Advanced therapies in neovascular AMD and DMO: Experts weigh in

In a recent Viewpoints roundtable discussion series from Ophthalmology Times Europe, three leading retina specialists looked back at the past 20 years of anti–vascular endothelial growth factor (VEGF) therapies. They put neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DMO) under the microscope to assess the modern retina specialist’s clinical best practices at the molecular level.

The panel was hosted by John Kitchens, MD, a vitreoretinal surgeon with Retina Associates of Kentucky in Lexington, Kentucky. Joining Dr Kitchens were Richard Gale, PhD, MEd, MBChB, BSc, FRCP, FRCOphth, a consultant medical ophthalmologist and professor at Hull York Medical School, York, England, and Michael W. Stewart, MD, a professor and the chairman of ophthalmology at Mayo Clinic in Jacksonville, Florida.

Below are some of the highlights from their wide-ranging conversation on treatment goals, the current therapeutic landscape and clinical application of the treat-and-extend strategy.

From left: John Kitchens, MD; Richard Gale, PhD, MEd, MBChB, BSc, FRCP, FRCOphth; and Michael W. Stewart, MD.

Evolution of anti-VEGF agents and unmet needs in retinal diseases

Modern therapies for nAMD and DMO are a century in the making, Prof Stewart said, and retina specialists have a full stable of mainstay ocular therapies to choose from in the 21st century. He cited brolucizumab, faricimab, aflibercept and ranibizumab as examples of reliable and efficacious treatments for a host of ocular conditions.

Prof Gale said therapeutics like the ones Prof Stewart mentioned have changed the landscape for patients with AMD. “These blinding disorders can now have successful treatment in terms of halting visual loss. Around about a third of individuals have had some restoration or significant restoration of vision,” he said. “That means the rate of registration of blindness for neovascular AMD has been approximately halved.”

That “paradigm shift,” Prof Gale said, manifests in societal benefits, such as increased independence and reduced burden of care for patients and their families. Halting the progression of retinal disease
and restoring visual acuity also both result in broader healthcare outcomes; for example, Prof Gale said, severe vision loss can be associated with slip-and-fall incidents, mobility-limiting injuries and even premature death.

Prof Stewart also pointed out that, since 2004, when anti-VEGF injections first began to see wider adoption, clinicians have accumulated plenty of positive safety data. He cited this as evidence of how far retinal therapies have come. “We can say that from the standpoint of ocular safety, these drugs really have very good safety profiles,” he said. “They are, of course, not perfect, not [that] any drugs are. But the reality is, with respect to intraocular pressure changes, intraocular inflammation, very low risk of infection that follows any invasive intraocular procedures, these drugs really have excellent profiles.” In limited cases, he added, patients may have comorbidities which limit the suitability of anti-VEGF agents; those with AMD may experience age-related problems, while patients with diabetes are at higher risk of systemic cardiovascular events. But for the most part, he said, these adverse effects are not common enough to limit accessibility. “It’s not very common that [systemic problems] actually adversely influence our choice of medications,” he said.

Advantages of the molecular structure of aflibercept

Dr Kitchens introduced the next chapter of the discussion by mentioning the molecular design of aflibercept and its proliferation as a long-term treatment for patients with AMD and DMO. “We’ve had aflibercept 2 mg for over a decade. It’s got to be getting close to 10 million total doses given globally,” he said. “What has given it that lasting ability for a decade to help stabilise and improve our patients with a variety of retinal diseases?”

“The molecule itself is a recombinant protein, and therefore it has a low likelihood of inducing inflammation within the eye,” Prof Gale said. This translates into a lower incidence of anti-drug antibodies, and thus a lower likelihood of reactions such as iritis or vitritis.

Prof Stewart further explained how this differentiates aflibercept 2 mg from other therapeutics. “Of all the anti-VEGFs we have, it’s the only one that’s not an antibody-based molecule,” he said. Whereas other anti-VEGF molecules are antibody-derived, then humanised to make them more immunologically compatible, all the protein sequences within aflibercept are native to the human body, he said.

“The consequences of binding sequences from those two receptors is that you bind all of the ligands that go to those two receptors,” Prof Stewart continued. “We know, for example, that binding to the isoforms of VEGF-A and inhibiting their interaction with VEGF-2 is key to stopping all of our anti-angiogenic processes. But the fact that there are VEGFR-1 binding sequences on aflibercept means you also bind the ligands to VEGFR-1, and those include placental growth factor, VEGF-B and Galectin-1. And so when you put it all together, it’s a multitargeted drug, and it’s that way based upon its actual structure.”

Additionally, aflibercept binds to both sides of the VEGF dimer, in what Prof Stewart described as a “two-fisted grasp.” “As a result, it has a very low dissociation constant. You have a very high binding affinity. You put all of that together, as well as a reasonably long intravitreal half-life... You put together a molecule that has very good pharmacokinetic principles.”

Treat-and-extend strategy with aflibercept

One of the advantages of aflibercept 2 mg, said Dr Kitchens, is that it’s “very predictable,” which can support clinicians in developing a long-term treatment strategy. Prof Gale and Prof Stewart attested to their own experiences using the treat-and-extend strategy in clinical practice.

“We’ve learned quite a few things about neovascular AMD and diabetic macular oedema,” Prof Gale said. “When I talk to my patients, I talk to them about AMD and neovascular AMD being a lifelong disorder, requiring, quite often, lifelong treatment. And so, I explain, we want to get the right treatment for them, at the right injection frequency to maintain disease suppression and to maintain vision as well as possible.”

“In my mind, treat and extend enables us, as clinicians, to find that correct treatment interval,” he continued. The personalised interval between treatments allows the patient and clinician to maximise efficiency, he said. “We continue to treat, until, perhaps, it begins to relapse. We know that interval is an important marker for us, of when to just rein back that retreatment interval... We can find the appropriate interval, in the medium- to long-term, for an individual.”

The resulting customised care protocol benefits everyone, Prof Gale concluded. “It’s a very safe and effective way of minimising burden for ourselves, our patients and our healthcare system, while giving the maximum treatment effect,” he said.

Assessing new therapies for retinal diseases

Dr Kitchens encouraged his colleagues to share their predictions for the future of retinal therapies. Prof Stewart said that, going forward, unlocking new levels of durability is likely to be a priority.

“Now, with anti-VEGF suppression, we have so many good drugs available to us,” Prof Stewart said. “When you look at the recent drug approvals, they’ve all been non-
inferiority trials... [But] we still have a gap, in terms of peak efficacy, [in] where we’d like to be. Really, our goal here now is durability, to try to decrease the number of injections, the number of visits that patients require.

“We do have this thought, that maybe there’s a [superior] drug somewhere along the way that gives us better peak efficacy,” Prof Stewart said. “And there are a number of drugs that are looking at that. The trouble is, that’s a very high bar to hurdle in terms of statistical superiority to anti-VEGF therapy. We’d all love to see that, but I’m not holding my breath. I’m hopeful, but I don’t have any great expectations.”

Meanwhile, Prof Gale predicted that in years to come, clinicians may shift their focus on treatment aims, especially as clinical trials influence how practitioners approach treatment. “Some of the key studies in both neovascular AMD and DMO actually don’t aim for completely dry retinas,” he said. “They aim for maintenance of baseline, which is achieved usually after the loading phase. And then, at that baseline, measurements are taken, and that is then the benchmark for the rest of the patient journey within the trials.”

“As clinicians, we have to take these trials and we have to translate the results into our clinical practice,” Prof Gale continued. “Many clinicians now are still aiming for a totally dry retina, particularly with neovascular AMD. What does that mean? It means that perhaps we extend our loading, perhaps we are slightly more attentive to intensive therapy at the beginning of the patient’s journey. So my typical practice would be to try and achieve
dry retina.”

But on the flip side, he said, some pivotal studies indicate excellent visual outcomes even without complete drying of the retina. That means clinicians need to choose what they want to prioritise. ”What is the investment, in terms of patient commitment, the number of injections, perhaps trade off of a few letters more?” Prof Gale asked. “It’s a really interesting discussion.”

For more, see the full Viewpoints series—all episodes streaming now.