The history of AMD treatment and a look at therapeutics in development

Jennifer Lim, MD, of the University of Illinois, talks about the evolving treatment landscape for patients with age-related macular degeneration (AMD), as well as new approaches on the horizon.

Question:

Can you talk about the history of anti-VEGF therapies for AMD and how the potential tyrosine kinase inhibitor (TKI) treatments in clinical trials could impact physicians’ treatment protocol moving forward?

Jennifer Lim, MD:

I’m old enough that when I started my practice of retinal treatments for patients, I was actually using photodynamic therapy, which was a form of, if you will, cold laser that was a 689 nanometer diode wavelength that activated a verteporfin that was injected intravenously into a patient, and it shut down the neovascular membrane, but it didn’t work that well. But we were using this because we had nothing else except laser.

Then in approximately the 2004 to 2006, the clinical trials were going on of anti-VEGF injections into the eye. Finally, when the results came out, we found out that indeed you could actually now improve vision. This was revolutionary because there was no other treatment that could result, say, even in a 15% percent of patients improving 3 or more lines. We were blown away by that.

The paradigm shifted from preventing visual loss to what percent of patients could have maintenance of their good vision and improvements in vision. That started with the first drug that really worked, which was ranibizumab. Of course, prior to that, the pegaptanib sodium was out there. It was trade name was known as Macugen, and it was pretty close to PDT, photodynamic therapy. But there were some improvements in vision, a little bit greater than with PDT. But with the advent of ranibizumab, that’s where we saw the large percentages of eyes, relatively speaking, that could be improved by 3 or more lines and the great maintenance of vision.

When that result came out in ANCHOR and MARINA, the drug was not yet available. What happened is people reached for drugs that were available that were being used, say, in the oncology space such as bevacizumab. That was the genesis of the use of intravitreal bevacizumab.

At Bascom Palmer, Philip Rosenfeld, MD, PhD, decided to take this bevacizumab and inject it into patients initially intravenously and then subsequently intravitreally, and that’s how the use of bevacizumab became so widespread. It was available before the ranibizumab could be out there and marketed.

Then we fast-forward and we look at the development of other drugs such as aflibercept, which is also an anti-VEGF, but also an anti-placental growth factor. That was studied in the VIEW1 and VIEW2 studies and that was compared to ranibizumab. In this study, it was shown that aflibercept every 8 weeks could achieve the same results as ranibizumab every 4 weeks. People started reaching for that.

Now, of course, in that study, the ranibizumab was not allowed to be spaced longer because it had to be given on label. That being said, there were other studies that were done that looked at perhaps dosing ranibizumab at baseline times 3 and then quarterly. That didn’t work as well. People thought, “Well, okay, it doesn’t have the durability.”

At that point, it was looked at and said, “Well, why don’t we look at the OCT and guide the therapy based on the OCT?” This, again, came out of Bascom Palmer with Phil Rosenfeld leading that study. It was shown that indeed, if you do that and use the OCT, if you will, as a VEGF meter, then you can treat and get similar results. Based on that, people started doing treat as needed and then treat and extend evolved.

Then we fast-forward a little bit further now, and we see that there are other ways of treating with anti-VEGFs and drugs that are combined mechanisms of action such as anti-VEGF and anti-Ang-2, which is known as faricimab. Faricimab was approved about 2 to 3 years ago already, and that had great durability when compared to aflibercept. Aflibercept was dosed on label every 8 weeks after loading. The faricimab was given with loading, and then had different ways of dosing it. You could dose it, say, every 12 weeks or every 16 weeks. It was found that dosed even at that interval, the results were similar to aflibercept dosed every 8 weeks. That led to greater durability.

Then even in terms of drying, when we looked at the head-to-head phase where patients were given the same amounts, we saw greater reductions in the central subfield thickness, indicative of greater drying effect. Maybe that’s why you can go longer. Of course, it could also be the anti-Ang-2. We have that in our armamentarium.

Another anti-VEGF that’s useful for neovascular AMD is 8-mg aflibercept known as high-dose aflibercept. This also has been shown to result in lower needs for dosing. This was also studied and compared to aflibercept 2 mg. That’s yet another option for our patients.

More recently, in the last few years, the class of drugs known as tyrosine kinase inhibitors have become very popular and have been very much studied in clinical trials, including age-related macular degeneration. This class of drug known as TKIs for tyrosine kinase inhibitors, to me, is very interesting, because it doesn’t work in the extracellular milieu, it works intracellularly.

Basically, if you have a lot of VEGF that the body’s producing in the eye and it’s floating around and it’s binding to the receptors, where this drug works is after the binding to the receptor, it shuts down the signaling. You can see how that can be very powerful. The eye can still produce the VEGF. You don’t necessarily have to worry about that because you’re now blocking the intracellular signaling. It will also affect multiple other cytokines aside from VEGF.

One of these drugs that was studied is known as vorolanib. Vorolanib will go ahead and block that VEGF receptor signaling intracellularly. It was shown in the DAVIO 2 study that when you compare this to aflibercept, that you ended up with the same mean change in best corrected visual acuity and about the same changes in OCT.

You’re wondering, well, then what’s the benefit? Well, the way the study was designed is that you gave aflibercept at baseline, and then a month later and a month later, and you look to make sure the patient was responding, because we wanted patients who were VEGF-responsive. Once you got to that point, the patients were then randomized to the drug known as EYP-1901 2 mg or EYP-1901 3 mg or to aflibercept going forward every 8 weeks. This was a single dose of EYP-1901. Basically, the patients were then followed, and during the next 6 months until the primary endpoint, they were allowed to receive supplemental aflibercept as needed.

Now, interestingly, 87% of aflibercept eyes did not need supplemental, meaning they didn’t break through the Q8, and 63% of the EYP-1901 2 mg and 63% of the EYP-1901 3 mg also did not break through with a single use of that insert. That was really interesting to me.

We see now that despite the fact that you only give 1 injection, you can go the 6 months in a significant proportion of patients and they won’t break through. This has now led to the LUGANO and LUCIA studies, which are going forward. These are the phase 3 studies investigating the use of EYP-1901, vorolanib is the drug, and comparing it to aflibercept.

Now, of course, there are other TKIs, and these include axitinib as well as sunitinib. Sunitinib was initially tested as a microsphere injection into eye, but there was some dispersion involved, and I think that’s no longer going forward.

Now, the other TKI known as axitinib is being studied by the OTX-TKI study, and that is a similar design comparing it to aflibercept as well. In this study, again, they’re looking at durability with the single injection and seeing how long can this drug go in comparison to how long can aflibercept go. The design in the SOL study, SOL 1, is to allow the patients to, if you will, recur with their CNV in a very careful way, because they’ve, again, been loaded up front so that they don’t drop more than 5 letters below baseline in comparison to the durable TKI that’s being studied.

We have now in 2025 many drugs that have greater durability than what we were able to use in the past. It’s hopeful that these phase 3 studies will go forward and give us yet something else in our armamentarium to use.

Now, aside from that, there’s yet another durable way to treat AMD, and that is using the port delivery system (PDS), which is an implantable device filled with a proprietary solution of ranibizumab, and you do this in the operating room, but you refill it in the clinic at 6 months on average. This too had great results in terms of best corrected visual acuity and OCT as compared to ranibizumab given every 4 weeks in the study, in the Archway study. This led the approval of the PDS.

Now, of course, in 2022, there was a recall of the PDS due to septum dislodgement, which actually did not cause visual problems or morbidity in patients. It was a safety precaution. The company, Roche Genentech, withdrew the PDS device, reworked it such that they tested the septum to make sure it wouldn’t dislodge, and now it’s been re-released and available for use. That’s yet another durable way to treat a patient. Of course, you wouldn’t use that firsthand in a patient because you don’t know is this a patient who’s going to be a high-needs injection patient or not. It’s generally reserved for patients who are high-needs anti-VEGF patients.

Question:

How do you see the treatment landscape progressing in the future for AMD?

Jennifer Lim, MD:

I’m really excited about the future of the treatment landscape of AMD, especially neovascular AMD at this point. As we’ve discussed, there are very great durable treatments available now and durable treatments that will be evolving as well.

I think in the future, we will also see a role for gene therapy. We didn’t touch upon that earlier, but there gene therapies that can put the formula, if you will, for, say, a ranibizumab drug or aflibercept drug into the eyeball and have it manufactured, so like a little factory producing an anti-VEGF. Of course, as you can imagine, then you would have a continuous supply of the anti-VEGF and not necessarily have to inject.

Of course, there’s some caveats, there have been some RPE areas of atrophy noted. There’s also some concern that if you have continuous anti-VEGF production, are you going to lose some of the effect that VEGF does for the eye in terms of the good effect, the constitutive role of VEGF, and the fact that you can’t at this point turn it off. Of course, those all have to be worked out, but that I think is going to be useful.

In terms of the non-neovascular or the very severe form of dry macular degeneration, of course, we have the drugs that are available now, and these are FDA-approved drugs. We have pegcetacoplan and avacincaptad pegol. They do slow down the rate of geographic atrophy. But as you know, particularly with pegcetacoplan, there were rates of retinal vasculitis seen, albeit low, less than 1 in 4,000, but still very devastating for the patient if that should happen. There are also associated rates of optic neuritis that can occur, and of course, higher rates of conversion to wet, which of course is treatable.

That being said, some of the newer treatments in the future that will work for geographic atrophy that’s severe will probably include transplantation of RPE and then transplantation of RPE with photoreceptors and maybe perhaps even regenerative treatments that can get that back.

Some of the other treatments also being looked at are siglecs and other drugs that can, if you will, help with the turnover and get rid of the sick RPE. A lot of research is going on in this regard as well.