Geographic atrophy Image: Dr Stephen Cohen, RetinaGallery.com
Dr Amy Cohn
MBBS(Hons) MMed FRANZCO
Visiting Medical Officer, The Royal Victorian Eye and Ear Hospital
Senior Research Fellow, Centre for Eye Research Australia
As eye health-care professionals, we are aware of the significant burden age-related macular degeneration (AMD) is on our community. It can be detected in one in seven (14 per cent) patients older than 50 years, and this increases to 25 per cent by age 90.1,2
AMD represents one of the major causes of vision impairment in Australia. Fortunately, in the past decade we have been able offer patients with wet (neo-vascular) AMD treatment with anti-vascular endothelial growth factor (VEGF) agents and this has completely altered the therapeutic landscape. Not only have we been able to prevent worsening of vision, in some cases we are now able to improve vision.3-5 This has led to an increase in both doctor and patient expectations regarding what we can hope to achieve with AMD treatment.
Despite these wonderful advances, there is still very little we can offer patients who are diagnosed with early, intermediate or advanced dry AMD.
The role of vitamin and antioxidant supplementation was established in the AREDS 1 study, which suggested that for patients with intermediate drusen, one large drusen, non-central geographic atrophy, advanced AMD or loss of vision in one eye due to AMD, there could be a benefit from specific supplements.6 In addition, secondary exploration of the AREDS 2 study showed that there may be some benefit in replacing beta-carotene with lutein/xexanthine for prevention of AMD progession.7
One other area that continues to be an issue is the ‘plateau’ effect we see after initiation of anti-VEGF for wet AMD. We are familiar with the graph of initial rapid improvement in visual acuity and macular thickness, which is then followed by a period of maintenance.3-5 In addition, extension studies, treat and extend regimes, and PRN dosing—regardless of which agent is used—show a gradual loss of efficacy.8,9 This has led to increasing interest in how we can better use anti-VEGFs or develop alternatives to offer sustained visual acuity gains for our patients.
Early dry AMD
Outside of vitamin and antioxidant supplementation, we have nothing to offer patients with dry AMD.
I am involved in a randomised controlled trial currently being conducted at the Centre for Eye Research Australia (CERA). The LEAD Study (Laser for Early Age-related Macular Degeneration) is looking at the Ellex 2RT nanosecond laser versus sham in patients with bilateral high-risk drusen and RPE change.
Our pilot study of 50 patients showed that with the nanosecond laser the drusen load decreased in the treated eye and macula function improved.10,11 This retinal rejuvenation has led to the formal international, multicentre trial underway with preliminary results hopefully available towards the end of the year. With the help of referring optometrists, CERA has recruited almost 300 patients for the trial.
|Intermediate AMD, large drusen
|Drusen on Spectral domain OCT
Late dry AMD
Late dry AMD affects five million people worldwide with no current treatment available. There are several studies underway both in Australia and abroad looking at treatment options. Although the underlying patho-physiological mechanisms are not completely understood, one key area of research is prevention of photoreceptor and RPE cell loss via neuro-protection, oxidative damage prevention and visual cycle modification.
One such study is a Roche-sponsored trial looking at lampalizumab versus sham in patients with bilateral geographic atrophy due to AMD. Lampalizumab is an antigen binding fragment (Fab) of a humanised monoclonal antibody directed against complement factor D. Complement factor D is an enzyme involved in activation of the alternate complement pathway. Several studies have suggested that inflammation and increased complement activation play a direct role in AMD development and progression.12-14 In addition, certain genetic polymorphisms in complement pathway genes determine a patient’s likelihood of developing AMD.15-17
Phase 2 study results (the MAHALO study) showed that patients treated with lampalizumab showed a reduction in progression of geographic atrophy on fundus autofluorescence and this was even more significant in patients with a certain CFI biomarker (clinicaltrials.gov identifier NCT01229215).
One of the major issues with current anti-VEGF treatment is the frequency of injections required to maintain visual acuity. New posterior segment delivery devices (PSDD) for both wet and dry AMD hope to afford patients longer drug duration and therefore reduce the number of retreatments.
Another trial for geographic atrophy due to AMD is sponsored by Allergan and is investigating a new PSDD to administer brimonidine into the vitreous cavity. Brimonidine is an alpha-2-selective adrenergic agonist and in various studies has been shown to be neuro-protective to photo-receptor/RPE cell complexes.18-20 The hope is that in a sustained release formula injected into the vitreous, brimonidine will slow the progression of geographic atrophy (Clinical.Trials.gov identifier NCT00658619).
Another neuro-protective agent that uses PSDD technology being studied is ciliary neuro-trophic factor (CNTF). CNTF has slowed photoreceptor cell loss in several models of retinal degeneration.21,22 Renexus (formerly NT501) uses encapsulated cell technology with live human RPE cells that are genetically modified to secrete CNTF for up to two years. A Phase 2 trial that studied low dose CNTF versus high dose versus sham showed that at 12 months follow-up, there was a statistically significant increase in retinal thickness in the low and high dose groups compared to sham. In addition, CNTF appeared to preserve vision. There was a 0.8 letter gain in the high dose CTNF group compared with a loss of 9.7 letters in the combined low dose and sham groups. However, there was no prevention of progression of geographic atrophy on fundus autofluorescence (FAF) imaging in the treatment arms.23 A Phase 3 study is planned.
As clinicians continue to observe the significant treatment burden regular anti-VEGF treatment places on the patient and the plateau effect of therapy, research continues apace to address this. For wet AMD the current areas of research include better anti-VEGF agents, combination treatments that are additive or synergistic in their effects and longer-acting delivery systems touched on previously.
ESBA-1008 is a single chain antibody fragment that is significantly smaller than current anti-VEGF agents and will hopefully be able to be packaged into a sustained delivery device. In addition, it is a pan-VEGF inhibitor that has much greater binding capacities than current molecules.
A Phase 2 study comparing ESBA-1008 to Lucentis shows that it was non-inferior at the two higher doses and there was a trend to increased efficacy at the highest dose. In addition, there was a 30-day difference in the time needed to re-treat, which is of obvious benefit to patients on monthly injection regimes.24
Designed ankyrin repeat proteins (DARP-ins) are genetically engineered small molecular weight proteins that have a higher affinity for VEGF-A binding sites than antibodies or antibody fragments. A current Phase 2 study is underway comparing them to Lucentis.
Conbercept is a recombinant fusion protein that combines extra-cellular domains of VEGFR1 and 2 with the Fc region of human immunoglobulin. It is able to target multiple isoforms of VEGF and is already approved in China for treatment of wet AMD.25
Much of the early work in this area was done by our oncology colleagues who identified the way in which neo-vascular complexes develop in tumours. Sprout or tip cells lead the growth of tumour vasculature. The tip cells secrete platelet derived growth factor (PDGF) and VEGF which recruits pericytes to cover and protect the neo-vascular complex. The tips themselves are not protected by pericytes and therefore are the only part vulnerable to anti-VEGF agents.26
When anti-VEGF treatment is initiated, it is presumed the tip cells die but the underlying neo-vascular membrane remains. One new agent, Fovista, is a pegylated aptamer against PDGF and prevents PDGF binding to pericyte receptors. This renders the new vessels more susceptible to effects of anti-VEGF agents. Phase 2 studies showed that combination Lucentis/Fovista was superior to Lucentis monotherapy (ClinicalTrials.gov identifier NCT01089517) and Phase 3 studies are underway.
Squalamine (OHR-102) binds to calmodulin to inhibit downstream activation of VEGF, PDGF and basic fibroblast growth factor. Is has been developed as an emollient eye-drop. Current Phase 2 studies are comparing baseline Lucentis plus PRN Lucentis with Lucentis and BD Squalamine plus PRN Lucentis.
A Phase 3 study has also been approved. Interim analysis from the Phase 2 IMPACT study showed there was an improvement in visual acuity in the combination group compared with Lucentis monotherapy.27
The INTREPID study is a randomised controlled trial to assess safety and efficacy of low voltage, external beam stereo-tactic radiotherapy (STR) in patients with neovascular AMD. Patients enrolled were not treatment-naïve and had to have had three or more anti-VEGF injections in the preceding 12 months.
The primary outcome was to track the number of PRN Lucentis injections over 52 weeks. All patients had baseline Lucentis and then PRN Lucentis defined by set criteria. SRT was associated with 26 per cent reduction in the number of anti-VEGF treatments over the two-year follow-up.28
Research into all forms of AMD continues rapidly. While this is not an exhaustive review of all agents currently being investigated, it does provide a snapshot of the exciting times ahead. One hopes that we will soon have options to treat our patients at all stages of AMD successfully and safely.
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- Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 1995; 102: 10: 1450-1460.
- Kaiser PK, Blodi BA, Shapiro H, Acharya NR. Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007; 114: 10: 1868-1875.
- Kaiser PK, Brown DM, Zhang K, Hudson HL, Holz FG, Shapiro H et al. Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol 2007; 144: 6: 850-857.
- Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology; 121: 1:193-201.
- Age-Related Eye Disease Study Research Group et al. 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: 10: 1417-1436.
- Chew EY, Clemons TE, Sangiovanni JP, Danis RP, Ferris FL 3rd, Elman MJ et al. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol 2014; 132: 2: 142-149.
- Singer MA, Awh CC, Sadda S, Freeman WR, Antoszyk AN, Wong P et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 2012; 119: 6: 1175-1183.
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- Guymer RH, Brassington KH, Dimitrov P, Makeyeva G, Plunkett M, Xia W et al. Nanosecond-laser application in intermediate AMD: 12-month results of fundus appearance and macular function. Clin Experiment Ophthalmol 2014; 42: 5: 466-479.
- Jobling AI, Guymer RH, Vessey KA, Greferath U, Mills SA, Brassington KH et al. Nanosecond laser therapy reverses pathologic and molecular changes in age-related macular degeneration without retinal damage. FASEB J 2015; 29: 2: 696-710.
- Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002; 134: 3: 411-431.
- Anderson DH, Radeke MJ, Gallo NB. The pivotal role of the complement system in ageing and age-related macula degeneration: hypothesis revisited. Prog Retin Eye Res 2009; 29: 2: 95-112.
- Charbel Issa P, Chong NV, Scholl HPN. The significance of the complement system for the pathogenesis of age-related macular degeneration - current evidence and translation into clinical application. Graefes Arch Clin Esp Ophthalmol 2011; 249: 2: 163-174.
- Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 2005; 102: 20: 7227-7232.
- Hageman GS, Hancox LS, Taiber AJ et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 2006; 38: 8: 592-604.
- Baird PN, Islam FM, Richardson AJ, Cain M, Hunt N, Guymer R. Analysis of the Y402H variant of the complement factor H gene in age-related macular degeneration. Invest Ophthalmol Vis Sci 2006; 47: 10: 4194-4198.
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- Lai RK, Chun T, Hasson D, Lee S, Mehrbod F, Wheeler L. Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat. Vis Neurosci 2002; 19: 2: 175-185.
- WoldeMussie E, Ruiz G, Wijono M, Wheeler LA. Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest Ophthalmol Vis Sci 2001; 42: 12: 2849-2855.
- Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM. Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 1990; 347: 6288: 83-86.
- LaVail MM, Yasumura D, Matthes MT, Lau-Villacorta C, Unoki K, Sung CH, et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 1998; 39: 3: 592-602.
- Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ, Fullmer KR, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA 2006; 103: 10: 3896-3901.
- Dugel PU. Results of ESBA 1008, a single-chain antibody fragment for the treatment of neovascular AMD. American Society of Retinal Specialists. San Diego, CA, 2014.
- Li X, Xu G, Wang Y, Xu X, Liu X, Tang S et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study. Ophthalmology 2014; 121: 9: 1740-1747.
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- Pecen PE, Kaiser PK. Current phase 1/2 research for neovascular age-related macular degeneration. Curr Opin Ophthalmol 2015; 26: 3: 188-193.
- Jackson TL, Chakravarthy U, Slakter JS, Muldrew A, Shusterman EM, O’Shaughnessy D et al. Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study. Ophthalmology 2015; 122: 1: 138-145.