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Promising options for AMD

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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.

140-Figure -2.-Intermediate -AMD---large -drusen _OL
Intermediate AMD, large drusen

140-Figure -3-OL
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.

Wet AMD

 

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.

Newer anti-VEGF

 

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

Combination treatments

 

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

Other options

 

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.

140-Figure -4_OL
Neovascular AMD

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

Conclusion

 

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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