2022 Research Update: Innovation continues in macular disease treatment

Lucentis® and EYLEA® are highly effective treatments for several macular diseases and their regular use has preserved vision for many, yet they remain burdensome. On average people receiving these treatments require 5–7 injections in each affected eye every year to maintain their vision and may need to continue treatment for many years.

This is a burden that many people cannot maintain, for reasons including high cost,
difficulties with travel and transport, and treatment fatigue. Medical researchers and pharmaceutical companies continue to innovate and develop new drugs that aim to:
•extend intervals between eye injections
•target different mechanisms
•simplify treatment, for example “once-anddone” eye injections or tablet dosing
•treat currently untreatable macular diseases.
MDFA is closely watching over 30 potential treatments in late-stage clinical trials and more
than 90 in early-stage studies. Several late-stage drugs are of particular interest and if successful may be available for people with macular disease within a few years.

2022: An important year for macular disease treatments

New treatments expected soon Fifteen years ago, Australia saw the introduction of Lucentis® (ranibizumab), followed in 2012 by EYLEA® (aflibercept). These drugs target
VEGF and are the mainstay for the treatment of neovascular (wet) age-related macular
degeneration (nAMD), diabetic macular oedema and other macular diseases and have helped delay or prevent significant vision loss in many thousands of Australians.
During 2022, two potential new treatments – Vabysmo® and Susvimo® – have been under
review by the Australian regulatory authorities for new medicines.
Vabysmo® (faricimab) was shown in clinical studies to be an effective treatment for nAMD
and diabetic macular oedema with the possibility that more than half of patients could extend intervals between eye injections up to 16 weeks.
The drug received a positive recommendation from the Pharmaceutical Benefits Advisory
Committee and approval from the Therapeutics Goods Administration (TGA) recently and is expected to be available for prescription in Australia before the end of 2022.
Susvimo® (ranibizumab port delivery system) uses a small, implanted device that slowly
releases ranibizumab into the eye over 6 months or more. This promises to reduce the
frequency of visits to the eye doctor substantially

However, in a recent setback, Roche – who manufacture the product – identified a rare
problem with the device. Roche will continue to explore bringing Susvimo® to Australian patients, but this problem will undoubtedly lead to a delay before the product could be made available.

Cautious optimism for geographic atrophy treatment

Development of treatments for atrophic AMD, or geographic atrophy, continues with the recent presentation of 2-year results for pegcetacoplan from the OAKS and DERBY studies.
The drug, developed by Apellis, continues to show up to 30% slower lesion growth over two years of study, with some evidence that treatment can preserve visual function. The safety profile continues to be promising.
In the USA, the pegcetacoplan findings are being reviewed by the Food and Drug
Administration (FDA), with a decision expected by the end of November 2022. It is anticipated that Apellis will submit the latest data to the Therapeutics Goods Administration (TGA) in the near future.
Meanwhile, in September, 12-month results for avacincaptad, a second potential treatment for geographic atrophy, showed similar slowing of lesion growth. That study is ongoing.

Major clinical studies ongoing

Tarcocimab tedromer, also known as KSI-301, is an anti-VEGF antibody being developed by Kodiak Sciences. The molecule treats macular diseases in the same way as current treatments yet is expected to increase injection intervals beyond 12 weeks.
Results from two clinical trials have been reported in 2022.
In February, the DAZZLE study in nAMD, reported promising outcomes. About 60% of patients achieved a treatment interval of 20 weeks while maintaining good vision.
However, about 30% of patients could not extend beyond 12-week intervals and may
have benefited from more frequent treatment.

The BEACON study in people with retinal vein occlusion compared tarcocimab with EYLEA®. Initial findings were released in August and showed both drugs had similar effects on visual acuity, while tarcocimab required fewer injections. The study is continuing.
Four further clinical studies in different macular diseases are ongoing and expected to report results in late 2023. Melbourne-based company Opthea is running two major late-stage trials with their drug OPT-302. Both trials are currently recruiting worldwide and here in Australia, with initial results expected in late 2024.

This agent is similar in design to EYLEA® but neutralises different VEGF molecules. It is
intended to be used in combination to benefit those people who do not respond optimally
to current treatments.
RGX-314 is being developed by REGENXBIO as a possible “once-and-done” treatment for
macular diseases. The idea is to inject a gene vector into retinal cells that encourages them to produce their own anti-VEGF agent in situ. Results from early clinical studies are
encouraging. A late-stage trial is under way and due to complete in late 2024. If successful, this approach could substantially reduce the burden of treatment for people with macular disease. The gene vector approach is not unique. Luxturna® is approved in Australia to treat certain forms of retinitis pigmentosa. Several other treatments are being studied for inherited retinal disorders, and additional anti-VEGF gene therapies are in early development.

New stem cell models for dry AMD

A years-long collaboration between some of Australia’s leading experts in stem cell biology, ophthalmology, and computational biology has produced a genetic roadmap for age-related macular degeneration (AMD) that could be a gamechanger for the discovery of
novel treatments.
Professor Alice Pébay from the University of Melbourne, said without the funding from
MDFA’s Research Grants Program in 2018, the cross-disciplinary project would never
have got off the ground.

A model for therapy development

The study, recently published in the prestigious international Nature Communications journal, was a collaboration between experts in stem cell biology, ophthalmology, genetics, and computational biology.
The researchers used patient skin samples to generate a special type of stem cells, called
induced pluripotent stem cells (iPSCs), and guided those to become cells of the retina
that are affected in AMD.
“As we observed new differences between the patients’ and controls’ samples at the genetic levels, we looked at the proteins in cells, which are the “products” made from the expression of genes. When a cell decides that a gene is important it will produce its corresponding protein. And again, we observed differences between those two cohorts at the protein level. In the differences we observed, the mitochondria (known as the powerhouse of the cells) seemed to be working differently between people with and without AMD.

Retinal pigment epithelium (RPE) cells obtained from patient derived induced pluripotent
stem cells. These cells are visualised by immunostaining of markers of their membranes
(in pink), nucleus (teal) and some of their proteins (yellow). RPE cells degenerate
in AMD and were the cells studied in this research. Credit: Ms Jenna Hall, University
of Melbourne.