Ladies and gentlemen, thank you for standing by. Welcome to PAVIA Topline Data Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you would need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would like now to turn the conference over to EyePoint Pharmaceuticals President and Chief Executive Officer, Dr. Jay Duker. Please go ahead.
Thank you very much. Good morning, everybody, and thank you for joining us this morning. With me today is our Executive Vice President and Chief Financial Officer, George Elston, and our Chief Medical Officer, Ramiro Ribeiro. This morning, I'm going to talk about updates to the topline data from our PAVIA phase II clinical trial, as well as some discussion around our upcoming phase III wet AMD trials for Duravyu, which is formerly called EYP-1901. We will be making forward-looking statements today, and you can go to our website if you want more details around these statements. EyePoint Pharmaceuticals is committed to improving the lives of patients with serious retinal diseases, and our lead clinical asset is called Duravyu, which is vorolanib intravitreal insert, formerly called EYP-1901. This has the potential to be a multibillion-dollar opportunity, in particular based on our positive phase II data in wet age-related macular degeneration.
We are on track to start the first phase III trial in wet AMD in the second half of this year. Today, we're reporting topline phase II data in non-proliferative diabetic retinopathy, with the full 12-month dataset expected in the third quarter of this year. We have a phase II diabetic macular edema study ongoing, and we anticipate topline data from that study in the first quarter of next year. In addition, our pipeline includes EYP-2301, which is razuprotafib, a Tie-2 agonist in Durasert E. Durasert has been injected into tens of thousands of patients. It is a safe and effective intravitreal drug delivery technology. The bioerodible Durasert E is what's being studied now in our phase II programs. EyePoint's got a strong balance sheet.
As of the end of last year, we had over $330 million of cash and investments, which gives us a cash runway through phase III top-line wet AMD pivotal trial data. This slide illustrates our pipeline, which I've discussed already. In addition to razuprotafib EYP-2301, we are also studying complement inhibition in sustained release. Vorolanib is a small molecule tyrosine kinase inhibitor that has activity against all the VEGF receptors, thereby blocking all isoforms of VEGF as well as PDGF. We have composition of matter patent out to 2037. In a preclinical retinal detachment model, vorolanib has shown the potential for neuroprotection. Its activity against PDGF should lead to antifibrotic benefit as well, and because there's no activity against Tie-2 at clinically relevant doses, we should not be upregulating Ang-2. This picture shows a Duravyu insert inside the eye.
They are solid cylindrical inserts injected in the office in a routine intravitreal injection that retina specialists do multiple times every year, rather every day. The inserts are about 1/5,000ths of the vitreous volume, and we can inject up to three inserts with a single injection. There's a favorable safety profile in the studies done to date. There have been no systemic or ocular SAEs related to Duravyu. And the inserts allow the vorolanib to be immediately bioavailable with an initial burst of drug followed by zero-order kinetics for approximately nine months in humans. The vorolanib is fully eluted prior to complete bioerosion of the matrix, and this allows us to control release and allow a redosing regimen. Also, Duravyu can be shipped and stored at ambient temperatures, in contradistinction to the other drugs and devices that are being developed as sustained release anti-VEGFs for wet AMD.
So on to the PAVIA topline results. PAVIA was a randomized multi-center double-masked single injection trial of two doses of Duravyu compared to sham injection. The patients enrolled had either moderately severe or severe NPDR, and they could not have center-involving diabetic macular edema. The primary outcome that was measured was the percentage of patients with a two-step improvement in the DRSS. The DRSS is a scale that evaluates the severity of diabetic retinopathy via fundus photographs, and the evaluations are done by an independent masked reading center. Secondary endpoints that we looked at were reduction in vision-threatening complications, occurrence of DME, and of course, safety. This slide shows the overall structure of the study. On day one, patients received either 2 mg of Duravyu, 3 mg of Duravyu, or a sham control injection, and then they were observed.
The primary outcome, again, that we're reporting is at week 36, but the study end is at week 48. This is the baseline characteristics, and as you read across the slide, I think you'll see they were balanced for all three arms: the 2-mg Duravyu, 3-mg Duravyu, and control sham. Note that the severe NPDR scale of 53 on the DRSS was approximately one-third to 40% of the patients enrolled. The patients had good visual acuity, which is typical of NPDR trials, and the mean CST was relatively normal with a wide range, again, because center-involving DME patients were excluded. This slide shows in graphic form the primary endpoint, the percentage of patients who improved 2 steps on the DRSS, and as you can see, there was really no difference between the levels of Duravyu achieved and what happened in the sham control.
This slide, however, shows the results for reduction in rate of disease progression. So this shows that more patients had a two-step worsening in sham control than in either doses of Duravyu, and while the N is low, there does appear to be a potential dose response here. More eyes that received Duravyu were stable or improved on DRSS, as illustrated on this slide. Over 80% of the Duravyu patients remained stable in the nine months of the study. And this slide, again, looks at both improvement and worsening, but this is a one-step improvement. And to the right of the slide, I think you can see that more patients had a one-step improvement in the two doses of Duravyu versus control, and there does appear, again, with respect to worsening of NPDR, a benefit to Duravyu in a potentially dose-related fashion.
With respect to safety, congruent with the other studies that we have reported, there were no study-related SAEs, either ocular or systemic. There were two ocular SAEs reported in the study eye, not deemed to be drug-related by the investigators. One of them was in a control eye that converted from NPDR to PDR, and the other was a posterior vitreous detachment that was hemorrhagic two months after dosing with 2 mg of Duravyu. No drug-related systemic SAEs, no cases of insert migration, no endophthalmitis, no retinal vasculitis. There was also a low patient discontinuation rate, and none of the discontinuations were related to Duravyu. This slide summarizes both efficacy and safety. We believe that Duravyu has shown a biological effect with a favorable safety and tolerability profile. Duravyu demonstrated stable or improved disease severity with reduced rates of NPDR progression at nine months in both doses.
86% in the 3 mg and 80% in the 2 mg arm demonstrated stability or improved disease versus 70% in the control arms. None of the patients in the 3 mg arm worsened, 5% in the 2 mg arm worsened, and 10% in the control arm. A similar proportion of patients treated with Duravyu and the sham injections achieved a two-step improvement on DRSS. From a safety perspective, again, continued favorable safety profile, no drug-related ocular or systemic SAEs. The TEAEs were comparable between Duravyu and control arm, and again, some of those serious complications that can occur with intravitreal injections, like endophthalmitis or retinal vasculitis, were not observed. The two ocular AEs were not drug-related, and one occurred in a control arm, and again, low patient discontinuation rate. So here are our take-home messages.
We believe Duravyu has shown a biological activity in NPDR with trends toward reduction and worsening NPDR, even though there was no benefit to the primary endpoint. We are awaiting the 12-month data for any further conclusions on the efficacy, safety of Duravyu and NPDR, and we will report them when we have them. In general, their safety really for Duravyu continues to look flawless. We've had no safety issues in the form of SAEs reported in over 170 patients that have been treated with Duravyu. In addition, we have a database of approximately 150 patients that were treated with oral vorolanib in the X-82 studies with no evidence of any ocular toxicity when delivered orally. The NPDR result that we're reporting this morning appears to be disease-specific.
When you look at all the TKI studies that have been done with either oral delivery of TKI or posterior segment delivery of TKIs, we've had five phase I trials and two phase II trials. The phase II trials were the oral vorolanib X-82 trial and the DAVIO 2 Duravyu trial. All seven of those trials have shown a benefit in wet age-related macular degeneration. With regard to NPDR, we now have two intravitreal trials that showed modest results, and therefore, while we can't say with certainty, it does appear that these results are disease-specific to NPDR, and we remain quite confident in Duravyu's ability as a maintenance therapy for wet age-related macular degeneration. So to remind you, we had 160 patients enrolled in our phase II wet AMD trial as a maintenance therapy. That's the DAVIO 2 results.
They were excellent at eight months, no change essentially statistically in visual acuity between either the two doses of Duravyu versus the Eylea control. We had approximately 80% reduction in the treatment burden and no safety issues. Our phase III plans are progressing nicely, and we are on target to have first patient enrolled in the first wet AMD phase III trial in the second half of this year, and our cash guidance remains solid. So with respect to Duravyu and wet AMD, we believe in this whole sustained release wet AMD space that we have the best drug, we have the best delivery system, and we certainly have the most robust phase II dataset.
We continue to show an excellent safety record, which you all know is paramount in treating retinal disease, and given the size and results of our phase II program, we believe we have the most de-risked program. So I'm now going to be happy to open this up to any questions that you may have.
Thank you. As a reminder, to ask a question, please press star one one o n your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please limit to one question with no follow-up questions so we have time to get everyone. Please stand by while we compile the Q&A roster. The first question comes from Tess Romero with J.P. Morgan. Your line is open.
Good morning, Jay and team. Thanks so much for taking our question. So first one is, do you believe that loading doses of an anti-VEGF might be necessary to see response with EYP-1901? And second question is, Jay, you alluded a little to this in your end remarks here, but why do you think TKIs like axitinib and vorolanib have shown lower levels of efficacy in DR versus approved agents like Eylea and Lucentis, even though these approved agents, TKIs, have demonstrated efficacy in wet AMD? Are you able to provide a little more color on how you think about this? Is it mechanistic, indication-driven, or anything related to the clinical trial design? Thanks so much.
Yeah, great questions, Tess. Thanks for them. So first of all, with respect to the loading doses, obviously, we didn't test that in NPDR, and the reason is, first of all, the immediate bioavailability of vorolanib and Duravyu. And secondly, I just want to remind everybody that the loading doses that were given in our Wet AMD trial, we gave one dose in the phase I and, of course, three doses in the phase II. The loading was really prompted by discussions with the FDA over potential pivotal trial design. We didn't feel that a load was necessary for Wet AMD, but it was based on some regulatory interaction, it was used.
Had we given a single shot or even a full 3-shot load in NPDR, in the short term, based on data from the PANORAMA trial, I would have expected in the short term that we would see a benefit from the load. On the other hand, we also know in NPDR, once you stop treating with an anti-VEGF, the disease within four, five, six months returns back to its baseline, and therefore, any benefit that the load would have given in the short term would most likely have washed out by month 6, and almost undoubtedly washed out by month nine. And of course, in the pivotal trial, it's month 12 that the FDA cares about.
So we don't know because we didn't test it, but we don't think that the long-term result at month nine or month 12 would have been influenced by anything that was done initially in the trial. The second question is more complex, and while it certainly appears to be a true statement that the sustained release anti-VEGFs, small molecule TKIs, don't give the same result in NPDR, I think there are several hypotheses as why this may be. I think, again, generally saying disease-specific is probably a good enough statement, but going deeper into that, the tyrosine kinase inhibitors, while they're very active against the VEGF receptors, also have activity in other tyrosine kinase receptors, and it's very difficult to develop a matrix of those potential activities in various receptors and try to determine what they may do in a various disease state.
I will remind everybody that diabetic retinopathy, while it certainly has a strong VEGF driver to it, VEGF is not the only cytokine that is involved in the pathology. So more work to be done, and I think we're going to wait for the 12-month data to draw any further conclusions, and I'm happy to ask our Chief Medical Officer, Ramiro, to make any other comments on the potential reasons why the TKIs may not be showing a benefit.
Yeah, no, I think you summarized it really well, Jay. As the clinical data has shown, both in our program as well as some other clinical programs, that we see a strong benefit in Wet AMD but not in NPDR. So that leads us to believe that this is more related to disease-specific rather than the compound itself.
Thank you for taking our questions.
One moment for the next question. The next question comes from Tyler Van Buren with TD Cowen. Your line is open.
Hey, guys. Good morning. So you guys stated that you plan to provide an update on the path forward for Duravyu and NPDR following review of the 12-month data. So what specifically will you be paying attention to at 12 months, or will you be looking to confirm in order to make that decision?
Thanks for the question, Tyler. I think, again, since the primary endpoint that the FDA wants to see is 12 months, that I think it's important that we look at the 12-month data to see if we have a potential pathway forward with the current dosing levels and the current intervals in trial design for NPDR. Recently, there's been a second pathway forward for drugs in NPDR, which is the ability to prevent worsening of the NPDR as opposed to actively making things better. We are seeing a trend for that, and we want to see if that continues at 12 months. That really is the full dataset at 12 months, and we'll be awaiting it before we draw any conclusions about potential further trials in NPDR.
One moment for the next question. The next question comes from Yatin Suneja with Guggenheim. Your line is open.
Hey, guys. Thanks for taking my question. So the question is on the read-through. I think, Jay, you mentioned this is most likely disease-specific, but the question is, are there any read-through to the DME study that you are conducting? And if the single injection isn't able to improve or provide enough benefit in NPDR, what should we think about, or how should we consider DME? Any changes you could make to that study now that you have more learning from the NPDR study? Yeah, that's the question.
Yeah, no, it's a great question, and I'll answer the last part first. No, no changes planned at this point. So DME, again, is an active disease that gets actively treated like wet AMD, and we believe Duravyu's benefit in DME would be similar as a maintenance therapy. We're studying it as inactive DME patients along with a single injection of aflibercept. So while there's no full load there, there is a single injection given for everybody in that study, and that's, again, because these patients have active disease, and therefore, we wanted to, essentially, level the playing field so everybody starts with the same level of VEGF in the eye. One of the best read-throughs, frankly, is we had no safety issues. We had never studied Duravyu in a younger patient population, which the diabetics tend to be, in patients with retinal vascular disease such as diabetes.
So it's very gratifying to see that the safety record of Duravyu continues to be quite clean. No new issues, no any issues have really come up, which gives us more comfort that that will also be true in DME. So while there was no significant improvement in NPDR, we did show the potential to slow down worsening of NPDR, which also, again, as a read-through, gives us some confidence that as maintenance therapy in DME, we may be effective.
Okay. If I may, one more. With regard to your negotiation with the FDA on the pivotal study, I mean, is there a possibility for you to just move with a single dose, and then are there critical I mean, assume that you already had a meeting with the FDA, probably waiting for the minutes. Are there critical points of discussion where you think there is a differentiation with FDA and how you think about the pivotal program? Thank you.
So with respect to the pivotal wet AMD program, yes, we had a successful end-of-phase II meeting with the FDA, and we are awaiting the final minutes before we make any public statements about the details around that. I would say, in general, the way this team operates is we try to leave no stone unturned, and therefore, we've looked at a lot of potential changes in inclusion/exclusion criteria as well as potential dosing with just a single dose of Duravyu in the phase III. So no conclusions on any of that have been reached, but we are evaluating ways to de-risk the program and get the drug approved in wet AMD faster. So more details to come. We are considering a lot of potential, again, I wouldn't say major issues, but more honing of the protocol in the inclusion/exclusion criteria.
I really can't make any bigger statements around the end-of-phase II meeting until the minutes are out, but we remain confident and optimistic that our program, as we've outlined, will be acceptable and on a go-forward basis with the FDA.
One moment for the next question. Our next question comes from Jennifer Kim with Cantor Fitzgerald. Your line is open.
Hi, guys. Thanks for taking my questions. Maybe to start off with a factual question. In the datasets you've presented, I saw 20-21 patients per arm. I'm just wondering, it was 77 patients total. Is the discrepancy from discontinuations or something else? Maybe we'll start there.
Sure. I'm going to let Ramiro answer that question.
Yeah, Jennifer, thanks for the question. So as you know, the primary endpoint analysis was the nine-month. So for that analysis, we only included patients that had nine-month data available. So you're right. It's mainly because of the discontinuation.
Or potentially missed visit, correct?
Correct. Yeah.
Okay. And then a bigger question, just going back to waiting for the 12-month data in NPDR, if you are considering an alternative primary endpoint for potential pivotal, do you have any, I guess, efficacy bars in mind in terms of what you'd like to see in the 12-month data?
Well, from the efficacy perspective, we have public statements from the FDA and, obviously, other programs that have stated potential approvable endpoints of 2-step improvement or blocking of 3-step worsening. So those are the obvious ones because we know or believe that they are FDA-acceptable endpoints. On the other hand, if we see strong evidence of efficacy and may be able to do some other type of endpoint, we would explore that with the FDA as well. So until we see the data, I don't think I can go into any more detail on that, but I think we really need to await the 12-month data to see if we have a pathway forward directly to pivotal versus potentially another phase two trial.
Okay. All right. Thanks, guys.
One moment for the next question. The next question comes from Graig Suvannavejh with Mizuho. Your line is open.
Okay. Thank you very much. Tough to see the data this morning, guys, but curious, in light of the recent data from Ocular and the response that they saw, is there anything about maybe the TKI and vorolanib and differences with axitinib that might I realize they're different trials, and it's tough to compare against different trials, but anything in perhaps the TKI in itself that might explain the differences in the data that you're seeing on the two-step improvement on DRSS? Thanks.
Well, I think the first thing is you have to realize the size of the trials, that ours was essentially a phase II with originally 77 patients enrolled. Ocular's trial was phase I. The number of patients who received their drug was in the mid-teens, and so the ends of the trial are very different, and therefore, it's really hard to compare. I think you have to look at the baseline patient population as well, and I think overall, the question is if there is attempted read-through, the read-through would be for NPDR only. It's not going to be outside of NPDR. And therefore, if you're trying to make cross-trial comparisons here, I think you need to just limit it to the NPDR disease. But once again, I think cross-trial comparisons with two different trials, different patient populations, and very different ends is of little value.
Okay. Maybe a quick follow-up. Is there anything that you could point to in the 12-month data that you're expecting to see where perhaps you might see a difference in the slope or the magnitude effect that you're seeing at 9 months that would give us some reason to be optimistic about 12-month data?
Well, I think the data we showed is the data. I think that we believe our drug releases for approximately nine months. I think it can release potentially longer in some eyes. And while it's sustained release, there may be a bit of a crescendo effect that occurs over time here, and I wouldn't rule that out until we see the 12-month data.
Thanks, Jay.
One moment for the next question. The next question comes from Colleen Kusy with Baird. Your line is open.
Good morning. Thanks for taking our questions. Maybe a quick follow-up on that last comment, Jay. So is there anything in the kinetics of response that you've seen so far in the 9-month data in terms of kind of when patients flip to one or two-stage improvements that make you think that the 12-month data might look different?
Thanks, Colleen. That's a really good question, and I'd have to defer because I don't think we've had time to go over this in a sense of patient-by-patient fashion to really look at this. I would say more to come on that, but given that the data was just recently unmasked for us, we don't have that level of detail.
Understood. Thank you. A quick follow-up if I can. You spoke to a couple of data points that may suggest a potential dose response in DRSS. Can you maybe just any theory on why you might be seeing a dose response in diabetic retinopathy, but we didn't necessarily see it in wet AMD?
Yeah. So that gets back to the basic question of why we should see such a great and robust response for Duravyu in wet AMD, but a more modest response in NPDR. And probably, if we knew the answer to that, we could speak to the fact of whether or not there truly is a dose response, and is it really necessarily to get higher doses or more, I should say, higher tissue exposure to increase the ability for Duravyu to control NPDR? Those two questions are tied together, and we just need some more data before we can make a conclusion on that.
Understood. Thank you.
One moment for the next question. The next question comes from Daniil Gataulin with Chardan. Your line is open.
Hey, good morning, guys. Thank you for taking the question. I'm not sure if you had a chance to look at the data yet, but still wanted to ask if you see any differences in responses between patients with moderately severe versus severe NPDR?
Thanks, Daniel. I'm going to ask Ramiro to comment on that. I think he's delved into the data a little bit deeper at this point, so.
Yeah. I think when we look at those type of subgroups, we see a consistent result with the overall, Daniel. So the same changes that we presented for one step, we see across those subgroups.
Okay. Got it. Thank you.
I show no further questions at this time. I would now like to turn the conference back to Dr. Jay Duker for closing remarks.
Again, thanks, everybody, for your attention, and thanks for the excellent questions. To summarize again, we remain very optimistic about our wet AMD program. We look forward to updating you all in the near future when we have seen and digested the end-of-phase II meeting minutes and look forward to further progress in our DME and our wet AMD programs as well as the full 12-month dataset from NPDR. Just a quick reminder to you guys, we are not going to be having earnings calls at this point. Given that we are no longer a commercial company, we will obviously be having a press release coming up soon for the quarterly earnings, but we are not going to be doing a call for the time being. Thanks again for your attention, and look forward to talking to you all again soon.
This concludes today's conference call. Thank you for your participation. You may now disconnect.