Antioxidant, abundant in the macula||Meta-analysis of 445 participants||Increased macular pigment optical density with mild improvement in BCVA|
|Vitamin E39||Antioxidant||39,876 female participants aged ≥45 years||No effects on the risk of AMD|
|Vitamins B6, B9, B1240||Improved endothelial function||5,442 female participants aged ≥40 years||Reduced risk of AMD|
|Zinc42||Cofactor for antioxidant and metal-chelating enzymes; increase glutathione||Both treatment and placebo arm enrolling 40 participants with BCVA 20/25 to 20/70, macular drusen, and pigment changes||Improved visual acuity, improved contrast sensitivity, and shortened macular light flash recovery time|
|Statins43,44||Lipid lowering and anti-inflammatory||114 participants with bilateral intermediate AMD or unilateral nonadvanced AMD with advanced AMD in the fellow eye receiving simvastatin; 26 participants with diagnosis of AMD and the presence of many large, soft drusenoid deposits receiving atorvastatin||Reduced risk of AMD|
|Gingko biloba45||Increased blood flow and reduced free radicals||119 dry AMD participants in two separate trials||Improved visual acuity|
|Saffron46||Antioxidant||25 participants with early AMD||Increased fERG amplitude, decreased fERG thresholds, and mild improvement in visual acuity|
|Trimetazidine48||Improved choroidal circulation and oxygen supply||1,086 participants with soft drusen and/or retinal pigment epithelium abnormalities in one eye and choroidal neovascularization in the contralateral eye||Neither prevents choroidal neovascularization or progression of GA|
|Aspirin50||Anticoagulant and anti-inflammatory||Meta-analysis of 177,683 participants||No effects on the risk of AMD|
|Emixustat hydrochloride52||Reduced accumulation of lipofuscin and A2E||72 participants with GA||Suppressed rod photoreceptor sensitivity|
FUTURE DIRECTIONS FOR AMD THERAPY
The treatment for dry macular degeneration continues to be elusive. However, some compounds, such as lampalizumab, seem to be closer to possible approval due to the fact that they have progressed to phase 3 studies. In addition, stem cell therapy seems to have potential for vision stability and recovery. However, there are hurdles that must be addressed, including refinement of cell administration techniques as well as immunosuppression, prior to their approval and widespread adoption. Other therapies may be promising, but only time will tell if they are going to be viable options for treatment of this chronic progressive debilitating disease. These new therapies will provide both a new set of opportuinites and challenges for both patients and physicians. RP
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