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Clinical Trials of Alternative Targets in Wet AMD


Key opinion leaders in ophthalmology comment on the potential role of alternative targets beyond VEGF-A including VEGF-C/VEGF-D and tyrosine kinase inhibitors.

Charles C. Wykoff, MD, PhD: Diana brought this up, but let’s come back and talk directly again about faricimab. I’m curious about everyone’s perspectives here. This is the latest and greatest phase 3 data we have to digest; it just came out publicly a couple weeks ago. It blocks angiopoietin-2 in addition to VEGF-A. We have the neovascular AMD [age-related macular degeneration] data as well as the DME [diabetic macular edema] data. It’s unusual to have 4 phase 3 trials to digest at once, 2 in wet AMD and 2 in DME. We heard Diana’s perspective. I completely agree with that. Sophie, what was your takeaway from the faricimab data that were presented?

Sophie J. Bakri, MD: Certainly in AMD, faricimab [Genentech] was compared to Q8 [every 8 weeks] aflibercept. And yes, about half of the patients on faricimab could go out to Q16 [every 16] weeks. I just know that from our clinical practice, that does not occur. Even though in the trial, technically, they didn’t compare 16-week aflibercept to 16-week faricimab, most of us who have treated a lot of patients are very hopeful when we see those numbers and that extension. It holds great promise. I’m looking forward to its approval.

Charles C. Wykoff, MD, PhD: Yes, exciting. Let’s talk about the other non–VEGF-A targets from the other molecules. You have OPT-302, briefly, which is targeting inhibition of VEGF-C, and D, in addition to VEGF-A, with concurrently administered either ranibizumab or aflibercept. There was a large phase 2 trial that suggested superior vision outcomes. That’s moving forward in a pair of phase 3 trials, a global phase 3 program is initiating enrollment supposedly soon. Any hope, Mark, that blocking additional VEGF family members is going to add value in this disease phase?

Mark P. Breazzano, MD: We see it now with the agents that we have, the more different VEGF molecules we get, potentially the more robust the response. And as you pointed out with the trial data so far, it hasn’t been disappointing. It’s helpful. There have been some preclinical data with some other molecules as well, showing that ultimately VEGF is a beneficial target for us. But at the same time, we do have the capability of looking at other ways to target the neovascular disease. The more molecules we can target, certainly the better, and maybe even new pathways as well. For example, there’s the Runt-related transcription factor 1, it came out in The American Journal of Pathology, and it seemed like a robust target potentially for another agent down the line as well. It’s exciting to see everything that’s coming out.

Diana V. Do, MD: Charlie, it’s always interesting when you’re employing combination therapy because the OPT-302 requires a separate injection from the anti-VEGF agent. It’ll be interesting to see if it does show some added benefit such that patients would want 2 injections in 1 visit.

Charles C. Wykoff, MD, PhD: Yes, great comment. Diana, take us even further downstream. Now we have all of these TKIs, these tyrosine kinase inhibitors, in the space. The theory here is to block intracellular signaling from all of the VEGF family members. You get the effect of OPT-302 plus Eylea or plus Lucentis, or whatever other medication blocking VEGF you’re going to use. Do you think these TKIs have a role in our space? We’ve talked about them for years.

Diana V. Do, MD: Yes, I know TKIs, tyrosine kinase inhibitors, are being evaluated by several companies. axitinib is being evaluated by Clearside [Biomedical] as a suprachoroidal injection that could have beneficial effects and long duration of action. In addition, Graybug [Vision, Inc] is evaluating sunitinib as a long duration, every 6 month-administered intravitreal injection. And of course, EyePoint [Pharmaceuticals, Inc] is evaluating their drug as well looking at a sustained delivery of a TKI inhibitor. All these in theory have the potential of working and will be put to the test when they go against our current anti-VEGF therapies.

Charles C. Wykoff, MD, PhD: It’s exciting. There is a tremendous amount of activity in trying to achieve better and more sustainable outcomes for our patients.

Transcript edited for clarity.

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