Expert insights: Ashkan Abbey, MD discusses 1-year results of DAVIO-2 trial

Video Transcript:

Editor's note: The below transcript has been lightly edited for clarity.

Ashkan Abbey, MD:

Basically, we were looking at the one-year data for the phase 2 DAVIO2 trial, which compared EYP-1901 to aflibercept for wet age-related macular degeneration. Specifically, previously treated patients with wet AMD. We'll start by describing what EYP-1901 is. EYP-1901 is a combination of vorolanib, which is a tyrosine kinase inhibitor that is a very potent pan-VEGF receptor inhibitor. It inhibits VEGF receptors 1, 2, and 3 while also not inhibiting the Tie2 pathway, which the Tie2 pathway actually can promote blood vessels stability in the retina, so it avoids inhibiting that. [It] allows that to continue to promote stability of the vessels, while also inhibiting angiogenesis and vessel leakage by intracellularly inhibiting VEGF receptors 1, 2, and 3.

This is the medication that's actively being used for this traditional injectable insert, and it's being released with zero order kinetics with a constant release over the course of about 6 to 9 months using something called the Durasert E technology, which is a proprietary technology for EyePoint Pharmaceuticals, who's creating this medication. This is a bio-erodible matrix that slowly elutes the drug over the course of that time period, and then the matrix itself will degrade and be completely eroded after all of the drug has been eluted so there's no free floating drug in the eye.

In the Phase 1 trial, they only occurred 1 time for these patients, so if you look at the study design, they brought in patients who were previously treated, [they] had to have had at least 2 injections in the prior 6 months before enrollment. But many of these patients actually were heavily treated, so they had received, on average, 10 injections in the year prior to being enrolled, and so they were a high treatment need patient group. 

They get enrolled in the study, and they're randomized into 3 different groups in the study. One group is a group that receives high dose EYP-1901, which was a 3 milligram dose. There was one group that received a 2 milligram dose, which is a low dose group, and then the third group did not receive EYP-1901. It was a treatment group of just aflibercept every other month dosing, and that was after 3 loading doses. It’s important to note that also all 3 of the groups received 3 loading doses of aflibercept prior to getting either EYP-1901, which was received in the treatment groups during the third visit where they received the third aflibercept injection, they also got EYP-1901. Again in the other group, the patients who got aflibercept 3 loading doses, then they went to every other month dosing after that.

These patients were followed for one year, and the important other aspect of this study design is that every single time they were seen on a monthly basis during the study, they would qualify for potential retreatment based upon pre-specified criteria. These are standard boilerplate criteria that you may see in many other of the trials that we have that are looking to reduce treatment burden. Specifically, in this one, it's a combination of vision and also central subfield thickness changes on the OCT or the presence of a macular hemorrhage would trigger the potential for a retreatment with aflibercept at any of these visits, and that was for all 3 of the groups that could be retreated any of their monthly visits.

The primary endpoint of this study was specifically looking at change in visual acuity from baseline at a blended time point between weeks 28 and 32, so weeks 28 and 32 roughly is equivalent to the time that it was about 5 or 6 months after receiving the EYP-1901 treatment. We’re trying to see if there was a non-inferior change in best grade to visual acuity between the treatment group and the group that just received aflibercept, and what we did find was that there was a non-inferior change. All three of the groups at the blended time point of weeks 28/32, when you combine them, they all on average gained one letter of vision over the course of that time point, so there's really no difference between all three of the groups in terms of how they did respective vision. That primary endpoint was met for the study.

If we take the patients that all went to the one year visit, actually, you'll see at the one year visit that the patient still maintained their vision. It was really again no significant change in the best corrected visual acuity from baseline all the way up to the month 12 visit. There was no difference among the 3 groups as well when it came to those changes from baseline vision. Also, if you look at central subfield thickness all the way out to year one, again, there was stability on the OCT in terms of the maintenance of a thinner retina over the course of time. It was a really good, strong, and tolerant control. 

The important thing to note is there also wasn't a significant amount of fluctuation in terms of the central subfield thickness. In the aflibercept group, there was a bit of a sawtooth pattern where you could see an up and down seesaw-looking appearance to the graph, if you chart it out in terms of central subfield thickness, due to the fluctuations that we expect to see because we're doing every other month dosing with the aflibercept, and we know about the half life with respect to the 2 milligram of aflibercept with that. We don't see that in the EYP-1901 group. We see a straight, constant, stable, central subfield thickness all the way out for one year, and that really shows us that zero order kinetics pharmacodynamics that we know about with EYP-1901 and that it is just constantly releasing the drug steadily over the course of that time period.

Really important to note that this trial also looked at treatment burden, and I think that’s one of the major advantages of this potential therapy for us if it gets FDA approval. When you look at the patients who received EYP-1901, 63% of those patients were supplemental injection free 6 months after receiving the implant, so roughly two thirds of patients didn't need a single injection for 6 months after they got it. Pretty significant reduction in treatment burden. And if we look at it a different way, both the overall treatment burden when you compare patients the year prior, the number of injections they got, to the 6 months later and and further on, we had about an 85 to 90% reduction in overall treatment burden compared to when they entered the trial.

Finally, I think we have to always address safety when it comes to anything new that we're trying to put into an eye, and in this case, the safety profile was quite good. There have been 190 injections of EYP-1901 over the course of multiple different clinical path programs that they've done so far. Out of those 190 injections, there hasn't been a single serious adverse event that has been either ocular or systemic that's been reported with related to the EYP-1901. There were no cases of occlusive vasculitis, and there were no cases of anterior segment migration of the implant as well, so overall, good safety profile so far.

The final point is that we have in the future coming down the pipeline right now, we have these 2 pivotal Phase 3 clinical trials that we're looking at EYP-1901 compared to again just aflibercept dosing, with every other month dosing. And in this case, those patients are receiving a 2.7 milligram dose instead of the 3 milligram dose. It's slightly less than the high dose that was used in this DAVIO2 trial. This has already been enrolling, and they essentially have 2 cohorts. It's just the 2.7 milligram group and then the aflibercept group, and they're looking at doing this for as a 2- year trial where they give the EYP-1901 after 3 loading doses every 6 months. The patients will be receiving it every 6 months for 2 years in the study, and again, looking at non-inferior change and best corrected visual acuity, very similar to the DAVIO2 trial as well. Looking forward to having that further enrolled right now. It's actually been enrolling quite quickly, but that's going to be the future for this medication hopefully to get good results in Phase 3 and have approval in the next few years.

I think it's going to allow us to feel much more comfortable, in my opinion, doing a treatment and extend protocol that goes past what we currently feel comfortable with, which is about 4 months. So to me adding this on in the background while I'm treating with our current second generation anti-VEGF agents like vabysmo or faricimab also high-dose of aflibercept. I think those agents are the most durable agents we have on the market right now, and if we have this insert in the eye in the background constantly releasing the tyrosine kinase inhibitor to support our ability to feel good about going longer between our treatments without having a recurrence of fluid or hemorrhage, I would say that this could significantly allow us to reduce our visit burden and treatment burden. Right now, my limit for most of my patients with the anti-VEGF just currently available is 4 months for wet AMD patients. I don't let them go past 4 months, but I think I would feel comfortable starting to have them go out to say 4 ½ or 5 months on a follow-up visit if I knew I had EYP-1901 working in the background as well.

There has been a small trial that's been done for diabetic macular edema with EYP-1901. There are small numbers so far, but it was actually very promising in those small numbers; we saw when you basically treat a previously treated diabetic macular edema patient with EYP-1901 as opposed to just aflibercept a single injection comparison between the two, you see that EYP-1901 actually had a more significant improvement in vision compared to the patients who received the aflibercept, and they also had a more significant improvement in central subfield thickness compared to those that received aflibercept. It was a small numbers, initial pilot trial, that they were looking at just to see if there was a significant effect, and they found that that was the case. I think they most likely will have a plan to pursue some sort of a clinical trial, a Phase 3 trial, for diabetic macular edema with this agent as well in the future. Although, we haven't heard any data or any news about that as of late yet at least.

I think one final point that I would make about all of the tyrosine kinase inhibitors that are potentially going to be coming to us in the next few years is that this is not just ‘Okay, more anti- VEGF just over the course of a longer period of time.’ I think it falls into a category on its own as a way to supplement anti-VEGF therapy, not just for durability purposes, but also potentially as a kind of multi-modal treatment regimen for our patients. One of the trends that I think we're seeing in ophthalmology, in retina specifically, is that we are needing to start treating our diseases more holistically and not just based upon one pathway, but multiple pathways. Much like many oncologists are treating their patients who have different types of cancer, they try to attack it from multiple different ways instead of just one treatment pathway or mechanism of action. These TKIs are going to add a different pathway in terms of treating the patients with respect to pan-VEGF inhibition, and also some inhibition of say FGF and pdgfas well. Maybe reducing fibrosis, maybe things like that. There are new advantages to using something that is affecting different pathways like this. We're using the anti-VEGF, a strong, durable therapy that we currently have. I think this is the future of how we're going to be treating our patients, especially in the vascular disease paradigm that we have right now. It's not just going to be attack them with a lot of anti-VEGF, but use the anti-VEGF and add some other stuff in addition to give them the best possible visual outcomes, durability outcomes and anatomical outcomes overall.