Angiogenesis 2024: Targeting Ang2 and VEGF – Biology, Pharmacokinetics and Latest Clinical Data in nAMD and DME

Jennifer I. Lim, MD, FARVO, FASRS sat down with Hattie Hayes of Ophthalmology Times Europe to discuss her findings, including exciting advancements in targeting Ang2 and VEGF from the Angiogenesis Exudation and Degeneration 2024 event.

Video Transcript

Editor's note - This transcript has been edited for clarity.

Hattie Hayes:

Hello, I'm Hattie Hayes, editor of Ophthalmology Times Europe. Joining me today is Dr Jennifer Lim, who is a speaker at this year's Angiogenesis Symposium. Her presentation on biology, pharmacokinetics and the latest clinical data in nAMD and DME is our topic of discussion today.

Dr Lim, thank you so much for joining me. Could you please give us a brief overview of your presentation?

Jennifer I. Lim, MD, FARVO, FASRS:

Yes, happy to, Hattie. Thanks for having me here today. During my presentation at angiogenesis, I discussed some of the new findings regarding faricimab. And one of them was that we actually did get samples from the aqueous of patients with DME and AMD of the Angiopoietin-2 levels. And we showed that when you gave faricimab, the Angiopoietin-2 levels were actually lower, and that this did not occur with the aflibercept. So this was some confirmation that indeed, the faricimab, which is a bi-specific anti-Ang2 and anti-VEGF, was actually targeting and hitting the Ang2 based on the pathophysiology of disease. And we know that in AMD, and in diabetes, that Angiopoietin-2 plays a role. We know that Ang2, when it's increased, drives vascular instability. And this leads to breakdown of vessels, which of course, will then lead to exudation and fluid in these eyes, and to what we see clinically.

The second point was the fact that the clinical trials, the way they're designed, can actually affect the durability that you achieve. So for instance, in the faricimab studies, the interval was capped at Q16 weeks. And, in fact, when we went back, and we looked at the retreatment criteria, and we said, based on absence of drop in vision, absence of fluid increase, or in nAMD, the absence of, say, bleeding – if we use the same criteria for the DME and the AMD eyes, and we applied it to patients who were already achieving every 16 week intervals, what percent of those patients would have been able to theoretically be dosed at Q20 weeks. And we found that over 50% of patients in DME and AMD could actually be dosed at Q20 week intervals. So it just kind of points to the fact that the design of studies can affect what you actually find out. And we also analyzed the data for retreatment criteria itself. So for instance, when we looked at the faricimab data, we said, "Okay, if the vision dropped, or if the thickness of the retina increased, or blood occurred, you would retreat." Now, let's say we flipped that. And let's say...let's say we required, as some other studies have done, that we have a drop in vision, and we have a certain increase in the thickness of the retina or the presence of blood. What would have been the percent of eyes that could have achieved Q12 week or longer? And we found that that number went way up, it went from 70, all the way up to 95%. So again, the clinical trial design can affect what you achieve.

And then lastly, I also presented on real world data, specifically looking at all the databases, such as Vestrum, and alluding to other real world databases, such as FARETINA, and TRUCKEE and TAHOE. And those will be you know, of course, discussed by other speakers during angiogenesis. And basically what they all showed was that the rates of intraocular inflammation were not higher than what was seen in the clinical trials. And lastly, that the BALATON and CAMINO retinal vein occlusion IOI rates were also quite low and in line with what we saw with AMD and DME. So altogether, I think it shows that that faricimab was hitting the target that it wanted to, that it was achieving durability, and that perhaps the durability could have been even longer, and that it did so in a safe fashion.

Hattie Hayes:

Is there anything in your presentation that you think others might find surprising or novel?

Jennifer I. Lim, MD, FARVO, FASRS:

Yeah, I really think that it's the fact that clinical trial design can really impact the outcomes that you get, and that, that when we change the recruitment criteria, or when we increase the options for interval extension, that we could actually get results that are similar to maybe what we're seeing with 8mg aflibercept, for example. And so we have to be really careful, when we look at outcomes, to understand how the design can affect the outcome.

Hattie Hayes:

What are the key points you hope conference attendees will take away from this research?

Jennifer I. Lim, MD, FARVO, FASRS:

I think you know, the key point is is that Angiopoietin-2 is really an important target. We saw this in the phase two RUBY study that gave us the first evidence that Ang2 combined with anti-VEGF can have an outcome. And we see it here in the faricimab studies, when we look at head to head dosing, and the fact that you can quadruple the anti-VEGF dose. It has been done with Lucentis – we saw that when we quadruple the dose of Ranibizumab, that there was no benefit in terms of anatomy. And this was true for the HARBOR study, and as well as [inaudible]. And we also see that when we quadruple the aflibercept dose, as was done in PHOTON and PULSAR, that we didn't get an improved anatomic event either. So I really think that there's something to be said about Ang2 inhibition in combination with anti VEGF, and that there is biologic plausibility. And indeed, we now show anatomic evidence that there is some impact on the actual anatomy and outcomes and in our patients.

Hattie Hayes:

Wonderful. Dr Lim, thank you so much for speaking with me and for sharing your research.

Jennifer I. Lim, MD, FARVO, FASRS:

My pleasure. Thanks for having me, Hattie.