Ashkan Abbey, MD, of Texas Retina Associates, spoke with Ophthalmology 360 at AAO 2025 about the latest clinical updates on the investigational treatment vorolanib or EYP-1901. Phase 3 trials are underway investigating the tyrosine kinase inhibitor (TKI) for the treatment of age-related macular degeneration and diabetic macular edema.
Question:
Can you talk about the use of vorolanib for retinal exudative diseases?
Ashkan Abbey, MD:
Vorolanib is really interesting. What we’re thinking about it right now in is the EYP-1901 intravitreal insert, which is essentially a bioerodible insert that releases vorolanib over the course of maybe 6 to 9 months continuously in the eye after it’s injected with an intravitreal injection. What it is specifically is a tyrosine kinase inhibitor, and in this case the tyrosine kinase inhibitor works intracellularly and it inhibits all 3 of the VEGF receptors intracellularly. It helps to kind of stabilize retinal vascular diseases by doing that, but it also importantly spares the TI-2 pathway. The TI-2 pathway, we know we want it to continue to function properly, because it does enhance vascular stability as well.
We are learning about other mechanisms of action of vorolanib and tyrosine kinase inhibitors. I think we have a lot more to learn and I think there are other things that we can address of kind of new findings that are coming around from it as well, which I think we can think about in the context of inflammation as well. Very recently, the company that’s producing EYP-1901, EyePoint, released some interesting in vitro data that showed that there could be an inhibitory effect on IL-6, which we know can play a role also in the inflammatory component of diabetic macular edema. Maybe it also will work on that kind of a multimodal way of treating DME both through VEGF receptors but also through IL-6 mediated inflammation, so maybe it gives it a little bit more of an extra multimodal effect from that as well.
Question:
How does vorolanib, a TKI, differ from the anti-VEGF therapies typically used in DME treatment?
Ashkan Abbey, MD:
Yeah, the JAK pathway is essentially what IL-6 is activating, and in regards to vorolanib right now, when we say that there could be an inhibitory mechanism there in vitro, we see that the actual vorolanib molecule can bind to IL-6 and thereby inhibit its ability to activate the JAK pathway, specifically JAK1. When that is inhibited, we thereby don’t allow for the downstream inflammatory of the activation of that JAK receptor. In theory, we may have a way to reduce inflammation in our diabetic macular edema patients as well through that pathway.
Question:
What are some highlights from the phase 2 DAVIO 2 and VERONA trials?
Ashkan Abbey, MD:
Yes, the EYP-1901 clinical trial program is the most robust out of the other tyrosine kinase inhibitors that are currently being evaluated, primarily because they went through the traditional process of doing at least for wet AMD, a phase 1, a phase 2, and now a phase 3 trial. The DAVIO trial was the phase 1 trial looking at the safety and showing proof of concept of the use of EYP-1901 in wet AMD. Now, the DAVIO 2 trial was their phase 2 trial. In that trial, they looked at a larger number of patients specifically who were previously treated with wet AMD, and these patients importantly we know were very high-treatment-need patients. They had actually an average of 10 injections in the prior year prior to being enrolled in the study. Once they were enrolled in the study, they were randomized to receive either a higher dose 3-mg injection of EYP-1901 or a lower dose 2-mg injection, or they received the aflibercept injection with a sham of EYP-1901.
In the control group, those patients then went on to get every other month dosing with aflibercept according to standard of care, but in the 2 treatment groups with EYP-1901, those patients were then followed monthly. All 3 groups, by the way, received 3 loading doses of aflibercept prior to being followed monthly, it’s just that on that third dose they would get either EYP-1901 or sham. The monthly follow-ups, the patients will be evaluated based upon vision and OCT measures, and if they met certain criteria they would actually be retreated with rescue treatment with aflibercept 2 mg.
What we found in the DAVIO 2 trial was that patients who received the EYP-1901 had a significant reduction in the number of treatments they needed compared to 2 mg every other month aflibercept over the course of 6 months after receiving EYP-1901. In particular, two-thirds of the patients who received EYP-1901 roughly did not require any supplemental treatment for the 6 months after receiving their dose of EYP-1901. Also, we saw roughly about an 85% reduction in treatment burden overall compared to the prior year of treatment in the EYP-1901 treated groups.
When it comes to vision and also anatomy, what we saw is that the patients who received EYP-1901 had a statistically non-inferior change in best-corrected visual acuity compared to the aflibercept-only treated group, and that was the primary endpoint which was met for the study. Also with respect to anatomy, we saw an improvement in the anatomy that was sustained in more of a linear fashion over the course of 6 months compared to a sawtooth pattern that we see often with 2-mg aflibercept due to the fluctuating levels that we have when we do every other month dosing. We saw more of a consistent stable control, which speaks to that kind of steady release of the drug from the EYP-1901 insert in the eye.
In addition to the wet AMD program, which now is going into … it has actually completed enrollment in their phase 3 LUGANO and LUCIA trails, which looks at treatment-naive and previously treated wet AMD patients, so we expect a readout of that data next year actually for phase 3 for wet AMD.
The DME side is also being explored right now, and we’ve already completed the VERONA trial, which is specifically for previously treated DME patients. This trial design is a little bit different, because it specifically looked at just a single injection on the first day after a washout period from their previous treatments of either a high milligram … sorry, a high dose 2.7 mg EYP-1901 with an injection of aflibercept on the same day, or a lower dose 1.3 mg dose with an injection of aflibercept on the same day, or the control group, which was 2 mg aflibercept with a sham injection. That was 1 injection and the patients were followed monthly for 6 months after that, and they could be rescued at every treatment visit after that based upon pre-specified reduction in visual acuity or increase in fluid, a standard that we would expect from the re-treatment criteria.
What we saw is that we had an immediate effect after one injection with EYP-1901, particularly the higher dose, the 2.7 mg, which is the one that’s being explored in the phase 3 trials currently. We saw a pretty significant improvement in visual acuity and a pretty significant reduction in the anatomy, which was greater than the patients who received aflibercept alone just one month in after the injections. What we can surmise from that is that there was that early bioavailability of the drug with EYP-1901 injection just after one month of injection, which I think was somewhat surprising when we initially saw that, ’cause many thought that it just would take a little time to build up, much like our previous experience with say a similar delivery device in the fluocinolone plan. We know that that one takes a little bit more time to take effect, maybe 2 to 3 months, whereas this one we saw the effects really within 1 month of treatment.
There’s early bioavailability of the actual drug vorolanib in the eye, which shows up in the visual acuity changes and also in the anatomy changes. In addition to that, the patients remained with a stabilization of their vision anatomy over the course of the 6 months of the trial. If you look at the supplemental injection-free patients, we see that in the high-dose EYP-1901 group, 73% of the patients were supplemental injection-free after that 1 injection, whereas in the aflibercept group, it was only 50% of the patients that were supplemental injection-free at 6 months, and so there was a higher proportion of patients that did not have to have any supplemental injections.
Also kind of interesting, another analysis that was done was looking at macular leakage in these patients, and what they saw was that there was a greater reduction in macular leakage on fluorescein angiogram 6 months after receiving EYP-1901, particularly the high-dose one compared to the aflibercept group. I think that kind of speaks to the possibilities of vascular stabilization from possibly the inhibition of IL-6, and then also the added vascular stability that comes from pan-VEGF receptor inhibition.
This is all really exciting data in the VERONA trial, and so what’s now the next step for the DME component of this is that we’re going to be seeing phase 3 trials called COMO and CAPRI that are going to be starting probably in the first quarter of 2026, so we’ll be looking forward to enrolling those trials very soon.
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