Recent Advances in the Management of Age-related Macular Degeneration: What to Expect Over the Next Few Years
Report from the 2017 Annual Meeting of the American Academy of Ophthalmology (AAO)
New Orleans, Louisiana November 10-14, 2017
By Jason Noble, MD, FRCSC
In the past decade, significant advances have been made in the management of age-related macular degeneration (AMD). More recently, novel therapeutic approaches have demonstrated promising results in late-stage clinical development, with improved treatment of neovascular AMD and innovative approaches for non-neovascular AMD on the horizon. In addition, new imaging modalities offer improved visualization of retinal structures that can offer biomarkers indicative of disease activity and progression. This issue of Ophthalmology Scientific Update summarizes the key findings and discussions of the therapies and novel imaging modalities introduced at the 2017 American Academy of Ophthalmology meeting and accompanying Retina Subspecialty Day.
The development of vascular endothelial growth factor (VEGF) inhibitors in the mid-2000’s heralded a new age in the management of neovascular (“wet”) age-related macular degeneration (AMD). In the ensuing years, clinical research and real-world experience allowed clinicians to further individualize anti-VEGF therapies to optimize outcomes and reduce the incidence of blindness from neovascular AMD worldwide. Despite this remarkable success, however, numerous questions remain regarding the underlying pathophysiology and management of this serious, vision-threatening condition. Furthermore, a large unmet need remains in the management of non-neovascular (“dry”) AMD, affecting 85%–90% of patients; prophylactic supplementation with a combination of anti-oxidants and zinc remains the only proven therapeutic approach. Considerable progress has also been made with respect to visualization techniques, which allows for a better understanding of the pathophysiological processes underlying AMD and can help direct research and treatment towards particular stages of the disease.
The Complement Pathway as a Potential Therapeutic Target
for Geographic Atrophy (GA)
Progression of non-neovascular AMD into GA is associated with severe vision loss. The degenerative process includes progressive loss of areas of the retinal pigment epithelium (RPE), photoreceptors, and underlying choriocapillaris. Loss of visual function secondary to GA is irreversible and often bilateral, with 50% of individuals developing GA in the fellow eye within 7 years of the initial GA diagnosis. As such, GA presents a significant public health concern. Currently, no therapeutic interventions are available for the prevention or treatment of GA; however, several agents are being evaluated in clinical trials, many of which target the complement cascade. The complement cascade is the part of innate immune system that can cause inflammation and cell death. Dysregulation of the complement cascade has been associated with the development of GA,[3-5] and complement inhibition has been identified as a potential modality for therapeutic intervention. For example, lampalizumab, an antibody designed to target complement factor D, showed promising results in the Phase II MAHALO trial, especially in complement factor I (CFI) risk-allele carriers, in reducing the rate of progression of GA secondary to AMD. Based on these results, 2 identically-designed Phase III trials were designed: SPECTRI (NCT02247531) and CHROMA (NCT02247479). The results of the SPECTRI trial were presented at AA0 2017 by Jeffrey S. Heier, MD. Unfortunately, the primary endpoint of reducing progression of GA lesion area size, as evaluated by fundus autofluorescence (FAF), was not met. Roche has since issued a statement indicating similar results were demonstrated for CHROMA. One of the potential explanations, and a source of ongoing debate regarding the treatment of GA associated with dry AMD with complement-targeting therapies, is whether treatment must be initiated at an early stage in the disease in order for the therapy to work. Irrespective of the lacklustre results from these large trials, a more in-depth evaluation of the data is underway to help better understand the clinical underpinnings of GA and to help direct future research.
While the results from the aforementioned Phase III trials were disappointing, the results of the Phase II FILLY trial [NCT02503332] with altered peptide ligand – 2 (APL-2) presented by David S. Boyer, MD, showed some promise.8 APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol (PEG) polymer that binds specifically to C3 and C3b, effectively blocking all 3 pathways of complement activation (classical, lectin, and alternative).[5,8] The FILLY trial is a multicentre, randomized, single-masked, sham-controlled clinical trial conducted at 40 clinical sites, located in the United States, Australia, and New Zealand. Unlike with lampalizumab, patients treated with APL-2 do not need to undergo biomarker (CFI) testing. In the study, APL-2 was administered as an intravitreal injection in the study eye monthly or every other month for 12 months, followed by 6 months of monitoring after the end of treatment. Eyes were evaluated for GA progression by FAF. The trial met its primary endpoint with APL-2 significantly reducing GA lesion growth (Figure 1). However, no differences were observed in visual outcomes between the sham and treatment groups and furthermore APL-2 appeared to increase risk of new-onset wet AMD (Table 1). A dose-related increased risk of endophthalmitis was also noted in patients treated with APL-2 compared to sham (2.3% in APL-2 monthly versus 1.3% in APL-2 every other month versus 0% in sham). Thus, although these preliminary results are encouraging, the concerns regarding the increased incidence of neovascular AMD and endophthalmitis may limit the clinical feasibility of this agent.
Figure 1: FILLY trial primary endpoint: reduction in GA lesion growth from baseline to Month 12
GA = geographic atrophy; APL = altered peptide ligand; CFI = complement factor I; LS = least square; SE = standard error
Table 1: New-onset wet AMD observed in FILLY trial
AMD = age-related macular degeneration; CNV = choroidal neovascularization
Dr. Boyer also provided an overview of other emerging treatments for dry AMD. Among these, complement inhibitors such as CLG561 and LFG316 (factor 5 inhibitors developed by Novartis), POT-4 (C3 inhibitor, Potentia Pharmaceuticals), eculizumab (C5 inhibitor, Soliris/Alexion Pharmaceuticals) and ARC1905 (C5 inhibitor, Ophthotech) are being evaluated. Brimonidine (Alphagan®), approved as an antiglaucoma medication, is also being investigated as a possible neuroprotective agent. Targeting inflammatory mechanisms using agents such as Iluvien®, the fluocinolone acetonide intravitreal implant used in diabetic macular edema, is also being actively researched.
Emerging Options for Wet AMD
Since the introduction of anti-VEGF therapy for the treatment of wet AMD, retina specialists have sought ways to optimize visual outcomes while reducing the treatment frequency to improve convenience for patients and their caregivers, improve safety, and reduce costs to the healthcare system. The treat and extend (TAE) approach commonly used by clinicians worldwide presents such an attempt at reducing the number of injections administered while maintaining the visual acuity (VA) gains achieved vis à vis regular, fixed-interval dosing.
Mark Gillies, MBBS, PhD, described treatment patterns, disease activity, and visual outcomes during the maintenance phase of the TAE protocol applied to 3257 wet AMD patients in Australia, of whom 2220 had ≥12 months of follow-up from the first grading of inactivity. The majority (82%) of patients received ranibizumab, with 17% treated with aflibercept, and 2% receiving bevacizumab. VA was generally well maintained during the study period (2006–2014). The mean change in VA from baseline at the start of maintenance was +4.3 letters, and the overall mean change in VA at 3 years follow-up from the initiation of the maintenance phase was -1.5 letters. Extension of treatment intervals from 3 to 4 months was associated with a substantially increased risk of reactivation (recurrence of fluid, loss of vision); 50% of eyes reactivated within the first year of maintenance, and the most common interval at which disease reactivation first occurred was 8 weeks (17.4% of eyes). This study provides real-world data and it is also very applicable to Canadian practice where retina specialists tend to follow similar treatment patterns as their Australian colleagues. The trial also highlights a current unmet need in the treatment of AMD – a therapeutic approach with efficacy beyond 2 months.
It is anticipated that a number of novel agents may be able to fulfil some of the current treatment gaps in wet AMD. Emerging therapies for wet AMD target several different pathways:
Extracellular VEGF pathway: abicipar pegol and brolucizumab are in Phase III clinical development and OPT-302 in Phase II
Platelet derived growth factor (PDGF) pathway: pegpleranib and rinucumab failed to demonstrate additional benefit in best corrected (BC) VA in Phase III and II trials, respectively, and are no longer being studied
Tyrosine kinase pathway: multiple agents in Phase II development
Multiple pathways: OHR-102 in Phase III clinical trial
Brolucizumab (RTH258) is a humanized single-chain antibody fragment (Figure 2). Due to their small size, enhanced tissue penetration, rapid clearance from systemic circulation, and drug delivery characteristics, single-chain antibody fragments are favourably pursued in drug development.[12-19] In preclinical studies, brolucizumab inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction.[20-22]
Figure 2: Comparison of various anti-VEGF molecules.[12-19]
a Molecular weight expressed as a range to reflect glycosylation status.
CH, constant heavy; CL, constant light; Fab, fragment, antigen-binding; Fc, fragment crystallizable; IgG, immunoglobulin G; VEGFR, vascular endothelial growth factor receptor; VH, variable heavy; VL, variable light.
Brolucizumab versus aflibercept for neovascular AMD
The HAWK (NCT02307682) and HARRIER (NCT02434328) studies investigated the efficacy and safety of intravitreal brolucizumab in comparison to aflibercept in patients with neovascular AMD.23 The HAWK trial was conducted in North, Central, and South America, Israel, Australia, New Zealand, Japan, and across several Canadian centres. HARRIER was conducted in Europe and Asia. Following the 3-month loading phase, patients received brolucizumab 6 mg (with a 3-mg dose also tested in HAWK) every 12 weeks (q12w) with an option to adjust to a q8w dosing interval, based on masked disease activity assessments at defined visits. Aflibercept 2 mg was administered according to its label with q8w dosing. The primary efficacy endpoint of the trials was noninferiority of brolucizumab to aflibercept according to the mean change in BCVA from baseline to Week 48. Secondary endpoints included the proportion of patients on a q12w interval at Week 48, the average mean change in BCVA over the period between weeks 36 and 48, and anatomical parameters.
Brolucizumab met the noninferiority endpoint in both trials (Figure 3). These results were achieved while a majority of brolucizumab patients (57% in HAWK and 52% in HARRIER) were maintained on a q12w dosing interval through the 48-week study period. Furthermore, patients treated with brolucizumab (6 mg) had superior reductions in retinal fluid when compared to aflibercept (Table 2). At the predefined data point of Week 16, the treatment assessments for brolucizumab and aflibercept were identical, which provided an opportunity to observe how both drugs performed in a matched comparison. Significantly fewer patients in the brolucizumab group had active disease at Week 16 versus aflibercept: 23.5% of brolucizumab 6 mg patients versus 33.5% of aflibercept patients in HAWK, and in 21.9% of brolucizumab patients versus 31.4% of aflibercept patients in HARRIER (P=0.002 for both).
Figure 3: HAWK and HARRIER: primary endpoint – change in BCVA
BCVA = best-corrected visual acuity
Table 2: Reduction in retinal fluid in the HAWK and HARRIER trials
SRF = subretinal fluid; IRF = intraretinal fluid; RPE = retinal pigment epithelium
Brolucizumab safety was comparable to aflibercept with the overall incidence of adverse events similar across all treatment groups in both studies. In both trials, ocular adverse events were similar in all arms with no notable differences between any of the study arms. The incidence of arterial thrombotic events was 3.9%, 2.5%, and 5.5% for brolucizumab 3 mg, brolucizumab 6 mg, and aflibercept, respectively, in HAWK, and 1.6% and 1.1% for brolucizumab 6 mg and aflibercept, respectively, in HARRIER.
Thus, these results provide support for similar and possibly superior anatomical outcomes with brolucizumab compared to aflibercept when dosed according to the study protocol. As a new agent, brolucizumab may also represent an alternative for patients not responding adequately to other currently available anti-VEGF agents such as those with persistent edema.
Advances in Imaging Modalities: Clinical Application
Several presentations at AAO 2017 discussed the clinical utility of optical coherence tomography angiography (OCT-A).[24-27] This novel and noninvasive modality utilizes movement disparities in the capturing of consecutive OCT scans to identify vascular structures that exhibit sufficient blood flow characteristics, allowing the imaging of the retinal and choroidal circulation in high resolution without the use of extraneous dyes. OCT-A has been demonstrated to be helpful in the diagnosis and management of multiple retinal disorders, such as AMD, choroidal neovascularization (CNV), diabetic retinopathy, retinal vascular occlusion, and central serous chorioretinopathy. However, limited clinical trial data on the utility of OCT-A exist and clinical treatment guidelines do not incorporate OCT-A findings into their algorithms. Similar to the initial period in the introduction of OCT itself, it will take some time to properly correlate OCT-A images to histopathological findings and thereby fully establish OCT-A as a clinically relevant test that clinicians are comfortable interpreting. Among the challenges identified by Karl Csaky, MD, are difficulties in image interpretation and analysis (i.e., distinguishing between CNV from overlying retinal vasculature projection artifacts), the time required to analyse and interpret results, limited data on its utilization in the context of anti- VEGF therapy, and interpretation of clinical significance. There is also the economic consideration that OCT-A tests are not yet reimbursed by most insurance providers. However, as the technology evolves and improves, it is anticipated that many, if not all, of these challenges will be overcome and OCT-A will become a mainstream diagnostic tool in the evaluation of many retinal conditions.
FAF, as described by David Sarraf, MD, is a noninvasive imaging technique that detects fluorophores, naturally occurring molecules that absorb and emit light of specified wavelengths. Lipofuscin is the predominant ocular fluorophore in the retinal pigment epithelium. Multiple commercially available imaging systems, including the fundus camera, the confocal scanning laser ophthalmoscope, and ultra-widefield imaging devices, are available to the clinicians (Table 3). As it may detect abnormalities beyond those observed on fluorescein angiography or OCT, FAF can be used to elucidate disease pathogenesis, form genotype-phenotype correlations, diagnose and monitor disease, and evaluate novel therapies. FAF is now an important tool for the identification of specific disorders and abnormalities such as AMD, macular dystrophies, retinitis pigmentosa, white dot syndromes, and in monitoring for retinal drug toxicity (such as screening for hydroxychloroquine retinopathy).
Table 3: Fundus autofluorescence: instruments and images
Ursula Schmidt-Erfurth, MD, discussed the use of OCT imaging to identify early pathomorphological changes and predict AMD progression. The most critical features associated with the disease progression include outer retinal thickness, hyperreflective foci, and drusen area. Identification of these features can provide clinicians with an idea of disease activity and likelihood of progression. These features may also be important from a screening perspective and could become part of telemedicine in the future.
Ongoing developments and advances in imaging techniques and modalities continue to deepen our understanding of the underlying pathophysiological features of AMD upon which novel targeted therapeutic options are being developed. With many novel drug candidates in development for both neovascular and non-neovascular AMD, it is expected that we will witness a significant influx of novel agents which will expand the therapeutic armamentarium available for treating retinal disease, and in turn provide our patients with better visual outcomes.
Dr. Noble is Assistant Professor and Associate Alumni Director, Department of Ophthalmology & Vision Sciences, University of Toronto and Sunnybrook Health Sciences Centre.
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Disclosure Statement: Dr. Noble has served as an advisory board member and speaker for Novartis, Bayer, Alcon, and Allergan. He wishes to thank Radmila Day for her assistance with the preparation of this manuscript.
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