Feature, Macular disease, Report, Therapies

Prof Robyn Guymer: Is Australia ready for the latest AMD therapies?

The treatment landscape for wet and dry AMD is undergoing a seismic shift in Australia. CERA’s head of macular research PROF ROBYN GUYMER discussed this at SCC 2022, as well as challenges that need to be overcome so eyecare professionals are equipped for new therapies when they reach our shores.

Since ranibizumab (brand name: Lucentis) was listed on the Australian Pharmaceutical Benefits Scheme (PBS) in 2007, anti-VEGF therapies have been regarded as a turning point for patients with neovascular age-related macular degeneration (nAMD), and associated macular diseases. And this was bolstered with the arrival of aflibercept (brand name: Eylea) in 2012, with Australia being just the second country in the world to introduce the therapy. 

While these anti-VEGFs have been the mainstay for well over a decade, they aren’t perfect, leaving the door open for newer, longer-acting therapies that overcome the treatment burden so often associated with patient drop out, as well as other issues like macular scarring or fibrosis. 

This rapidly evolving field was the focus of Professor Robyn Guymer’s intriguing presentation at the recent Specsavers Clinical Conference (SCC). The Centre for Eye Research Australia (CERA)’s deputy director and head of macular research outlined why it is such an “exciting time” for patients with either form of late-stage AMD, with a new treatment for nAMD pending PBS listing in Australia and the first approved therapy for geographic atrophy (GA), or dry AMD, most likely just around the corner. 

While this is a promising time for patients, Guymer described how it poses new challenges for Australian eyecare professionals when it comes to defining disease and deciding who will most benefit from new therapies. Also, the true benefits of the newer therapies won’t be fully known until more real-world data is available.  

Longer-acting therapies and beyond 

Beginning with nAMD, Guymer explained why there’s still a major unmet need, despite the game-changing nature of the existing suite of anti-VEGF therapies.  

Highlighting the real-world outcomes from America based on 50,000 eyes, she demonstrated how a significant proportion of patients were receiving fewer than the desired number (approximately seven) of intravitreal injections in the first year (Figure 1), a trend that exists around the world.

Figure 1 – Histogram showing a nearly normal distribution of nAMD patient eyes stratified by number of anti-VEGF injections received in the first year of treatment. The median number of anti-VEGF injections received in the first year of treatment was seven. Credit: Ciulla et al. Ophthalmology Retina 2020;4:19-30.

She said this mattered because data from the same population showed a “linear relationship” between visual acuity (VA) improvement and the number of injections, particularly between four and 10 injections in the first year (Figure 2). At the lower end of the range, patients with five or fewer injections in year one generally lost vision.

Additionally, in the real world after one year of treatment, Guymer pointed to a long-term UK study over 10 years showing that even if vision is improved in the first one to two years, vision still declines gradually over time. A similar trend was also shown in a Denmark study with 4,678 treatment naïve eyes. 

Figure 2 – There appears to be a linear relationship between mean letters gained and mean number of anti-VEGF injections, between four and 10 injections over the first year of treatment, after which the relationship plateaus. At the lower range, those patient eyes that received four or fewer anti-VEGF injections in one year generally lost vision at one year. Credit: Ciulla et al. Ophthalmology Retina 2020;4:19-30.

“When we looked at the (Save Sight Institute) Fight Retinal Blindness! Registry, which essentially started in Australia and New Zealand and has now spread internationally, using real world cohort data from 3,192 patients with nAMD treated in routine eye clinics between 2007 and 2015, we developed a model to predict vision for the rest of someone’s lifetime after starting anti-VEGF treatment, which averages around 11 years,” she said.

“Even with optimal dosing frequencies, we estimated 12% would retain driving VA at time of death and an estimated 15% retained reading VA in at least one eye. Maybe you could say that is terrific news because before these treatments virtually no one ended up with this sort of vision with nAMD, but on the other hand, given such good treatments now, why is it that we cannot preserve reasonably good vision until death in more people?”

Guymer said questions remain whether the industry can do better with longer-acting therapies to reduce under-treatment, as well as therapies that do more than just block VEGF. Another major unmet need was vision loss due to scarring, or fibrosis, and atrophy, which no treatment addresses yet.  

Figure 3 – Retinal scans of a 95-year-old female presenting 6/18 with choroidal neovascularisation (top) before sustaining fibrosis/scaring post-treatment (bottom). Five years later, despite a great response to anti-VEGF long term, visual acuity was not maintained due to atrophy and fibrosis caused by current treatment approaches.

Enter faricimab (brand name: Vabysmo), a treatment approved in Australia in 2022, and now recommended for PBS listing. According to its manufacturer, it is administered by four initial four-weekly injections, but thereafter, the frequency will be determined by the treating physician up to 16 weeks apart.

According to Guymer, the therapy’s point-of-difference is its anti-VEGF effect combined with an anti-Ang-2 component – the latter thought to have an important role in vascular instability and inflammation – potentially reducing fibrosis. 

In the Phase 3 TENAYA and LUCERNE trials, Vabysmo patients were treated every eight, 12 or 16 weeks and compared to Eylea every eight weeks. Non-inferior vision gains were demonstrated in all Vabysmo groups. However, the studies did not extend the Eylea control arms beyond eight weeks, so it didn’t present a true head-to-head comparison, Guymer added.

“After 48 weeks, the studies showed 80% of faricimab patients could be treated every 12 weeks or longer and 45% could be treated every 16 weeks,” she said, noting that subsequent two-year data had shown that – even though vision was declining in both groups – a large proportion of Vabysmo patients can be kept on 12 weekly treatment (14.7%) and 16 weekly treatment (63.1%), which was 77.8% combined. 

“So it might be possible to let more patients go longer with this new drug compared to Eylea, but it wasn’t a true comparison, so we will have to wait until real world use of this drug to see if we can get this proportion of people truly out to three or four monthly treatment. And we will need to wait for longer term outcomes to see if there is less fibrosis and atrophy and thus better longer term vision.”

Slow release therapy shows promise 

Another therapy seeking to overcome the treatment burden barrier is a re-fillable port delivery system (PDS) implanted in the eye that slowly releases ranibizumab. The brand name is Susvimo PDS and while it has been granted approval in the US, it is still under review in other jurisdictions, including Australia.scar

Guymer said the aim of this reservoir-like treatment implanted in the sclera is to increase treatment intervals even further, possibly out to six months, however safety challenges remain. 

“Phase 3 trials, only conducted in America, have been completed comparing this long-acting device with monthly ranibizumab and the primary objective was to see whether the six-month refill was equivalent to monthly ranibizumab,” Guymer said.

“After an initial drop in vision due to the surgery, they found vision picked up and there was equivalency between these treatments. There’s a Phase 3b study still going on outside America and Australia is part of that.” 

Guymer pointed to significant safety concerns due to it being surgically implanted and, as such, there are strict protocols for surgeons to follow to reduce any surgical complications.  

Findings of ocular adverse events of special interest were reported in 19% of the PDS 24 weekly arm, and 6% in monthly ranibizumab.

In the PDS arm:

  • 1.6% endophthalmitis cases
  • 0.8% retinal detachment
  • 5.2% vitreous haemorrhage
  • 2.4% conjunctival erosions
  • 2% conjunctival retractions 

Most adverse events occurred within one month of implantation. 

“As you can see, there are some safety concerns, particularly around conjunctival erosion and retraction, which isn’t ideal as the conjunctiva should be covering the device,” Guymer said.

“We need to think about surgical safely and long-term implant safety and a question remains as to how we should best monitor these people who potentially only need treatment every six months?

“Do we want to see them more often, and if so, maybe they’d be better with a longer acting drug, so there’s work to do to determine where this might fit into our treatment armamentarium. But there is some thought that if we can home-monitor these patients, we can stop them coming in to be checked. For example, vision monitoring at home is available with certain apps and at-home OCT might be applicable here.”

Dawn of a new era for geographic atrophy 

In the other late form of AMD, geographic atrophy (GA), patients have had little hope with no approved therapies yet. But Guymer said there are several late-stage novel therapies that, once approved, will pose different challenges and opportunities compared to anti-VEGFs for nAMD. 

“When we have the first treatment approved for GA, it’s going to completely change the lives of patients, but also yours and mine as eyecare professionals,” she said.

“We will need to determine who to treat, when to treat, which treatment and whether it should be done in one or both eyes; these are just some of the questions we haven’t addressed as a community yet.

“It’s going to be different to nAMD where we treat almost anyone. It’s unlikely we will be able to individualise treatment – there will not be judging whether someone receives four or 16 weekly treatment because there isn’t much to measure in trying to slow the growth of patches of atrophy. It is more likely going to be a forever treatment for everyone and many people with GA have few or no symptoms early on, so how you ‘sell’ this therapy to the patient will present challenges.”

To start with, Guymer said optometrists will be required to distinguish between GA and inherited retinal disease (IRD) – both can present similarly on scans but treatments under development for these conditions differ drastically. 

“Fundus autofluorescence has come into its own for GA. It seemed to be a technique looking for a reason, but it’s now a great way to look at growth of atrophy over time. One plea I’d make to the eyecare community internationally is to start taking images so we can obtain baseline images to determine growth rates – that’s going to be crucial when starting to talk to people about treatment,” she said.

According to Guymer, one of the great challenges with GA is that researchers still don’t precisely know its cause, but they have identified some of the likely pathways involved. This has led to investigational therapies that target and regulate the complement system to suppress inflammation. 

One late-stage therapy adopting this approach is by Apellis Pharmaceuticals and its therapy pegcetacoplan, which is being trialled at sites in Australia. 

Guymer pointed to the completed Phase 3 OAKS and DERBY studies involving 1,258 participants across 200 global sites. Patients in the treatment group were given either monthly or every-other-monthly pegcetacoplan, with the aim of slowing growth of the GA area. Secondary endpoints – reported at 24 months – include functional outcomes such as best corrected visual acuity, low luminance visual acuity, reading speed and microperimetry.

Figure 4 – Pegcetacoplan, which could be one of the first therapies approved for geographic atrophy, showed clinically meaningful reductions in GA lesion growth from baseline out to two years.

“The OAKS study showed a statistically significant overall slowing of GA growth across the whole pegcetacoplan group and if you look at patients who had extrafoveal lesions – where it tends to grow faster – the therapy seemed to have a bigger impact,” she explained. 

“Unfortunately, the DERBY study did not reach significance in its primary endpoint and there was little difference in growth rate overall, but when they looked at extrafoveal lesions there was a significant difference in one of the arms.”

However, at 18 months, both studies reached significant slowing in lesion growth and then, more recently in September 2022 at EURETINA, 24-month data showed there was significant slowing in both trials. 

“As you can appreciate this isn’t a miracle in a sense that we haven’t cured the disease, but given we don’t have a treatment, anything that’s stopping that growth, especially extrafoveal lesions getting to the fovea, is a good thing,” Guymer said.

“Apellis is awaiting an outcome in the US in late 2022 and, if successful, the rest of the world including Australia will apply for approval shortly afterwards.”

New hope with gene therapies 

Other companies are also targeting the complement system, but in different ways for GA.

Guymer said one novel method is the Complement Factor B anti sense program using RNA technology, which targets treatment in the liver, meaning it can be delivered subcutaneously. This would offer the opportunity to treat both eyes simultaneously with a systemic treatment, while offering the ability to self-treat at home.  

But a one-off treatment could be even more advantageous and this is where gene therapies come in. CERA is a trial site for a therapy developed by Gyroscope Therapeutics (acquired by Novartis in February 2022) called GT005, with Dr Tom Edwards the first to deliver the therapy locally at The Royal Victorian Eye and Ear Hospital in 2021.

“With this therapy, they’re hoping to augment Complement Factor I which will down regulate the alternative complement pathway,” Guymer said. 

“Originally, this therapy was designed for people only with a mutation in a particular gene with very low levels Complement Factor I, but now they’ve found it’s probably useful for anyone with a complement-based genotype, which is 95% of patients with GA, so now enrolment is almost open to anyone with GA.”

To find suitable candidates, Guymer said CERA has been involved in the TELESCOPE study, a community-based genetic screening study designed to identify people with GA. It involves 12 optometry practices in Victoria who have been recruiting GA patients for the GT005 trial.

“We are trying to grow a network of optometrists to help recruit patients for ongoing GA studies,” she added. 

In conclusion, Guymer said the pathophysiology of GA is complex and most therapeutic approaches are trying to slow growth rates, particularly by targeting the complement system. 

“Once treatments are approved, these patients will need regular intravitreal injections, but this won’t be the final mode of delivery – it can’t. There’s a huge number of people with GA who, in early stages, don’t have much in the way of symptoms, so we will need longer acting therapies and perhaps this is where gene therapies can help.”

More reading

Vabysmo recommended for PBS as two-year trial confirms fewer treatments for wet AMD

Aflibercept 8mg could become AMD standard-of-care after pivotal trial

Gene therapy trial for dry AMD under way in Australia

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