Good morning, everyone. Welcome to our London Jefferies Healthcare Conference. I couldn't think of a better way to start off this conference than with EyePoint Pharmaceuticals. With a clear vision for success, we have CEO Dr. Jay Duker and CFO George Elston. Welcome, gentlemen. How are you doing?
Great. Thanks for inviting us, Kambiz. We're really excited to be here this morning.
Awesome. Well, let's just get right into it. You have an amazing clinical candidate, Duravyu, sustained TKI in development for Wet AMD and DME. Can you provide us a high-level overview of your Phase III program in Wet AMD?
Sure. So again, our lead product is called Duravyu, also known as EYP-1901. It's the small molecule tyrosine kinase inhibitor, Vorolanib, which has activity against all the VEGF receptors. It does work at the receptor level. It means it blocks all isoforms of VEGF, and it also blocks PDGF, which theoretically should make it antifibrotic. At doses we use in humans, it does not block Tie-2 , which is a good thing. You don't want to block Tie-2 because if you do block Tie-2 , you upregulate angiopoietin-2, which dysregulates the retinal vasculature. Duravyu is in our patented delivery system we call Durasert. Durasert has been in four FDA-approved products previously. Those four products all were non-bioerodible. They were designed that way because of the solubility of the drugs we were using.
To make them non-bioerodible, there was a polyamide shell that was wrapped around the core matrix of the drug. That shell is inert and never disappears. What we're using in Duravyu, however, is fully bioerodible. We took away the polyamide shell. Again, the solubility of Vorolanib, as well as the time for which we wanted it to work, meant that we didn't need the shell any longer. We've studied Duravyu now in a Phase I Wet AMD trial and a Phase II Wet AMD trial. And, as you just indicated, Kambiz, we just recently dosed our first patient in the Phase III trial, the first of two. The second trial, we are on schedule to dose the first patient before the end of the year. So this trial was designed after our success in the Phase I and Phase II, and after several consultations with the FDA. Started in 2022.
At the time, we had just finished our successful Phase I trial, and we're internally contemplating the possibility of going right to pivotal after Phase I. So we met with the FDA, had a Type C meeting, had a nice exchange, and at the end came up with a protocol for potential pivotal trials that the agency essentially signed off on, and then we decided strategically not to go right to pivotal at the time. I think in retrospect, I have to say it was the right decision. We learned an awful lot about our drug and how to recruit patients from the Phase II trial that we did do, but that Phase II trial was really designed around the interaction we had with the FDA.
And so as we saw the results and decided to go ahead with the pivotal trials, we again met with the agency back in April for an End of Phase 2 meeting, which has solidified the structure of the trial. So we are running two near-simultaneous trials. It will recruit patients with both naive, so untreated, recently diagnosed Wet AMD, as well as previously treated. In the previous trials, we only enrolled previously treated patients. The trials will last one year for efficacy, and they are non-inferiority trials. Non-inferiority trials are the way the last five products were approved in Wet AMD, as well as Diabetic Macular Edema. So it's kind of a tried and true way to get drugs approved in this space. The non-inferiority margin is minus 4.5 letters. And as I said, it's a one-year trial. We're going to run the trials two years.
The second year is safety only. There's no non-inferiority margin for the second year. One other change that we're doing from the Phase II is we're dosing our drug every six months. Patients get randomized on day one. They all receive three loading doses of Eylea, even the previously treated patients. That's the control arm. At week eight, after their third dose of Eylea, 30 minutes later, they either get our drug in a dose of 2.7 milligrams or they get a sham. They're then watched monthly. Every other month, the Eylea arm gets another dose of Eylea. The Duravyu arms every six months get another dose of Duravyu through the second year. That structure again is very similar to the Phase II trial that we ran, the DAVIO II trial, for which we again got excellent results.
Just to remind people who may not be following the story that closely, at the eight-month point in the Phase II trial, our two doses of the drug that we tested in that trial, three milligrams and two milligrams, were essentially no different than Eylea. I will make another comment about the dosing. We have tested now three different payloads for our inserts.
Yeah.
440 micrograms, one milligram, and now 1.34 milligrams. Through process improvement, we've been able to increase the payload to 1.34 milligrams. What that does, and that's the dose we're using in the pivotal trials. And by the way, the doses we used in the DME Phase II trial. So we've tested this in humans already successfully, but it allows us to get that high dose of 2.7 milligrams with two inserts.
Yeah.
Might add these, we have a sterile pre-packaged delivery system. It's a syringe injector, and we can deliver up to three inserts with a single injection, which is what we did in Phase I and Phase II. Phase III, it will only be two inserts. The other bit unique, I would say, for the space is our drug is shipped and stored at room temperature. Does not need to be refrigerated. And unlike gene therapy, does not need to be frozen at minus 80. And I think from a commercial perspective, we think that has clear advantages. So the higher payload actually is now 94% drug, only 6% matrix. And the drug we believe has reliably gone by nine months in humans. And there's always variability. And we think at six months, there's still, for virtually everybody, drug in the eye.
And that's why we, one of the reasons we picked the six-month interval. But again, at nine months, 94%-95% of the weight and volume of the insert is gone. The matrix is fully bioerodible, and should go away over the next few months. And again, we you know feel like this process improvement has really been able to really maximize the drug payload, and minimize the matrix.
Excellent. And you alluded to that you could have potentially gone directly into Phase III, but you strategically ran the Phase II. What were some key learnings, such as on dosing, that you had in the Phase II, and then maybe on the Phase III after that? What was kind of some of the rationale, pursuing the non-inferiority path and as the FDA aligned?
Sure. So let me start out with, you know, our Phase I at 17 patients. And while we showed good safety in 17 patients, you really want to, safety in this space, for those of you who follow the retinal space, it, it's really, really.
Yeah. It's critical.
And so we've now dosed over 190 patients with Duravyu, with a very, very clean safety record. That gives us confidence that the pivotal trials, we would not expect any surprises. In addition, Vorolanib was studied years ago as an oral agent, by a company called Tyrogenex, for Wet AMD. And we have the data from those studies. And they dosed about 150 patients orally with Vorolanib and had no ocular toxicity. So we have a database of well over 300 patients with really good, good safety. So that was one of the issues. The second issue is you really want to find out, you know, how your drug's going to perform and are you going to be close to that non-inferiority margin.
Again, this is a statistical thing where the lower limit of the confidence interval of the change in visual acuity, the lower limit can't cross minus 4.5 letters.
Yeah.
So we learned in the DAVIO II trial, the Phase II trial, that our lower limit was minus 2.6 letters. So we were almost two letters above minus 4.5.
Excellent.
So that gave us a lot of confidence that we could replicate that in a larger study. The ability to recruit Wet AMD trials and the learnings we got from that and our interactions with the investigators and the KOLs, that's also invaluable to really help you be successful in the pivotal trial. You mentioned non-inferiority, and again, non-inferiority trials, it's the tried and true in retina. Ever since Eylea was FDA-approved, you go through all the rest of the approvals, they've all been non-inferiority, and so to me, that was an easy decision. That is a de-risking decision. The negative of non-inferiority is, generally speaking, you got to run larger trials. But the good news about our non-inferiority margin from the Phase II, we learned how we did, and so relatively speaking, our pivotal trials are a little smaller than other non-inferiority trials.
Great. Then, maybe we could just touch base on timing for that data. What do you expect in terms of enrollment rate and what's kind of the timeline to top-line data?
So, the enrollment so far, I think it's been three weeks maybe that the study's been open, but we are ahead of schedule for enrollment. We felt that we would do well out of the gate. And part of that is when you really think about how these patients come in, previously treated patients, these investigators in Wet AMD trials are pretty sharp now. And so they have databases and they can look up in the database who is previously treated and who might meet the requirements and really try to get them in at the beginning. And so we knew we would probably do quite well out of the gate and we are. We have guided that we believe we will have last patient in the second trial sometime in the middle of next year, which means top line data a year later, middle of 2026.
Excellent. And that's. That sounds incredible. Any difference in terms of geographic location between the two Phase IIIs?
Oh yeah. Yeah. Both Phase IIIs are international trials.
Yep.
There'll be probably the ratio of U.S. versus OUS sites is higher in trial one, the LUGANO trial. The LUCIA trial is probably still going to be the majority U.S.
Okay.
But, a little bit lower, just because of each country's requirements being a little bit different, it's actually easier to start trials in the U.S.
Yep.
That's where both studies will start.
Okay. Excellent. And then something that I really want to pick your mind on is, how, maybe on the commercial side, as we look down the line to when, Duravyu makes its market, how receptive do you think ophthalmologists will be to sustained TKIs and where do you think it will fit in the treatment paradigm there?
So that is a really good question. And part of the, you know, the insight I have is, you know, I've been practicing retina for over 30 years and I know, I'd like to think I know how retina specialists generally think and I'm in touch with a lot of them. And so retina specialists are caught right now because on one hand, injections, we like doing them in the sense that we like to have the control over the patient. We like to periodically see the patients and make sure they're doing well. And then there's no question about compliance. When you put the drug into the vitreous cavity, you know they're getting it. So there's advantages, but many of my colleagues are just overwhelmed.
Now that we have, complement inhibitors, which can't be treatment extended, it's even more of an issue where they'd like to decant some of the patients into longer treatment intervals.
Yeah.
And we've seen that. Look at the success so far of Vabysmo in the space. Vabysmo, the research indicates that it really only is offering maybe a week or two more in the treatment extension protocols, yet it's highly successful. Well, we believe we can take the majority of Wet AMD patients if our Phase II data holds out six months or longer. And we think that will be a real advantage. So if you just look at longevity, longevity alone, and we can take, if you know, our results in a very tough to treat population in the Phase II, by the way, you know, on average in our Phase II, the patients had 10 injections a year leading into the trial. On average in the United States, they get six injections a year. It's just tough to treat.
We took two-thirds of them out six months or longer with just our drug. If you just say, well, you're just longevity, well, okay, that's two-thirds of the population. We're more than that though. We may be neuroprotective. We've got some preclinical data that's suggestive of that.
Yeah.
We possibly could give better visual acuity results. We haven't talked about DME yet, but our DME results.
Yeah.
were, were.
Amazing.
Yes, exactly. With nine-letter improvement from our drug. So if we did offer some visual acuity improvements, some anti-fibrotic effect, neuroprotection, then I think doctors would be hard pressed not to use us.
Absolutely.
We have done some initial market research and using a TPP that was not as good as what we found in the Phase II, because we did this before Phase II.
Yep.
Doctors told us that we'd get market penetration between 25% and 45% with a TPP worse.
Wow.
Than what we got. So we think the market's ready for sustained release. We also have. I'd like to, you know, again, remind people, one and done is not what we're trying to do. We're an every six-month drug.
Yep.
Therefore, if a doctor needs to supplement with a standard anti-VEGF while Duravyu's on board, there's nothing wrong with that. That's not a failure. A failure for Duravyu would be a patient who is getting treated six times a year leading in. The doctor puts them on Duravyu and the next year they still get six injections. That's a failure. If they get five injections, two Duravyu and three of another anti-VEGF, everybody's happy.
Yeah.
Doctor's happy, patient's happy, payers are happy. So we don't have to work perfectly in everybody to get a very large market share.
Yeah. Absolutely. And that, you know, 25%-40%, I know it's, but that's for the Wet AMD market.
That's Wet AMD.
Right? And that.
It's a $10 billion market.
$10 billion market in the U.S. by the end of the decade.
Yep. And in talking to the European retina specialists, they're even more excited.
Yeah.
because the economics and the motivation in Europe are generally a little different than the U.S.
Yep.
They would really love to do fewer injections.
Safety is even more critical in Europe, we've learned.
Is safety, by the way, again. I go back to it.
Yeah.
Our safety track record is terrific. We've had no ocular or systemic SAEs related to our drug or inserts or the injection so far, and you know, the recent DME data.
Yeah.
Again, no ocular or systemic SAEs. There were only three TEAEs in the DME study in the first four months. One of them was elevated IOP, but it was in the control arm with Eylea.
Let's just get into those results. Those were amazing. You raised a very nice fundraising round on that DME data as well. What have you showed so far for Duravyu in Phase II, VERONA and DME?
So the VERONA trial was again Phase II DME, all previously treated patients, but unlike our Wet AMD trials, all the patients had active disease. This was the first trial that we had enrolled 100% patients who had wet maculas. They had fluid, they had to, and they had to have decreased vision. They were randomized to a dose of either 2.7 milligrams of Duravyu or 1.3 milligrams of Duravyu or an Eylea control 2 :1. We had 27 patients, 11 in the high dose, 10 in the low dose, and 6 in the control. Day 1, everybody got Eylea. And again, they came in with OCT, central subfield thicknesses of at least 325 microns. On average, they were over 400 microns, so they were thick. And so day one, they got Eylea. 30 minutes later, they got our drug or got a sham. Then they were watched monthly.
This is what I would call a PRN trial. I mean, treatment as needed. There were no other scheduled treatments for six months, but there were, the ability to supplement the eyes if they met criteria for supplementation. So the results really, we think were outstanding. Starting at week four, so immediately, both Duravyu arms showed significant improvement over the Eylea arm. By month four, the high dose of 2.7 milligrams had improved about nine letters. The Eylea control had improved about three letters. This was again, not explainable by the supplements because at month four, 82% of the high dose were still supplement free.
Yeah.
60% of the controls were supplement free. So what did we learn? Well, first of all, this was the first time we took a wet population, we dried them. 70 microns on average drying effect. And again, some of you may be aware that we did an NPDR trial, which while it showed a biological activity and safety, missed the primary endpoint. So then there was some, you know, negative feelings that first of all, we couldn't dry wet eyes. This shows that we can.
Yeah.
There was also some thought that we don't work in diabetic eye disease. We worked great in diabetic macular edema. Possibly you could argue even better than this industry standard of Eylea right now. We work quickly. We set all along our drug.
What do you attribute that immediate effect at four weeks?
Our immediate effect, you know, we said it all along. We know that we have drug levels in, you know, animal eyes in hours, and there, the way the inserts release the drug, there is a higher level of release early for the first week or two. It's approximately 10 times more than the steady state. And so we have pretty really high effective doses early on. Remember, I think we talked about the Phase II trial and the Phase III Wet AMD trials starting with a load of Eylea. And so some of the thought was, well, you, you're only going to work if you load. And we said, no, I don't, we don't think so. And this shows that we don't need to load.
Yeah.
But the early onset, again, immediate separation from one shot of Eylea didn't particularly surprise us or our scientists. That's what we would have expected. So again, load is not necessary. We work in diabetic eye disease. We may work better than the industry standard. We'll see. In that nine letters, what it really does is if you say, all right, let's talk about pivotal trials in DME, I think we've really de-risked a pivotal trial, certainly for non-inferiority. Remember, non-inferiority.
Yeah.
You don't have to be better than this industry standard. You really have to just tie them.
Yep.
I'd like to remind everybody that high-dose Eylea, eight milligrams, you know, obviously approved now. But it was 1.4 letters worse than two-milligram Eylea.
Yeah.
It was non-inferior and docs are using it, but it was 1.4 letters worse. So the fact that we could improve this population in four months, nine letters, really de-risk a DME Phase III program and also brings up the possibility that we could run a superiority trial.
Yeah.
in DME.
What's really critical there is going to be now that we have these great 16-week interim results, can Duravyu maintain its advantage at 24 weeks? Any reason it couldn't?
No, there's no reason to think it wouldn't.
Yeah.
We haven't seen all that data yet, but we did when we reported the interim data, the four-month data. We did report that two-thirds of the patients had completed six months and the trends continue with better vision, better OCT, fewer rescues and safety. So those trends continued with the Duravyu arm. So there's no reason to think that. And actually, from an external perspective, you know, my view is we've shown how good this drug potentially can work in this population. The six-month doesn't really change anything except internally. I think we're going to take a hard look about guiding us for what trials to run in DME.
Mm-hmm.
That's what we're looking for. And we should have that data out in Q1 of next year.
Excellent. We're all looking forward to that data. Similarly, I'm just as interested to learn kind of your perspective on Duravyu's commercial perspective, commercial ability in DME and maybe compare and contrast the unmet need in DME versus Wet AMD.
In the United States, DME is about 35%-40% of the Wet AMD market.
Yeah.
Now, so it's smaller, but the actual need for longevity is even greater in DME, and the reason is most of these patients are younger. They're diabetics. They have a lot of doctor's appointments and they really need intensive treatment in the first year or two. You know, DME is not a disease that's a forever disease.
Yeah.
Unlike Wet AMD, where you never cure it.
Yep.
DME can go away. But at the beginning, it really requires intensive treatment that many of these patients just cannot accomplish. So doctors are even more enthusiastic about the possibility of, you know, a sustained release maintenance therapy, for DME. So we think the percentage of the market that we could capture potentially in DME is even higher.
Amazing. Great. Now, maybe any other thing you want to touch base on?
Yeah.
On Duravyu before we touch a little bit on the pipeline?
Sure. What I really, again, like to mention is, you know, we had a really good October. We mentioned.
Yeah.
You know, first patient in, great DME data to raise money.
That's funny.
Yeah. We opened up a new facility, so that it became apparent to us four years ago that if we were going to be commercially successful with Duravyu, that we didn't have the capacity in our Watertown facility to make enough. So we did a search throughout the country and we ended up with a site about 45-minute drive west of Watertown, Massachusetts, and Northbridge, Massachusetts, where we built a new facility from the ground up for manufacture of Duravyu.
Yep.
Eight large clean rooms, state-of-the-art facility. It belongs to us, and we should be able to make over a million inserts a year in that facility. So we have been planning for success for a while and that, you know, commercial projections are important, but the ability to actually, from day one of approval, to be able to deliver the drugs and get them to patients, we've been thinking about that and executing on that as well.
Great. And maybe quickly touching base before the pipeline on, you know, your financial position.
Yeah. George is here and, champing at the bit. So our CFO, George, how are we doing?
Yeah. So as Jay said, we had a great October. We raised $161 million in the equity follow-on and we're sitting with cash into 2027, which is about a year on the other side of data.
Yeah.
in the Phase III Wet AMD trials. So it's been a really pivotal Q4 for us out of the gate.
Does that include or not include potential pivotal, registrational trials for DME?
Yeah. Great question. So, the guidance includes completion of our ongoing Phase II trial and the Wet AMD trials in Phase III and some early development work for the Phase III trials for DME, but just preparation, not the trials themselves.
Excellent. And then maybe just finally touching a little bit based on pipeline, you have an incredible platform technology. Are there any different therapeutic modalities you think you're going to test it in? Any INDs you're going to file?
Yeah. Go ahead, George.
Yeah. So our next program that we're looking to move forward is EYP-2301. It's a Tie-2 agonist called Razuprotafib. It's an asset that we own outright. It was previously studied as a subcutaneous delivery by a company named Aerpio. And it was AKB-9778. It was fairly well known at the time. We reformulated that into a Durasert E profile and we'll be looking to move that into IND-enabling trials into next year.
Great. And I would, I'd be remiss to forget there's also a complementary pipeline candidate in development. So, very exciting there. So I'd just like to thank everyone for joining us for the first day of the Jefferies Conference. I'll leave maybe the last 20 seconds for you, Jay, to close us out.
So, we're obviously very excited about where we are. We believe and are convinced that we are the leader in sustained release drug delivery in the back of the eye. We're the only ones with four FDA-approved products. We have great IP around both the drug and the delivery system. We have the largest Phase II trials with the best safety of any of the other candidates out there. And we believe that we're going to be able to recruit these trials fast and believe we're going to be first to market in sustained release.
Awesome. You're to hear first.
Thanks, Kambiz. Thanks, everybody.
Thanks.