EyePoint, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

Sure. Thank you very much for the invitation. Thank you for the question. The LUGANO trial was a phase III trial, which studied our vorolanib intravitreal insert, 2.7 milligrams per dose. Vorolanib is a small molecule tyrosine kinase inhibitor that has activity against all the VEGF receptors, PDGF, and JAK1. The control arm in this study was on-label 2 milligram aflibercept. We were studying it in wet age-related macular degeneration. The patient population, 75% of them were treatment naive, and 25% had been previously treated. The primary endpoint of the study was non-inferiority change in visual acuity from day 1 to the average between week 52 and week 56. As you mentioned, in the full analysis set, we did not meet the primary endpoint. But there were some really encouraging data that came out of the study, including the important secondary endpoints. First of all, safety. In the prior phase II, phase I trials that we've run with the insert, we really had no safety concerns, and that was really backed up in the phase III.

The safety looked quite clean. We also showed really good anatomic control of wet AMD. That's measured in the office by an instrument called optical coherence tomography, or OCT. At the end of the trial, there was only a negligible difference in retinal thickening between the study arm and the control arm. We were able to reduce the treatment burden by over 40%, which, if approved and in the real world, could mean 2 fewer injections per year on average. Over half of the wet AMD patients went the full year under control with our drug alone. In that group of patients, we were statistically non-inferior in change in visual acuity.

In the overall population, however, one of the things that really stood out as highly unusual is the number of eyes in the control arm that lost 15 or more letters. Historically, that occurs because some eyes just don't respond to anti-VEGFs. This is an elderly population, so some of these patients will lose vision for other reasons, like cataract or glaucoma or dry AMD. Typically, in the 2-milligram EYLEA arm at the end of a one-year trial, you expect between 4% and 5% of the eyes to lose 15 or more letters. In the LUGANO trial, it was only a half a percent. That again, is statistically highly unusual. We believe that was the primary reason for the miss. It certainly wasn't that our drug wasn't active. Again, looking at the secondary endpoints, our drug was durable and potent and safe.

There appeared to be a significant mismatch in these 15 letter losers. If you go back and look at our phase II trial, the DAVIO 2 trial, 7.7% of the control arm, the same control arm, 2-milligram EYLEA, lost 15 or more letters. So it went from 7.7% to a half a percent. In the phase II, in our high-dose arm, it was under 4% lost 15 or more letters. When we really broke it down, we ended up with nine patients in the DURAVYU arm that lost 15 or more letters for something other than wet AMD. In those eyes, when we looked at the visual acuities and, of course, the anatomic control and the overall clinical findings, six of them lost vision due to geographic atrophy, the severe form of dry AMD, versus none in the control arm. Again, highly asymmetric and unusual.

Two lost vision due to glaucoma, and one from a successfully repaired retinal detachment, where the patient developed a severe cataract after the successful surgery. So we believe that this asymmetry in the 15 letter losers was the primary reason that we missed the endpoint.

The geographic atrophy patients, I think, again, at the end of the trial, if you looked at their anatomic control of their wet AMD, it was quite good. In fact, of those 9 patients, 3 of them never received a supplemental injection. The reason they didn't receive it is the treating physician felt that there was no active wet AMD, and there was no reason to give them another anti-VEGF. We then did some further analysis to look at the possibility of our drug speeding the growth of geographic atrophy. We certainly hadn't seen that in any of the prior studies, and there's no preclinical data to suggest that.

In fact, the analysis that we've done shows quite clear that not only do we not cause new geographic atrophy, but in preexisting geographic atrophy, the rate of progression was no different than the fellow eye, for example, which is a nice internal control, and was actually less than what's been reported as the usual progression of geographic atrophy. What we did find is the eyes in the DURAVYU arm started with geographic atrophy closer to the center of the fovea. That means that even if they progress at the same rate, obviously, if you start closer, you're more likely to have visual loss from that. We think, again, it was just an asymmetric distribution.

The 2 patients that had a loss from glaucoma, one of them, unfortunately, every time they got an EYLEA shot, which was part of the trial for them to get EYLEA at the beginning, they spiked their pressure very high due to the EYLEA shot. Clearly, if that patient had been randomized into the other arm, they would have received EYLEA and had the same pressure spikes. Again, it appears certainly just a little bit of bad luck with the randomization in those cases.

I think, again, overall, the physicians we spoke to, and we've spoken to a lot of retinal specialists and shown them the data, they're quite enthusiastic about the secondary endpoints, including that reduction in treatment burden. The expectation or hope going into the trial from retinal specialists was that we would have at least a 20% reduction in treatment burden. When you look at the real-world analysis of medications like high-dose EYLEA and VABYSMO, which have been very successful, these second-generation anti-VEGFs, they appear to reduce treatment burden less than 20%, about one injection less per year on average. Yet they're quite successful. We think that that overall success of the reduction in treatment burden, if approved, would be very enthusiastically accepted by the retinal community.