Figure 1. Neovascular AMD with subretinal blood
Dr Daini Ong
Professor Robyn Guymer
MBBS PhD FRANZCO FAHMS
Centre for Eye Research Australia, The Royal Victorian Eye and Ear Hospital, Melbourne
Department of Surgery (Ophthalmology) University of Melbourne, Melbourne
Age-related macular degeneration (AMD) is the leading cause of severe, irreversible vision loss in people over the age of 70 years in Australia.1
There are two late forms of AMD in which vision is threatened: neovascular AMD (nAMD) (wet) and geographic atrophy (GA) (dry). Anti-vascular endothelial growth factor (VEGF) has revolutionised the treatment for nAMD. The two currently approved anti-VEGF treatments for nAMD are Lucentis (ranibizumab) and Eylea (aflibercept). Avastin (bevacizumab) is used off-label for the same indication.
The future treatment of nAMD focuses on the development of newer drugs with more ubiquitous blocking actions or with longer duration of action, thereby decreasing the frequency of the injections required. There is as yet no proven treatment for GA; however, several pharmaceutical studies are underway to determine the efficacy of possible treatments.
Neovascular AMD (wet AMD)
In patients who develop nAMD (Figure 1), there is often but not always a sudden blurring or distortion of vision. nAMD contributes to about 10 per cent of all AMD cases and had accounted for 90 per cent of severe vision loss from AMD prior to the era of anti-VEGF agents.2
To understand the mechanism by which anti-VEGF agents work in nAMD, it is useful to briefly review the current understanding of the aetiology of choroidal neovascular membranes (CNV). Abnormal blood vessels originate in the choroid which lies below the retina and supplies nutrients and oxygen to the outer retina. The pathological proliferation, migration and invasion of choroidal vessels, through Bruch’s membrane, into the subretinal space are driven by a complex signal pathway.
VEGF is a key signalling molecule in the initiation of angiogenesis, and is produced by the retinal pigment epithelial (RPE) cells and acts on the endothelial cells. VEGF also increases permeability of the vessels so that the abnormal vessels bleed and leak fluid intraretinally and into the subretinal space, resulting in damage to retinal cells and long-term scarring. Anti-VEGF agents block the actions of circulating VEGFs, thereby reducing the stimulus for abnormal blood vessel growth.
Ranibizumab is an anti-VEGF agent designed for ocular use. It is a fragment of the monoclonal antibody fragment acting on VEGF-A, the most potent VEGF isoform in the pathogenesis of AMD. The landmark ANCHOR and MARINA studies showed that fewer subjects in the ranibizumab group had vision loss from baseline compared to the sham control group (90-95 per cent vs 60 per cent, respectively).3,4
A significantly smaller number of patients in the ranibizumab group had severe vision loss comparing to the sham control group (one per cent vs 15 per cent). More people in the ranibizumab group gained vision compared to the sham control group (25-40 per cent vs six per cent, respectively). On average, the ranibizumab treatment group gained 7-11 letters of vision, while the control group lost an average of 10 letters. This translated to functional improvements for patients and improved quality of life.
Aflibercept is a fusion protein that imitates VEGF receptors. It binds with high affinity with multiple agents in the VEGF family such as VEGF-A, VEGF-B and placental growth factors. It consequently inhibits activation of the receptors and stops the undesired effects of angiogenesis. The evidence for its use in AMD is from the VIEW1 and VIEW2 studies. These studies demonstrated that with two doses (0.5 mg and 2 mg) and a two-dosing regimen (four-weekly or eight-weekly), each treatment arm was not inferior to monthly ranibizumab.5
Bevacizumab is a full-size monoclonal antibody which binds to VEGF. It was designed to stop angiogenesis in various cancers. Although it was not specifically designed for the eye and its use is off-label, it is effective in the eye. The CATT study was a head to head comparison of ranibizumab and bevacizumab.6 With the same treatment regimen, bevacizumab was not inferior to ranibizumab for nAMD treatment. When unsubsidised, bevacizumab is less expensive than other anti-VEGF agents and as such is offered alongside the approved therapeutic agents.
Figure 2. A patient receiving an intravitreal injection
Methods of administration and risks
All the anti-VEGF agents are administered as an injection into the vitreous under an aseptic technique (Figure 2). It is a 15-minute procedure commonly performed in treatment rooms or the ophthalmologist’s rooms. Topical ± subconjunctival anaesthesia is used at the time of injection to reduce discomfort. After the injection, it is common for the patient to have some ocular discomfort, conjunctival haemorrhage and vitreous floaters. The risk of endophthalmitis, non-infectious uveitis, retinal tear and cataract are rare but can be devastating for the long-term health of the eye.
As we become more familiar with the use of anti-VEGF medications, clinicians have tried to individualise the dosing schedule based on treatment responses. Common treatment protocols practised include:
• strict monthly treatment
• treat as required (PRN)
• treat and extend.7
The strict monthly treatment schedule is based on initial pharmaceutical studies in which patients were injected every month regardless of their response to the treatment. No active management decision needed to be made in this approach as all patients received the same treatment schedule.
Treat as required is an alternative treatment protocol. In the setting, after initial disease stabilisation, the patient is reviewed every month to check for disease activity and is injected only when there is clinical or OCT evidence of disease activity.8 If no disease activity is noted, the patient is not injected and is reviewed again in another month. This protocol usually results in more visits but fewer injections than the treat and extend protocols.
Treat and extend is widely practised in Australia. The principle of this treatment protocol involves initial monthly treatment with anti-VEGF agents until there is no further improvement in the patient’s vision and no signs of activity are noted: fresh haemorrhage, or intraretinal or subretinal fluid as determined on high resolution optical coherence tomography (OCT). The treatment interval is then extended by 1-2 weeks each visit. At each visit, the clinical and OCT signs of disease activity are monitored. If there is a recurrence of disease activity, the treatment interval is then shortened.
Over time we can individualise treatment and achieve an optimal treatment interval for each patient depending on their response to the administered drug. The treat and extend protocol reduces the number of visits compared to a monthly visit schedule. One can consider the treat and extend protocol as proactive, aiming to prevent the eye from reactivating, and the PRN protocol as reactive, with people receiving an injection only when the disease is active.
Future treatment for neovascular AMD
The new treatments under investigation for nAMD falls under two objectives: either to increase the duration between treatments or to have more effective treatments, which translates to more visual gains for the patient. Below are some of the studies underway in nAMD.
• HAWK study (Alcon)
The phase 3 study is investigating RTH258, a single chain antibody fragment, comparing its efficacy to aflibercept. RTH258 binds to VEGF-A with high affinity. The aim is to have a longer duration of action with three-monthly interval treatments, thus reducing the treatment burden.
• Fovista study (Ophthotech)
The phase 3 study is investigating an anti-platelet-derived growth factor (anti-PDGF). It targets another signal in the pathway of angiogenesis. With the promise of synergistic action by combining with an existing anti-VEGF agents, it promises to increase visual gain compared to the use of anti-VEGF agent alone.
• Sequoia study (Allergan)
The phase 3 trial is investigating abicipar, which is another antibody that binds to VEGF-A. It claims that with its small size, high potency and long intravitreal half-life, it would result in less frequent injections than ranibizumab.
Figure 3. Advanced geographic atrophy
Geographic atrophy (Figure 3), although having a slower onset than nAMD, is still associated with significant and permanent vision loss. It is four times more common than nAMD in people over the age of 85 years.9 Clinically, it is identified as areas of macular depigmentation with underlying choroidal vessels visible. Histologically, it corresponds to atrophy of RPE and photoreceptors. These changes often initially start in the peri-foveal region and as the disease advances it encroaches on the fovea, and the patient experiences central vision loss.
There is currently no available treatment to slow the progression of GA; however, new treatments are starting to be investigated. The end goal of these ongoing studies is to measure a decrease in the rate of growth of GA compared to the control subjects. To reliably measure the area of GA and document change, only patients with reasonably large areas of GA qualify for enrolment.
• Lampalizumab (Hoffmann-La Roche)
This is a phase 3 study of lampalizumab, a drug that acts to inhibit the complement pathway. It is also administrated in the form of intravitreal injections, the end point is to assess its effectiveness in slowing GA progression.
• BEACON study (Allergan)
This is a phase 2 study of brimonidine, a selective alpha-2-adrenergic agonist currently used as topical therapy for glaucoma. It is postulated to have neuroprotective properties via the activation of the alpha-2-adrenoceptor and inhibiting apoptosis, thereby slowing the progression of GA.
• FILLY study (Apellis Pharmaceuticals)
The phase 2 study is investigating APL-2 therapy which acts to inhibit the complement pathway. It is under trial for its safety and effectiveness in stabilising the size of GA. The subjects receive the injection every four to eight weeks.
There has been a revolution in the treatment outcomes for people with nAMD. In the past 10 years, the anti-VEGF treatments have more than halved the rates of blindness from this complication.10 For the first time in the treatment history of nAMD, improvement in vision is a possibility. The future of nAMD treatment holds promise of agents that work more effectively to improve vision and have potentially longer duration of action. For GA, multiple new agents are already in phase 2 or 3 studies with the aim of slowing the progression of GA.
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