As part of Macula Month this May, Insight examines drug development programs that could significantly alter the late-stage AMD therapy landscape. Leading experts also discuss why optometrists are such an important link in the success of both patient outcomes and clinical trials.
Macular Disease Foundation Australia figures indicate about one in seven Australians – or 1.29 million people – over the age of 50 years has some evidence of age-related macular degeneration (AMD). More than 200,000 of those will experience vision impairment and around 160,000 over 80 years will experience vision loss.
While a lot of clinical detail is known about the disease, including the various stages of AMD and associated symptoms, treatment remains elusive for many patient groups.
It’s widely-known to eyecare practitioners – but less so to patients – that there are very few, if any, medical treatments for early and intermediate stages of macular degeneration, and only one of the two forms of late-stage AMD (neovascular, or wet AMD in layman’s terms) can be medically treated.
For the other form (geographic atrophy, or dry AMD), research activity is gaining momentum with a wave of promising new interventions being trialled around the world, including Australia. However, the pursuit of new therapies relies on the success of clinical trials, which are contingent upon accurate initial diagnosis and patient recruitment.
To that end, experts in Australia have helped define the earliest changes seen in atrophy so that it might be possible to start interventions earlier than what is currently occurring in trials. Defining these earlier changes of atrophy also helps eyecare professionals counsel patients as to their stage of disease.
Incorrect terminology a major barrier
Historically, there has been considerable confusion over even basic terms in AMD.
An inconsistent approach to classifying or diagnosing the disease has led to confusion in what the terms actually refer to when considering the stage of disease. For example, ‘dry AMD’ has been used to mean everything that isn’t ‘wet’ but it should be used to describe a late stage of geographic atrophy (GA).
For Professor Robyn Guymer, deputy director of the Centre for Eye Research Australia (CERA) and head of macular research, using the right terminology continues to be a sticking point.
“Incorrect terminology makes it confusing when trying to recruit suitable AMD patients for trials. It makes it hard to work out which stage of AMD a patient is thought to have,” she says.
For consistency and continuity, Guymer points to the Beckman classification – created in 2013 and involving input from 26 AMD experts, including Guymer – which is based upon evidence drawn from the Age- Related Eye Disease Study (AREDS).
As the most current clinical classification scheme for AMD, it recommends that AMD should be classified into normal ageing, early AMD, intermediate AMD, and late AMD, of which there are two types, GA and neovascular.
According to the classification, normal ageing is defined by small drusen (≤63μm) and no AMD pigmentary abnormalities. Early AMD is defined by medium drusen (>63μm and ≤125μm) and no AMD pigmentary abnormalities. Intermediate AMD is defined by large drusen (>125μm), or medium drusen (>63μm) in addition to AMD pigmentary abnormalities.
Late AMD is defined as either GA and/or neovascular (nAMD). It is possible for GA and nAMD to coexist; the term dry AMD should be used as a lay term for GA, Guymer says.
According to Optometry Australia (OA), recent advances in nAMD research have shown that early detection and treatment is vital for best patient outcomes and, as such, optometrists have a major role to play in management.
New imaging has also meant that biomarkers, such as reticular pseudodrusen and nascent GA, can be identified and these indicate a higher risk stage of AMD, with increased risk of progression to late AMD.
OA’s 2019 AMD Clinical Practice Guide stipulates that in early AMD (medium drusen only), patients have a 3.1% chance of progressing to late AMD within five years. However, once a patient has large drusen and pigmentary abnormalities in both eyes (intermediate AMD), this risk increases to around 47.3%. If a patient presents with late AMD in one eye at baseline, the risk of progression in the other eye is slightly higher.
Patients needed for trials
Currently, there are no regulatory-approved treatments for GA, when the vision cells (photoreceptors) in the centre of the retina slowly die over time. According to OA, the standard of care is monitoring every six to twelve months depending on vision/driving status and the individual’s risk of progression.
However, Guymer says several trials are now recruiting patients, so optometrists should consider referral to studies if they think their patient is appropriate and interested.
One trial recruiting at CERA is the GOLDEN trial which is aiming to interfere with the body’s production of the protein called Factor B that is made in the liver and found in the eye, which may contribute to GA secondary to AMD.
The trial is recruiting patients at several locations in Australia, including CERA in Melbourne, the Lions Eye Institute (LEI) in Perth, the Royal Adelaide Hospital, and Sydney Eye Hospital.
“Optometrists need to be proficient at interpreting signs detected on OCT scans, so that they can appropriately stage the disease and refer appropriately,” she says.
Guymer has also co-created a University of Melbourne e-course for optometrists and other eyecare professionals to help them upskill in how to read these scans.
For a list of current trials, visit ClinicalTrials.gov, a database of privately and publicly funded clinical studies conducted around the world. The CERA and LEI websites also list current clinical trials, including those recruiting.
The neovascular AMD landscape
At the beginning of 2021, clinician-researcher Dr Fred Chen from LEI in Perth remarked that recognition of GA as a potentially treatable condition could be a key feature shaping retinal disease landscape this year.
He’s also eager to see the emergence of longer acting drugs for nAMD and new trials of port delivery systems for existing drugs, allowing longer actions.
One of those drugs is Beovu (brolucizumab), Novartis’ new intravitreal injection therapy for nAMD. Although registered on the Therapeutic Goods Administration (TGA), an application to have it PBS-listed had been denied three times – at the time of writing. The Pharmaceutical Benefits Advisory Committee considered Beovu is likely inferior to aflibercept in terms of comparative safety. While it had previously considered Beovu was non- inferior in terms of comparative efficacy, it also did not accept the evidence supported less frequent dosing. (Novartis disagreed with the decision, stating it’s an important treatment option, with an overall favourable benefit-risk profile).
If it’s able to clear this hurdle, Beovu would present a third major treatment option for nAMD alongside well-established PBS-approved therapies Lucentis (ranibizumab) and Eylea (aflibercept), which the government spent more than $610 million on last year.
NOTE: The PBAC has since approved Beovu as a second-line therapy.
Much of the marketing around Beovu has previously focused on its potential for extended dosing intervals in some patients based on the Hawk and Harrier trials, in which it was also reported to demonstrate non-inferior best-corrected visual acuity change from baseline at year one compared with competing therapy Eylea, which Chen described as an impressive feat. However, he is concerned that Beovu-induced retinal artery occlusion or inflammation cannot be prevented, predicted or treated effectively.
Chen is also closely watching for the result of a study on the port delivery system with ranibizumab (Lucentis), sponsored by Hoffmann-La Roche.
“A port delivery system is a combination of new surgical technique and treatment paradigm. A small device is sutured into the eye as a theatre- based procedure that takes about half-an-hour, or just slightly longer than the timeframe in cataract surgery,” Chen explains.
“A solution – containing Lucentis in this study – is injected into the port, which allows the drug to be diffused into the eye cavity. The concentration of the drug in the port will decline over six to nine months. The port stays in the eye and the participant returns for an outpatient procedure where the low concentration solution is replaced by a fresh, high concentration solution of Lucentis.”
The Hoffmann-La Roche study, which has yet to recruit in Australia, is aiming to enrol 1,000 participants and will evaluate the long-term safety and tolerability of the delivery system with ranibizumab 100 mg/mL with refill-exchanges administered every 24 or 36 weeks for approximately 144 weeks in participants with nAMD who have completed either Phase 2 Ladder study, Phase 3 Archway study or Phase 3b Velodrome study.
“There has been a delay setting up the Velodrome study in Australia due to COVID-19, but it is likely to be ready to recruit in the second half of the year,” Chen says.
In July last year, Roche announced detailed results from the Phase 3 Archway study showing the port delivery system with ranibizumab enabled more than 98% of patients to go six months between treatments for nAMD.
Another study sponsored by Hoffmann-La Roche is evaluating the efficacy and safety of faricimab compared with aflibercept (Eylea) in participants with nAMD. Known as the LUCERNE study, it involves 658 participants across 144 locations, including LEI, CERA, and six sites in NSW.
Designed to differentially extend treatment further than three months, Chen says the study is ongoing in Australia and no results are available yet. If successful, faricimab will be competing in the same space as Beovu for longevity and potency of the drug effect in nAMD.
Elsewhere on home soil, Melbourne-based biopharmaceutical company Opthea is commencing two global Phase 3 trials (known as SHORE and COAST) with its OPT-302 therapy for nAMD. Study locations include Parramatta, Sydney, Westmead and Perth.
Both clinical studies will enrol about 990 treatment-naïve patients each and assess the efficacy and safety of intravitreal 2.0 mg OPT-302 in combination with 0.5 mg ranibizumab (Lucentis) or 2.0 mg aflibercept (Eylea), compared to ranibizumab or aflibercept monotherapy, respectively. Opthea anticipates reporting top-line data in 2023.
Australia also recently became the clinical trial centre for a new molecule called EXN 407, stemming from research out of UNSW. Backed by Johnson & Johnson’s pharmaceuticals subsidiary Janssen, the novel eye drop therapy could be a radical advancement and eliminate the need for intravitreal injection delivery in future in nAMD.
What about geographic atrophy?
Both Guymer and Chen are optimistic that a treatment for GA could be a reality in the foreseeable future, particularly with a potential treatment approach focusing on the “complement cascade”, which is an arm of the immune system strongly implicated in AMD.
The complement part of the immune system is thought to damage the retina; research has demonstrated that inhibiting the complement cascade can protect the retinas of mice. Guymer says there are trials aiming to work on the complement pathway currently under way in Australia and internationally.
While two Phase 3 trials targeting the complement protein Factor D in GA patients were not successful, a separate trial targeting a different complement protein called C3 has shown promise.
The Phase 2 trial, known as FILLY, demonstrated that intravitreal injections of APL-2 (Pegcetacoplan) in patients with AMD were well-tolerated, and preliminary data indicate a therapeutic benefit in subjects with GA, according to Apellis Pharmaceuticals, who developed the therapy.
Apellis has now introduced two Phase 3 trials (known as DERBY and OAKS) to compare the efficacy and safety of APL-2 therapy with sham injections in patients with GA secondary to AMD.
Chen says based on the results of the FILLY trial, and now with DERBY and OAKS under way, this intravitreal therapy could be the breakthrough researchers are seeking.
“This could be the first treatment available for patients with GA,” Chen says.
Guymer agrees: “This particular trial of the complement C3 inhibitor Pegcetacoplan is looking promising and could become a possible treatment within the next few years.”
Associate Professor Alex Hunyor, a retinal specialist with more than 20 years of experience in the treatment of macular diseases, shares Chen and Guymer’s enthusiasm but is cautiously optimistic.
“There are several promising treatments in the pipeline, but as we have seen with a number of therapies over the years, for neovascular AMD for example, there have been encouraging Phase 2 results and disappointingly negative Phase 3 results, so we need to wait for Phase 3 results before raising our patients’ expectations,” he says.
Hunyor is a Clinical Associate Professor and member of the Macular Research Group at the Save Sight Institute, University of Sydney. He is also chair of the Macular Disease Foundation Australia Medical Committee.
He too believes Pegcetacoplan (APL-2) by Apellis Pharmaceuticals is the most advanced clinical trial stage treatment.
“The Phase 3 DERBY and OAKS studies are due to report their top-line results in the second half of 2021. If there is a positive result, it would probably still be at least a year before regulatory approval by the Australian TGA could be achieved.”
In addition to the GOLDEN study, Hunyor is aware of at least two other international GA studies that will commence recruitment in Australia in 2021. The first is the Phase 2 ARCHER study of ANX-007 (Annexon Biosciences) which blocks the action of C1q, the initiating molecule of the classical complement cascade. The second is a Phase 1b study of ONL1204 (ONL Therapeutics), an inhibitor of fragment apoptosis stimulator (Fas) receptor-mediated cell death. Both are given by intravitreal injection.
Similar to Apellis’ APL-2, another drug called Zimura, which targets the complement protein C5, slowed the growth of GA in a Phase 2 trial, and has moved on to a Phase 3 trial.
While both Apellis and Zimura are injected into the vitreous, another approach is to try to inhibit specific immune cells with the oral antibiotic doxycycline – which is now in Phase 3 clinical trials – according to Dr Joshua Dunaief, Adele Niessen Professor of Ophthalmology at Scheie Eye Institute, University of Pennsylvania.
Dunaief shared an update in November 2020 on the latest research in GA in an article published online by BrightFocus Foundation, a US-based organisation that funds scientific research worldwide into Alzheimer’s, macular degeneration, and glaucoma. In an approach to limit the toxic byproducts of vision cells, Dunaief says an oral drug called ALK-001 is being tested in Phase 3 clinical trials for GA.
“This drug is a modified (deuterated) version of vitamin A that inhibits formation of the toxic byproduct A2E,” he says.
In yet another treatment approach called “neuroprotection”, a biodegradable implant is surgically placed into the eye so that it will slowly release a potentially protective drug.
“One drug that showed positive results in a Phase 2 trial is brimonidine, which also lowers eye pressure and is used as an eye drop in glaucoma patients,” Dunaief says.
Cell transplantation is also being tested after it was established that retinal pigment epithelial cells (RPE) degenerate in GA.
“These cells are important because the photoreceptors die without them. RPE cells can be produced from other cells, then injected under the retina. Early clinical trials have suggested that this approach can be safe. Additional Phase 1 and 2 trials are under way,” Dunaief explains.
Chen says restoring cells is more difficult: “Cell suspension trials have not had any success in restoring vision; we need to put in photoreceptor cells.”
Perhaps one of the most exciting frontiers in modern medicine is gene therapy, which could have application in late-stage AMD one day. Ophthalmology is a leading medical field in this space, demonstrated by the success of Luxturna gene therapy for inherited retinal disease patients with the RPE65 gene mutation.
While developing a therapy for multi-gene conditions like GA is more complex, a Phase 2 clinical trial at the Columbia University Irving Medical Center in New York has commenced with the first patient receiving the therapy in December 2020. And – importantly – this trial is recruiting in Australia, Guymer says.
The investigational gene therapy (GT005) being studied delivers DNA that encodes for a protein that prevents the immune system from attacking cells in the retina.
Given as a single, one-time surgical injection underneath the retina, study participants will be followed for up to a year to determine if the therapy can slow the progression of GA and monitor for side effects.
“Gene therapies for other eye diseases exist, but this trial is the first to test the safety and effectiveness of a gene therapy for dry macular degeneration,” principal investigator Dr Tongalp Tezel says.
Whether a breakthrough treatment for GA is discovered through injectable therapy, oral antibiotics, eye drops, biodegradable implants, cell transplant or gene therapy, success will ultimately depend on recruiting patients.