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Feature

Mapping Macula: The fight against blindness and vision loss

02/05/2019By Myles Hume
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This May, Australia’s advocates for macular disease are increasing their efforts to seize upon the MDFA’s month-long national awareness campaign. MYLES HUME uncovers the latest work to fight this notorious, sight threatening condition.

May is Macula Month; a 31-day national campaign during which the Macular Disease Foundation Australia (MDFA) and its community focus on reducing incidence of blindness and vision loss related to macular disease.

The statistics behind macular disease and its various forms are well documented, yet when aggregated paint a daunting picture of the enormous challenge facing the eyecare sector.

It is estimated that some 8.5 million Australians over the age of 50 are at risk of the disease, while more than 1.7 million people demonstrate evidence of it. Moreover, age-related macular degeneration (AMD) alone is the leading cause of blindness and severe vision loss in Australia, accounting for 50% of blindness. Diabetic retinopathy (DR) is the main cause of preventable blindness among the country’s working-age population.

Although questions remain over the sustainability of the current care model, Australia classes itself as a global leader in addressing macular disease. Specific praise has been given to research, early detection rates and treatment outcomes.

Clinically, Australia is home to new laser and drug therapies that have the potential to dramatically strengthen the treatment portfolio for neovascular and early forms of the disease. Meanwhile, local research institutions are harnessing the capabilities of stem cells, leading to the development of gene-altering drugs and ocular tissue replacement therapies.

While the outlook is promising, Australia’s macular disease community is faced with the ever-present dilemma of determining how limited health resources should be distributed most efficiently to attain best outcomes for patients.

As such, the MDFA has initiated a conversation with the publication of its new National Strategic Action Plan for Macular Disease, a project designed to map a clear path forward towards improving areas of research, policy, treatment and patient support.

With this in mind, Insight drills down into the MDFA plan, and asks the nation’s foremost macular disease experts and treatment companies to assess the current state of play, and detail their latest work in the collective fight against macular disease.

MDFA – Action plan

Prepared by the MDFA for the Federal Government, the newly-released National Strategic Action Plan for Macular Disease is the first document of its kind produced specifically for macular disease in Australia.

A blueprint designed to reduce the impact of macular disease by identifying effective, evidence-based priority ‘areas of action’, the plan also aims to improve the coordination of resources across all levels of government.

Its launch was timed to coincide with the Federal Government’s announcement of a $3 million investment to help increase awareness of macular disease risk factors, and provide health professionals with information for macular degeneration management.

Together, they mark another significant achievement for the MDFA, which also celebrated the listing of the medications Ozurdex and Lucentis to the Pharmaceutical Benefits Scheme last October, seeing an additional 4,500 patients gain access subsidised care.



"These action points will help reduce – and ideally prevent – the economic, social and emotional costs of vision loss"
Dee Hopkins, CEO at MDFA

The MDFA’s action plan identifies 44 ‘areas for action’ across four categories; prevention and early detection; treatment; patient support; and data and research.

The plan highlights the need for improved macular disease education among the general public through new and existing campaigns. Greater understanding among health professionals was also deemed necessary. Citing organisations it needs to improve its relationships with, the MDFA pointed to Optometry Australia, GPs, diabetes orgainsations, the Pharmacy Guild of Australia and other public health entities, including tobacco and dietary bodies.

Of the most notable points, the MDFA recommended the development of a nationally-endorsed evidence-based set of clinical guidelines for the management of AMD, along with a review and update of the 2008 National Health and Medical Research Council Guidelines for the management of diabetic retinopathy.

Interestingly, it also expressed a desire to pursue Pharmaceutical Benefits Scheme and Medicare Benefits Schedule funding for newer treatments, and called for the introduction of optical coherence tomography (OCT) Medicare rebates to facilitate ongoing monitoring of disease.

According to the MDFA, access to treatment continued to present significant limitations and inconsistencies for some patients – in both urban and remote communities. While some public hospitals provided up to three initial treatments (with patients then referred to private clinicians), many were completely limited to the private sector.

“There is an urgent need for better access to intravitreal injection treatment for macular disease in the public hospital system. Not all public hospitals provide treatment, and waiting times for the public hospital treatment are very long in all states. Ready access to public hospital treatment is needed because late diagnosis and treatment can result in permanent vision loss,” the report stated.

Patient support services were listed as key to ensuring patients appropriately manage their disease and maintain independence. To enhance this, the MDFA proposed a Macular Health Patient Portal, strengthening health literacy and empowering people to self-manage their disease with diet recommendations, Q&A webinars, and navigational support for subsidies and Medicare information.

It also recommended the development of a national program of support for people with complex needs, and the establishment of a ‘National Vision Program’ to provide accessible, affordable and consistent low vision aids and equipment.

“Only about 10–15% of visually impaired people who could benefit from support access and use the services available to them,” the report stated.

In detailing necessary improvements in research and data collection, the MDFA proposed a stocktake of all existing data sources relating to eye health, diseases, treatment, outcomes, and eye health supports. An investigation into the feasibility of linking data sources was also warranted.

Additionally, the plan recommended access to real world data through a National Macular Health Patient Data Hub to assist decision makers, and proposed the development of a national agenda to coordinate both publically and privately funded research.

Finally, taking into account the emergence of artificial intelligence, the MDFA plan stated the sector should develop a professional position on the ethical, practical, access and regulatory challenges and opportunities associated with the clinical diagnosis and management of macular disease.

“These action points will help reduce – and ideally prevent – the economic, social and emotional costs of vision loss and blindness as a result of macular disease, greatly assisting the members of our community living with macular disease, their families and carers,” MDFA CEO Ms Dee Hopkins said.

While the MDFA action plan helps set a clear path forward, Insight also asked country’s leading macular disease researchers, ophthalmologists and treatment companies about the challenges at hand and the intriguing research programs currently under way.

 

ASSOCIATE PROFESSOR ANTHONY KWAN

State: Queensland

Title: Surgeon, director of vitreoretinal service, QEI

Specialties: Retina and macular diesease, including age related macular degeneration, diabetic retinopathy and retinal detachment

Queensland Eye Institute

Although anti-VEGF injections are considered a highly effective therapy in neo vascular AMD (nAMD), Queensland Eye Institute (QEI) Associate Professor Anthony Kwan believes widespread use of longer-lasting, less invasive treatments may only be a few years away.

Eye drop treatments, slow releasing formula and eye implant reservoirs that can be topped up by ophthalmologists are all new technologies under development, that Kwan believes will transform the way macular disease drugs are delivered. This is expected to lead to greater cost and time savings for both patients and practitioners.

Kwan said these treatments appeared to be the next logical step for nAMD, although in more challenging forms of macular and retinal disease stem cell and gene therapies held the key. He expected they could be in common use within 10 years.

As such, stem cells play a major role in a treatment under development at QEI, where researchers are formulating a method to repair damaged retinal tissue associated with macular and retinal diseases.

This involves the use of a substrate (biomaterial scaffold) made of a naturally occurring silk protein, which is derived from silkworm cocoon. After the cultured cells have grown and populated the substrate, it is implanted under the retina to help the replacement cells grow in the correct fashion. This could then reconnect to retinal tissue and generate – and in some cases regain – sight.

Previous work within this study has involved the attachment of retinal pigment epithelium (RPE) cells to the substrate, which would be useful in cases of atrophic AMD. However, Kwan revealed to Insight that QEI researchers recently extended the research to include induced pluripotent stems cells, which could one day treat a wider group of patients, particularly those with end-stage atrophic form AMD or other inherited forms of macular dystrophy.

“We are making good progress. The difficulty can lie in the cells not attaching to the scaffold in the right way, but so far all the signs are saying it’s doing what we hoped,” he said.

 

PROFESSOR ROBYN GUYMER

State: Victoria

Title: Head, macular research and deputy director CERA

Centre for Eye Research Australia

Centre for Eye Research Australia (CERA) deputy director Professor Robyn Guymer and her team have been working towards identifying novel anatomical and functional biomarkers in AMD that could be used as potential endpoints in studies for early intervention treatments.

Her team identified the early anatomical changes in OCT that indicate cell death and atrophy had begun, coining the term nascent geographic atrophy (nGA).

With regard to functional biomarkers, her team has been using a novel, dark adapted, two-colour chromatic perimeter called the DACP. It is designed and manufactured by Medmont in Melbourne. They have further described the changes in dark adaptation that occur early in AMD, particularly in those with reticular pseudodrusen, a high risk factor for progression to vision threatening disease.

The work on nGA has led to Guymer being lead author on a submitted manuscript describing early OCT changes in atrophy as part of an international consensus group on atrophy.

“We are involved in quite a few novel interventions for AMD, which are the early phases of development with a number of different ideas coming forward to try to intervene early, and I do believe that our work on nGA as an end point has enabled these companies to think about trialing other drugs or interventions that have been ideas for potential therapies for some time,” she said.

Guymer is also keen to improve the outcomes for anti-VEGF therapy, where earlier intervention should produce better visual outcomes. To this end, she has been working to develop new home monitoring applications to improve adherence.

 

DR FRED CHEN

State: Western Australia

Title: Head, ocular tissue engineering unit LEI

Lions Eye Institute

Gene-altering drugs for inherited forms of retinal disease – Stargardt Disease and Retinitis Pigmentosa – feature among the latest research programs at the Lions Eye Institute (LEI) in Perth.

Speaking publicly for the first time about the study, Dr Fred Chen is leading research that monitors disease progression in order to to develop personalised medicine for these two forms of disease, using the skin cells of patients. These skin cells have been reprogrammed into induced pluripotent stems cells, which are then used to grow embryonic-like retinas (organoids) in the laboratory. These are then used to understand how the disease occurs, and to test new medications designed for each patient.

“These medicines alter the way a faulty gene is processed so that retinal cells containing these mutations don’t continue to degenerate. They are made specific to the gene and mutation. Once safety studies are completed in patient cells, they could eventually be delivered into the patient’s eyes perhaps with an injection with effects that may last many months or years,” Chen said.

Currently, the drugs require additional testing so that biotech companies would be willing to invest in further development.

“As we prepare for the protection of intellectual property (IP), we are already in communication with several companies expressing interest to take over the IP to develop it” he said.

Looking ahead, Chen believes future research will focus on identifying biomarkers through blood tests, such as a current study at the Australian National University, and advanced retinal imaging for disease progression and treatment response. Although recent advances in treatment development hold great promise, a lack of ‘treatment-naïve’ patients posed a major challenge in recruitment for clinical trials to test new medications, Chen said. Exacerbating this is the effectiveness of existing treatments for some nAMD patients.

“There are a lot of doctors treating this condition using standard therapy – which is expensive to taxpayers. To test better and longer-lasting drugs, we need these treatment-naïve patients, however, in recent times, we have seen less of them because they are being treated promptly in the community by ophthalmologists.”

 

MR TOM SPURLING

State: South Australia

Title: CEO of Ellex Medical Lasers

2RT Nanosecond laser

Adelaide-based ophthalmic device manufacturer Ellex has developed the 2RT nanosecond laser, which the company claims to be the first treatment for intermediate age-related macular degeneration (iAMD).

Heralded as a breakthrough treatment, 2RT differs from the pharmaceutical treatment options currently utilised to manage symptoms experienced by AMD patients with the later stage form of the disease, by which stage vision loss and damage has occurred.

The company claims it is the only treatment demonstrated to address AMD in its early stages. Post hoc analyses of the Laser Intervention in Early AMD (LEAD) clinical trial last September showed that in patients who did not have coexistent reticular pseudodrusen (RPD), treatment with 2RT resulted in a clinically meaningful 77% reduction of progression.

“We know that over time we will need to understand the treatment better, but a lot of our doctors are saying: ’We think this is a pretty good outcome’," recently departed Ellex CEO Mr Tom Spurling said.

The 2RT laser is currently cleared for the treatment of early AMD and clinically significant macular edema treatment in Europe and Australia. In the US, the therapy is cleared for clinically significant macular edema treatment, and Ellex expects to establish a pathway for it to receive approval for iAMD treatment “in due course”.

“With no currently approved treatment options available for AMD in its early stages in these markets, or indeed anywhere in the world, we believe the LEAD data will be of significant clinical interest to ophthalmologists seeking an intervention for patients with the early stages of AMD,” Spurling said.

Although the therapy had shown a promising trend towards reducing the overall rate of disease progression in participants with less severe signs of AMD, conversely, 24% of study participants with coexistent RPD had a doubling of their progression rate when compared to those who were not treated

Researchers now want to conduct further studies to validate these initial results and explore why outcomes differ.

 

DR MEGAN BALDWIN

State: Victoria

Title: CEO and managing director of Opthea

Opthea

With the release of two Phase 2 clinical trials for its lead drug candidate OPT-302, 2019 has been earmarked as a crucial year for Melbourne-based biotech company Opthea.

Investigations into OPT-302 – a VEGF-C/D inhibitor – are focusing on whether combining the drug with Lucentis at high and low doses will improve visual acuity in nAMD patients (currently in Phase 2b) compared with standalone Lucentis treatment. A similar trial in combination with the drug Eylea in diabetic macular edema (DME) is currently in Phase 2a.

Opthea CEO Dr Megan Baldwin said results from both current phases of those clinical trials are expected to be announced by the end of this year.

“For the Phase 2b nAMD study, in particular, if we read out positive outcomes that will position us well to fully explore the next steps in the clinical development process. One avenue may involve raising sufficient funds to take it forward into Phase 3 clinical studies, which will set us up for marketing approval,” she said.

“The other option is to fully explore strategic opportunities, such as partnerships or licensing agreements, with larger pharmaceutical companies who are well placed to advance the drug into larger clinical studies.”

Both studies are being conducted on a randomised controlled basis, with the nAMD trial involving 366 patients, one of the largest Phase 2b nAMD trials being conducted in the world.

Baldwin said the fact the study recruited the required number of patients ahead of schedule bodes well for the drug. It also pointed to a significant need in a patient group that only has access to two approved products – Lucentis and Eylea – while cancer drug Avastin is prescribed off-label in some countries.

“The fact that we were able to recruit the trial ahead of schedule, I think, speaks to the investigators in the study being on board with our science, technology and understanding what potential benefits we may offer patients,” she said.

“From a patient perspective I think it speaks to their willingness to try new, innovative therapies, but also their understanding that there’s a need for additional drugs because their outcomes might actually be better.

“When it comes to nAMD and DME, it’s really dominated by two approved therapies, and both of them really do have the same mechanism of action, so there’s very limited treatment choice for treating physicians to offer patients.”

While the true magnitude of the task ahead may be difficult to fully comprehend, what remains clear is Australia’s standing as a world leader to address macular disease.

 

PROFESSOR MARK GILLIES

State: New South Wales

Title: Director of research at SSI, University of Sydney

Save Sight Institute

It is well-documented that establishing high treatment standards and early detection are perhaps the two most significant outcome predictors for macular disease patients.

According to the Save Sight Institute (SSI) and University of Sydney director of research Professor Mark Gillies, Australia can count itself a global leader in both fields.

Established a decade ago, the SSI’s Fight Retinal Blindness! (FRB!) registry is one of the most advanced in the world, and provides a scientific platform for Australian clinicians to efficiently capture high-quality data from real life practice.

Gillies said analysis of the dataset, including 13,000 eyes with nAMD, helps the sector identify new avenues of research inquiry, and allows the SSI’s macular research group to generate recommendations for best practice.

“A major observational study done in Europe, the WAVE study, Frank Holz et al, found surprisingly poor outcomes [in wet AMD patient management] – we have not been subjected to the same unpleasant surprise in Australia,” he said.

Additionally, Gillies believed Australia was performing well when it came to early detection rates, reinforced by the Australian-based RIVAL Study, which he said had the best starting visual acuity level for any study so far in nAMD patients.

 

DR ANGELICA LY

State: New South Wales

Title: Integrated care coordinator and lead clinician at the CfEH

Centre for Eye Health

Over the past decade, research has shown that fundus images using different wavelengths provide notably different key pieces of information in AMD, however, compiling the information for diagnosis and analysis can be time-consuming and complex.

This is an issue the Sydney-based Centre for Eye Health (CfEH) sought to solve, leading to the development of an automated image analysis approach for the integration and classification of multiple imaging modalities in AMD.

“What this means is that, rather than clinicians having to try and assess multiple images from multiple imaging modalities by eye – which is subjective, time, expertise and resource intensive – they could assess a single pseudocolour map comprised of information from all the imaging modalities created by our image analysis methods,” Dr Angelica Ly, CfEH integrated care coordinator and lead clinician (macula), said.

“In these maps, each colour represents a statistically separable spectral signature, which corresponds closely with the signs of AMD. This ‘snapshot’ representation empowers the clinician to make a more well-informed judgment regarding the disease diagnosis and best-practice management plan.”

Ly believed clinical decision support tools would continue to advance and become a major focus in future macular disease research. This includes systems for structured record keeping, analysis of clinical data against a knowledge base, automated image analysis, artificial intelligence, machine learning and outreach solutions.

However, in the short-term, Ly said the current care model for AMD treatment and rehabilitation needs rethinking.

“Patients with macular disease require lifelong surveillance and too many are slipping through the cracks. We need more holistic, patient-centred, systemic solutions to better co-ordinate care to ensure that the right patient sees the right professional at the right time for the right level of care,” she said.

 






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