Q1 2023 EyePoint Pharmaceuticals Inc Earnings Call

Nancy S. Lurker: Additionally, one other potential treatment benefit of EYP 1901's mechanism of action is the potential for neuroprotection and antifibrotic benefits for patients. We presented preclinical data on Borolina from a gold standard, of retinal detachment at Arvo at the end of April that suggests that this differentiated advantage, which could be another benefit to set EYP1901 apart from today's commercially approved are erodable durcert technology, which we call DuraCERTE, ties these improvements together, delivering the active drug consistently and reliable with steady zero-order kinetic dosing over six to nine months in the The underlying Durassert technology has been safely used in thousands of buys across four FD approved, and we are confident in its ocular safety profile, which is always a number one consideration for patients and physicians especially for treatments in the rest.

Nancy S. Lurker: Moving on, I am delighted to report the substantial progress we made in our two key phase two trials of EYP 1901 in wet AMD and NPDR. First and foremost, we completed enrollment in our phase 2 W2 clinical trial to evaluate EYP 1901 in Wedding. We were incredibly pleased to exceed the original target enrollment of 144 patients, enrolling a total of 160 patients due to the high level of physician and patient interest in the trial.

Nancy S. Lurker: We remain on track to report top-line results in the fourth quarter of this. When combining the phase one Davio results with the future phase 2 W2 data, EYP1901 is being studied in more eyes than any other TKI product in development for WETMD. And we believe this is very important, particularly as we look at strategic considerations with potential partners.

Nancy S. Lurker: The body of evidence we have been collecting for EYP 1901 to date, including both non-clinical and clinical data, supports increased confidence in 1901. The proven value of the anti-Vedgif pharmacological mechanism, not only in WETA&D but across a number of VEF-dependent retinal diseases, supports a strong rationale for efficacy of EYP1901 in NPDR. As a result, we believe that a smaller phase two trial in MPDR will provide ample evidence of both efficacy and continued safety and will allow an accelerated path to initiate a phase three program in this indication.

Nancy S. Lurker: Jay will talk further about our Pavia, and Looking ahead, we also plan to initiate a phase two trial evaluating EYP 1901 in diabetic macular edema in the first quarter of 2024. Importantly, we are keeping our eye on the future and remain actively engaged in expanding our sustained ocular delivery product pipeline beyond EYP1901. We continue to evaluate molecules for potential use in our DuraCert, which can be tailored to each drug and disease indication.

Nancy S. Lurker: As an example, in February, we announced our exciting research collaboration with Rally Bio to evaluate their C5 complement inhibitor using our DERS or E technology to develop a sustained delivery treatment option for geographic. We look forward to updating you on this evaluation over the coming. Turning to our Utique franchise, once again, our commercial team delivered a very strong quarter with $7.4 million in Utique net product revenue, which is a 60% increase over the first quarter of 2022 We remain very pleased with the performance of UT as it continues to be a profitable franchise in 2020.

Nancy S. Lurker: And we expect single-digit millions in positive cash flow from the Utique franchise. Scott Jones will provide additional color on this topic later on. Now, I turn the call over to Dr. Jay Duker, our president and chief operating officer, who will provide an update on our lead program, EYP 1901, as well as our other initiatives. Thank you, Nancy, and good morning to everyone.

Jay S. Duker: It's been an exciting and productive quarter for the Eye Point Clinical Team as we work to bring innovative ocular therapies to patients with serious eye disorders. Turning to our lead program, EYP 1901 is an investigational sustained release therapy that uses a bioerodable formulation of our Duracert technology, or Duracert E, with Borolin, a pyrusin inhibitor that acts through intracellular binding of all VEGF receptors, thereby blocking all VEF isoelisone, At this year's Arvo, 2023 meeting last month, we presented compelling preclinical data from a widely validated mouse model of retinal detachment that demonstrated varolinib's differentiated mechanism of action compared with standard of care like and block, which we believe may provide additional treatment benefits beyond the currently commercially available anti-vege. These data showed that varolinib significantly improved contrast thresholds in mice and resulted in both improved structure and functional endpoints compared with placebo, which suggests a neuroprotective effect against photoreceptor degeneration.

Jay S. Duker: Should this be reflected in clinical data, it would provide an important new mechanism of action for the treatment of VEGF-mediated, chronic blinding, poster segment diseases such as wet age-related macular degeneration, diabetic retinopathy, diabetic macular edema, and retinal vein Additionally, compared to other TKIs, varolinib features reduced off-target binding, Specifically, minimal activity against Taitu, leading DuracertE is based upon the same underlying technology used in our non-erodable products like Utique, but the non-erodable shell is removed.

Jay S. Duker: Durrassert products have been delivered to over 80,000 eyes with a consistently strong safety profile. And based on the extensive prior clinical data evaluating Durrassert in four FDA-approved indications, we are confident in EYP-1901's ability to consistently deliver the active drug, borolinib, with a sustained constant dose within the therapeutic window using our erodible delivery technology, Durisert. In wet A&D, EYP 1901 is being evaluated in our Phase 2 W2 trial as a treat to maintain therapy, with a goal to sustain the treatment effect for the majority of wet A&D patients up to six months or longer following a single injection of EYP 1901.

Jay S. Duker: By using EYP 1901 as a baseline maintenance therapy following the use of large molecule antivagefs, we aim to provide a sustained delivery therapy with a new mechanism of action so that patients and practitioners can potentially have the flexibility to safely reduce the number of visits to the retinal specialist without sacrificing visual quality. Last summer, we reported positive 12-month safety and efficacy results at the American Academy of Ophthalmology meeting in Chicago for the Phase 1 Davi The Dobio trial enrolled 17 patients, and each received a single in-office intravitreal injection of YPN01 at one of four different dose levels.

Jay S. Duker: All enrolled patients were previously treated with standard of care and positive therapy. No reinjection with the study drug was performed during the trial, and typical criteria for supplementation where the standard of care anti-GF was employed. Importantly, those 12-month data featured no reports of ocular SAEs or drug-related systemic SAEs.

Jay S. Duker: 53% of I's were supplement-free for up to six months, and up to one year, one-third of eyes were supplemental anti-vegetable-free after a single injection of EYP-1901. Additionally, there continued to be an impressive treatment burden reduction of 73% at 12 months compared to 75% at 6%. On the heels of these positive data, we initiated two separate phase two clinical trials of YP 1901, one for the treatment of wet age-related macular degeneration called DAVO2, and the other studying the drug in a nonproliferous diabetic retinopathy called the Pavia trial.

Jay S. Duker: As Nancy noted earlier, we completed enrollment in the Phase 2 W2 clinical trial in March of this year. All patients in the W2 trial were previously treated with a standard of care anti-guidep therapy and were randomly assigned to one of two doses of EYP 1901, approximately 2 milligrams or approximately 3 milligrams, versus an on-label dose of Plybercept. EYP 1901 is delivered with a single intervictal injection in the physician's office, similar to current FDA-approved anti-vege treatment.

Jay S. Duker: The primary efficacy endpoint of the W2 trial is non-inferiority, change in visual acuity to the Flibercept control as measured by best corrected visual acuity six months after the EYP 1901 injection. Secondary efficacy endpoints include change in CST as measured by OCT, time-to-first supplemental anti-vege-F, reduction in treatment burden, and overall safety. The trial ended up over-enrolling, a testament to patients and investigators' enthusiasm about EYP 1901. Instead of the planned 144 patients, we enrolled 160 patients.

Jay S. Duker: We look forward to progressing the W2 trial and anticipate top-line results in the fourth quarter of 2023. Turning to non-prolifficer diabetic retinopathy or NPDR, it is a very common eye disease that affects almost one-third of diabetic adults over the age of 40 and is projected to impact over 14 million Americans by 2050. In NPDR, blood vessels are weakened, potentially leading to swelling of the macula and eventually to abnormal blood vessel growth.

Jay S. Duker: If left unchecked, NPDR can be the harbinger of severe visual loss. However, as currently approved intravitral therapies for NPDR require a significant visit and treatment burden, the vast majority of NPDR patients are merely observed and not treated. This provides a significant market opportunity for EYP 1901, which may be able to be effectively delivered at nine months or longer intervals in NPDR. As a practicing retinal specialist, I would enthusiastically embrace a safe, effective, and tolerable therapy to prevent the complications of NPS.

Jay S. Duker: The first patient was dosed in the phase two Pavia clinical trial of YP1901 for the potential treatment of NPDR in September of 2022. Based on clinical and non-clinical data, EYP 1901 utilizes a proven anti-Vechf pharmacological mechanism that is a well-documented treatment across VEGF-mediated retinal diseases such as NPDR.

Jay S. Duker: And as a result of the strong proof of concept data, we have modified the phase two clinical trial evaluating EYP1901, to enroll a minimum of 60 patients, which will represent a reduction from the original planned N of 105 patients. This change allows for a shortened timeline to NPDR Phase 2 data and potentially an accelerated initiation of Phase 3 clinical trials. Inipovia trial patients are randomly assigned to one of two doses of YP-1901, approximately 2 milligrams or 3 milligrams, or to the control group, which will receive a sham injection.

Jay S. Duker: As in the W02 study, EIPB-1901 is delivered with a single intravenous injection in the physician's office. The primary efficacy endpoint of the trial is improvement of at least two diabetic retinopathy severity scale levels at week 36. Secondary endpoints include the onset of vision-threatening complications, the occurrence of diabetic macular edema and or proliferative disease, retinal ischemia and or non-perfusion, and safety. We anticipate completing enrollment for the Phase 2 Pavia clinical trial in the second quarter of 2023, with initial top-line data results in the first half of 2024.

Jay S. Duker: And with the abbreviated patient enrollment, we look forward to bringing this innovative treatment for NPDR to patients sooner. Additionally, we are on track to initiate a third phase two clinical trial evaluating EYP 1901 in DME in the first quarter of 2024. Looking at our UTK franchise, we continue to collect real-world data on the benefits of UTIC for the treatment of chronic, non-infectious posture segment UVitis in the Phase 4 Calm Registry Study, which is conducted in collaboration with the Cleveland Clinic.

Jay S. Duker: Data from the Utique Com registry study were presented in three poster presentations at the 2023 Arvo annual meeting in April and demonstrated Utec's effective control of inflammation in real-world patients living with chronic poster segment UVI. Finally, as Nancy noted earlier, we continue to evaluate potential product candidates through internal discovery efforts, research collaborations, and in licensing arrangements to build our pipeline. We are very encouraged by the potential of our recently announced collaboration with Ralebiot, in which we are evaluating their C5 complement inhibitor in our duracer technology for the treatment of geographic atrophy, or GA, a late complication of dry macular degeneration.

Jay S. Duker: We have been actively evaluating complement inhibitor molecules for use in our drug delivery technology, as we see a significant opportunity to provide a sustained delivery treatment for geographic atrophy and potentially earlier forms of dry AMD. Similarly to our approach with the YP1901, by providing constant dosing of the drug over time, we hope to see improved outcomes and reduce treatment burden for patients. As a practicing retinal physician, I am incredibly excited about the potential to treat patients with EYP 1901, as it represents potential game-changing treatment options for patients with a variety of eye diseases. This is what drives our team every day, bringing sight-saving treatment to patients at risk of losing their vision. Now, let me turn the call over to Scott Jones, our chief commercial officer, for the commercial update. Scott? Thank you, Jay.

Scott Jones: Our commercial business is exclusively focused on our unique franchise now that we're no longer actively marketing Dexecu in the United States. We reported a record-breaking first quarter for UTIC with $7.4 million in net product revenue, a 60% increase from the first quarter of last year. This represents the most profitable first quarter since the products launched, and we're particularly pleased with these results, given that first quarter demand numbers typically trend downwards due to insurance deductible resets for patients.

Scott Jones: Utique customer demand was approximately 930 units compared to approximately 650 units for the first quarter of 2022, a 43% increase. We're pleased with a continued customer demand increase for Utique based on continued utilization by retinal physicians and consistent messaging from our marketing and sales team. We're very pleased by the progress that we've made with our commercial business and expect a profitable Utique franchise with profits in the single digit millions this year.

Scott Jones: I'd like to thank our commercial team for their dedication to bringing Utique to physicians and patients in need. While Dexecute remains available to patients in need, we don't expect any substantial revenues from the product going forward as it's no longer actively marketed in the U.S. following the discontinuation of pass-through reimbursement by CMS on January 1, 2023. I would now like to turn the call over to George to review the financials. George?

George O. Elston: Thank you, Scott. As the financial results for the three months ended March 31st, 2023 were included in the press release issued this morning, my comments today will be focused on a high-level review for the quarter. For the quarter ended March 31st, 2023, total net revenue was $7.7 million compared to 9.3 million for the quarter ended March 31.

George O. Elston: at on March 31st, 2022.

George O. Elston: Net product revenue for the first quarter was $7.4 million compared to net product revenue,

George O. Elston: revenues of $9 million for the first quarter ended March 31st, 2022. The reduction in net product revenues was driven by a significant reduction in DECQ revenues due to the discontinued

George O. Elston: due to the discontinuation of Paster Reimbursement for that product, effective January 1, 2023. Net revenue from royalties and collaborations for the first quarter ended March 31st, 2023, totaled 0.3 million, consistent with the same period in 2022. Operating expenses for the first quarter ended March 31, 2021, 2023 totaled 29.2 million compared with 27.6 million in the prior year period. This increase was primarily driven by continued investment in R&G for EYP 1901 development, offset by a reduction in sales and marketing spend for DECC. Non-operating income net for the first quarter of 2023 totaled 0.4 million, and the net loss was 21.2 million or 56 cents Cash and Investments at March 31st, 2023 total 122.5 million compared to 144.6 million at December 31st, 2022.

George O. Elston: We expect the cash, cash equivalents, and investments on hand at March 31, 2021, and 2023 and expected net cash inflows from our product sales will enable us to fund our current and planned operations into the second half of 2024. In conclusion, we are pleased with iPoint's progress in the first quarter of 23 and are well capitalized to advance our product pipeline to key values. I will now turn the call back over to Nancy for closing remarks. Thank you, George.

Nancy S. Lurker: As you can see, 2023 is off to a strong start that sets us up for continued success as we execute on multiple clinical catalysts and strengthen our commercial business. We are well positioned to achieve a number of potentially value-creating milestones, including, most importantly, reading out our top line data from our Phase 2 W2 clinical trial in the fourth quarter of this year. Completing enrollment in the Phase 2 Pavia trial of EYP 1901 in NPDR and Q2, with top line data expected in the first half of 2024.

Nancy S. Lurker: Dosing the first patient in the phase two clinical trial of EYP 1901 in diabetic macchiata edema early next year, and advancing our discovery stage pipeline for both our wholly owned products and partner programs while continuing to grow revenue for UT. Before opening the call to your questions, again, I must reiterate how appreciative I am of our exceptional team at I. Across the board, this team of talented professionals brings a passion and work ethic that's unparalleled.

Nancy S. Lurker: I'm proud of all we've achieved and energized about the opportunities that lie ahead for us as we continue to transform the treatment landscape with innovative, long-term solutions to improve both the vision and the lives of patients with serious eye disease. Thank you all very much for listening this morning, and I'll now turn it over to the operator for questions.

Operator: Q Please identify yourself while we compile the Q&A roster. One moment for the first question. The first question comes from Yatinsunaja from Guggen High. Please go ahead.

Yatin Suneja: Hey guys, thank you for taking my question and for being my comrades and for all the progress. I mean, a couple of questions for me.

Yatin Suneja: So the first one is, you know, FD has recently issued this draft guidance for wet AMD studies. Can you maybe just comment on how your phase two stack versus phase two or phase through plan stacks against that guidance? And then in terms of the expectation for DAW2, we understand the study is looking at non-infurity, but curious to hear from you what sort of

Yatin Suneja: What sort of reduction in treatment burden? Okay, yeah, and let me explain.

Nancy S. Lurker: Okay, yeah, and let me take the first one on the draft guidance, and Jay will take the W2 reduction in treatment burden question. So we had a type C meeting with the FDA well before the issue that this guidance and before we actually started W2. So we planned our W2 study to mirror that guidance that came out because, again, the FDA did tell us when we had a type C meeting what they expected, and the guidance that came out mirrored what they told us.

Nancy S. Lurker: So we feel we're very well prepared for phase three. We expect there'll be, you know, minor changes to our phase three protocol from our phase two, but of course, it's going to be dependent on the data that we see that reads out. But right now, we believe we're in very, very good shape with both our phase three and our phase two so that it will meet that guidance that came out.

Nancy S. Lurker: So, Jay, why don't you take the reduction in treatment burden question? Jay, are you there? I think maybe he has to unmute.

Nancy S. Lurker: Okay, let me answer that question. Go ahead. Can you hear me now? Yes, now we can. Okay, sorry.

Jay S. Duker: Thanks, Nancy, and thanks, Yotten. With respect to treatment burden reduction, in the Pivotals, again, remind everybody that the primary endpoint is going to be non-inferiority change in visual acuity, which is not to say that reduction and treatment burden aren't important because they're very important to patients and practitioners. We had a significant reduction in treatment burden in Davio, in the phase one trial of 75% at six months and 73% at one year. I think if our reduction in treatment burden is in the neighborhood of 50%, that would be an excellent result.

Jay S. Duker: And anything better than that, obviously, would be a better result. In talking to practitioners and asking them what type of reduction in treatment burden would be useful to them in practice, they will actually quote a number even less than 50. Although, again, depending on their visual acuity results, the treatment burden will be in some way secondary.

Yatin Suneja: Got it. Thank you. Then just one more. I mean, there seemed to be an enthusiasm from

Yatin Suneja: a physician and that's what you're seeing in over enrollment and faster enrollment. Could you maybe just articulate that?

Yatin Suneja: to us like what's going on, what's driving that enthusiasm.

Yatin Suneja: among the physicians and what you're getting from the KOL, especially for this whole TKI class.

Yatin Suneja: TKI class in that MD. Thank you. Yeah, go ahead.

Jay S. Duker: Yeah, so at a high level, practitioners for years have been interested in extending patients out longer between treatment visits. We saw that, obviously, when Ilea became approved. That's one of the reasons it was accepted so rapidly.

Jay S. Duker: And I think we're seeing it again with Vibismo now. But those were extensions in the real world of maybe a week or two of treatment interval. What we're offering, we hope, for the majority of patients, is intervals of six months or longer between visits and injections. So again, we hope to see a significant increase in the interval between visits for the majority of wet AMD patients. What's also driving this, of course, is that the aging population means more patients getting injections; the growing diabetic population, same effect.

Jay S. Duker: And now we have an FDA-approved geographic atrophy drug that really can't be treated and extended beyond two months. That is going to fill up a lot of retina specialist offices. And so we're looking to safely offload patients to a longer treatment and visit interval without sacrificing the vision. So that's what's underlying it. Now, obviously, when you tell a patient, you know, you can sign up for a study and you might get a treatment just once over six months or longer, one injection versus your baseline of, you know, injection every six weeks, that really resonates with patients also.

Tyler Martin Van Buren: Thank you for the questions. One moment for the next question. For the next question, we have the line from Tyler Van Buren from Kovann. Please go ahead.

Tyler Martin Van Buren: Hey guys, good morning, great to see the progress. I wanted to ask about the moderate to severe non-prolissive diabetic retinopsy's opportunity. Can you elaborate on the size of the patient population there? And specifically,

Tyler Martin Van Buren: What percent is diagnosed, and then of those diagnosed, what percent are actually treated with available therapies? And then the second question is just related.

Tyler Martin Van Buren: treated with available therapies. And then the second question is just related to the C5 inhibitor Rally Bio Program for Geographic Atrophy, given that it's topical with the $6 billion Iverick acquisition announced earlier this week. Can you give us a sense of how long it might take to get that program in the clinic, or what steps need to be completed prior to getting it into the clinic? Yeah, Tyler, thanks for the question.

Scott Jones: Scott, our chief commercial officer, and also heads up our early commercial development, I'll have him answer the questions on the NPDR market. But let me just say really quickly, as an overview, though, that this is an undeveloped market. So while the prevalence is high, the percent treated is low. Scott King, if you have those numbers at your fingertips, And that is because, again, they're just the current treatments; no one's going to, I can connect the dots every month or every other month with the current therapies.

Scott Jones: We have a disease that's relatively unnoticeable to patients. And so it's basically watchful waiting until they start to see erosion of the vision, and that's when they start to treat it. We think we can change that paradigm. So Scott, I'll turn it to you for that. Sure, thanks, Nancy.

Scott Jones: So if you look at the number of patients with diabetic retinopathy in the United States, it's currently about 8 million people. That number is increasing very rapidly, and in fact, if you look at, you know, and I think Jayven quoted this in some of the discussion he was having about MPDR, you know, ASRS assumes that this number is going to grow just for NPDR to about 14 million people by 2050, so the market is expanding. very rapidly.

Operator: As Nancy said, it is an undeveloped market today, and what I mean by that is it's a small percentage of these patients that are actually being treated either with lasers or with an anti-vege-f therapy. You know, the vast majority of patients currently have a wait and watch kind of approach with annual office visits. So today, about 3% of NPDR patients are being treated with an anti-veg-F. Obviously, the driving factor there is the fact that these are younger patients who, you know, just don't want to come into the office quite so frequently. And so certainly, a long-acting product potentially allows us to, you know, rapidly expand that potential treated market.

Operator: Operator, next question. Or Tyler, if you have another.

Jay S. Duker: You had a question about the C5 program. Oh, I'm sorry. My apology. So, Jay, why don't you take the C5 question?

Jay S. Duker: Oh, I'm sorry. My apology. So Jay, why don't you take the C5?

Jay S. Duker: Yeah, so we're really excited about the collaboration and the potential ability to put Rally BioC5 inhibitor, which is an affibati, into one of our sustained deliveries. So the pathway, again, is, I would say, straightforward, not necessarily easy, but certainly straightforward. Formulation followed by, you know, typical pre-I&D talks in PK studies, get the I&D phase one for safety and dose and a little bit of look And based on that type of phase one, we might do a phase two slash three as the next study. So it's still early on, and when we have news to report, we will. But that's again the kind of high-level outline of how a product might, like a sustained release complementary, might be developed.

Jennifer M. Kim: Next question, we have the line from Jennifer Kim from Cantofigero. Please go ahead.

Jennifer M. Kim: execution this quarter, and I'm excited for the now two readouts over the next, I guess, 12 to 14 months, give or take. On that, I guess my first question is, on the NPDR trial size reduction, can you elaborate on, I guess, the body of evidence that compelled you to reduce the trial size? And also, is it fair to assume that the 60 patients' minimum would be evenly distributed by arm? And specifically, does that body of evidence relate at all to what you're seeing? I know it's on a blinded basis, but Davio 2 and as the safety or blinded doses or what goes into that evidence. Thanks.

Nancy S. Lurker: Yeah, I'll give an overview of that, and then Jay can elaborate. So, first of all, if you recall, on varolinib itself, there was a phase of phase one, well, first all, preclinical phase one studies that were done by our partner beta on varolinib. And those data all showed very solid efficacy in wet AMD, but no safety issues in the eye.

Nancy S. Lurker: So that gives us confidence for varolinib itself, coupled with this and phase one data on EYP1901, which, again, for the audience, is a combination of varolinib and our durcert e-formulation. Those data continue to show a very strong and positive safety profile, coupled with very, very good efficacy that we saw in the W1 data. Further, if you look across all the anti-veget-F antibodies, there's always been a very consistent read-through across these various retinal diseases.

Nancy S. Lurker: And again, to the layperson who might be listening in, basically that means that if you're showing a positive result in wet A&D, you always see a positive since there are no exceptions. Jay can confirm that in other diseases like diabetic metacididreddema, and diabetic retinopathy.

Nancy S. Lurker: So because of all that and the strong data that we've seen already across both Boronid and EYP 1901, we don't believe we need to have as large of a trial as we originally anticipated. And in addition, enrollment is going very nicely ahead of expectations. So based on all that, we've decided that we're going to reduce the size and be able then to get to phase three, phase three sooner. I'll let Jay talk about the distribution by arm and any other comments. Thanks, Nancy, and thanks Jennifer for the question.

Jay S. Duker: Yeah, this is all randomized, and therefore, we would expect, if randomization works, we would get approximately 20 in each of the three arms if we end up with 60. And again, we're saying 60 as a minimum. As the enrollment continues, we probably will end up with an enrollment of slightly greater than 60. That has not yet been determined. But it's a statistical flip of a coin how they end up, but we would expect in a 60 or more, it'd be pretty evenly balanced.

Jennifer M. Kim: Okay, great. And then my second question is, do you have any thoughts currently on,

Jennifer M. Kim: on, since the DR data is reading it in the first half of the year, any thoughts on the timing and sizing of a phase three program in that indication? We haven't really, we're not ready to disclose that publicly. That's still under development, and it's very early still. Okay, that's fine.

Nancy S. Lurker: And then my last question is, any comments on, I guess, the overall tone you're hearing in your latest conversations with potential partners? So let me just continue to state that we are prepared to do it by ourselves if we feel that it's best for the company and for investors. However, I want to state that right now, our goal is to partner on this. There are a number of reasons for that.

Nancy S. Lurker: Number one, these are large global studies. We feel having a global partner will help us execute on those studies. The second reason, of course, is from a financing perspective. We would expect a partner would participate meaningfully in the cost of those studies. So we continue to have strong interest across the large strategics that are in the ophthalmology space.

Nancy S. Lurker: So we're optimistic, but of course, I want to reiterate, it is dependent on the results that come out of W2. We do not expect that we will partner on this before those results come out. But what we do want to do is be prepared to move quickly if the results are positive. There was a goal that, certainly, in the first half of 2024, we would be able to announce a partnership. But suffice to say, the discussions are all going away. Okay, and then maybe one, sorry, one more quick question, and maybe this one's for Scott. Just on the UT Gris.

Jennifer M. Kim: in this quarter is pretty strong. I think it's higher than what I expected, at least. How do you see it, especially

Jennifer M. Kim: How do you see, especially in the first quarter of the year, that growth sort of sustaining over the next few quarters or does something drive that, or I guess how are you thinking about growth over the next few quarters? Thanks for the question, Jennifer. And, as always, we're not going to provide guidance on iron sales, but we are extremely happy with the UT performance and remain very confident.

Scott Jones: And I think it's largely driven by the fact that it's really about consistent messaging within the retinal space and patient identification. And I think this is what's, you know, has resonated extremely effectively with physicians. And we, you know, again, we remain very confident just based on what we're hearing anecdotally that physicians are starting to adopt the product more readily and more widely. So again, we remain confident moving forward.

Jennifer M. Kim: All right, thanks again, guys, and congratulations.

Colleen Margaret Kusy: Thank you. Thank you for the questions. The next question comes up on the line from Colleen Kusey from Barr. Please go ahead.

Colleen Margaret Kusy: Hi, good morning, and congratulations on the progress. Thanks for taking our questions. Maybe just a follow-up one on the FDA draft guidance and what AMD. Can you just remind us how the retreatment guide, your retreatment stipulations compared to the retreatment guidance that the FDA has laid out? Jay, why don't you take that one?

Jay S. Duker: So we've been saying all along that we were interested in getting a label and wet AMD for every six months. The overall guidelines from the FDA for a non-inferiority trial, which is what we intend to run as pivotal, would be that the, the, the, we would be up against either monthly Lucentis or every other month ILEA after an ILEA load. The guidance does not specifically state anything more than that. And so I think that our phase two trial, which is a single injection of EYP1901, against on-label Ilea. The pivotal, again, we expected to look very similar except for re-injection every once in a while.

Colleen Margaret Kusy: Got it, that's helpful, thank you. And then, just on the neuroprotective and antifibrotic data that you presented, what clinical data would give you confidence that this thesis is playing out in what AND? Okay, you can take that one.

Jay S. Duker: So ultimately, what matters most to physicians and patients and to the FDA is visual acuity results. And so we don't have to be numerically or statistically superior to ILEA to have evidence that we are neuroprotective. But I think it may turn out that in a subgroup of patients, we may show improvement in visual acuity beyond just a simple drawing. If we can do that, and especially if we can identify the subgroup of patients who may benefit visually from our drug, I think that would be very helpful for not only acceptability but also commercial success.

Jay S. Duker: as clinically meaningful to patients and practitioners, then they're just models. So that's what we'll be looking for. And again, as I stated, it doesn't have to be numerically superior or numerical advantage of visual acuity across the entire cohort if there's a subgroup of improvers. I think that that would be sufficient.

Jay S. Duker: Fibrosis is a little bit harder to show. And you can, again, that's a structural measurement that's really done on the basis of a fluoresce intrigam. That's the gold standard for measuring fibrosis. And like most wet-amdies, we're excluding patients at the beginning that have a lot of fibrosis. So you're already starting with a small amount of fibro

Jay S. Duker: And over a six-month period in W-O-2, I think it might be difficult to show a meaningful reduction in the advancement of the fibrosis. But we'll be looking for that as a secondary endpoint, and certainly we will measure that in the pivotal trial. As I said earlier, structural changes are terrific, but ultimately, we've got to show functional stability or, hopefully, at least, subgroup improvement. Yeah, let me just add as well that this is also one reason why we believe that we have a potential multi-billion dollar blockbuster on our hands if the data continue to play out.

Nancy S. Lurker: And the reason is that this pan-Bed-G-F new mechanism of action that we have versus the current large molecule anti-BedGF drugs, like Ilya, Lucentis, Fabismo, because they are like, Again, just for the audience, what they do is they latch on to the VED-JF in the eye and prevent it from blocking the receptors. But it's a very limited receptor base that they block In our case, we block multiple VEGF receptors. And if you look at some of the early data, particularly if you look at, They block not only are they a ligam blocker, but they also block ANG2.

Nancy S. Lurker: And we, with our receptor blocker, block the mechanism that causes ANG2 as well to increase. We block multiple VEGF receptors. We think there could be benefits to that, such as neuroprotection and antifibrotic benefits, as well as other kinases. And if you look at other large disease areas, they almost always tackle diseases from multiple disease drivers. In these retinal eye diseases right now, the only thing that's available is this one mechanism that's on the market today.

Nancy S. Lurker: So we believe that our pan-beds F, should that continue to play out, could be a real benefit to patients and also be a driver for uptake in the marketplace. We also think it's one reason why we're seeing keen interest from the strategics because they know not only the obvious benefit of getting this extended delivery important, but also having a different mechanism of action. So we remain very bullish because of the benefits we think that our product can provide.

Colleen Margaret Kusy: That's really helpful. Thanks for taking our questions.

Operator: for your questions. One moment for the next questions. Next questions, we have the line from Daniel Gatolling, from Chardon. Please go ahead.

Daniil V. Gataulin: Yeah, hi, good morning, guys. Thank you for taking the question. I wanted to follow up on the NPDR study. I just wanted to ask how reducing the trial from target enrollment of 105 patients to 60 affects your assumptions and confidence in the statistical analysis?

Jay S. Duker: Jay, you can take that. Yeah, so even at 105,000,

Jay S. Duker: Yeah, so even at 105 patients, the study was not powered for statistical significance or non-inferiority. So we were looking for the trend that was seen with the other anti-vege-Fs of improvement in the DRS scores. So if we observe that in the treated groups, even, I would say, percentage-wise, less than what might have been seen in the Lucentus and Ilea trials, I think that would give us great confidence that UIP-1901 is effective in NPDR.

Jay S. Duker: I think from a statistical perspective, again, the issues probably are a little bit more around determining the size of the pivotal trials based on those statistics. But we remain confident that even at 60 patients, 20 in a treatment arm, we'll get a very good idea of how effective our drug is over, you know, six months to nine.

Daniil V. Gataulin: Got it, thank you. And I also want to follow up on neuroprotection data. How significant is the neuroprotection issue in patients? Because you don't really hear that being discussed all that much. And do you expect other TTIs in development to provide similar benefits?

Nancy S. Lurker: Let me just give you a broad overview real quickly, and then Jay can go into more detail. So, let me just say this. Look, having launched lots and lots of drugs throughout my career, part of our job is to develop that market because it's not developed right now. And the reason is, again, because the current large molecule antivitaphs don't provide all the preclinical data, and I believe they've tried to run some clinical data over the years, they don't show this effect. Part of our job is to start to develop that market.

Nancy S. Lurker: There's a well-developed path to do that, and we intend to pursue that. So it's additional studies we'll be doing, both pre-clinical, as well as looking at some additional markers, potentially in our phase three studies, and then additional studies afterwards. So we intend that we will be pursuing this. As for other TKIs, yes, more than likely, other TKIs will show this effect as well. But I'm going to let Jay talk specifically about some of the two days we basically do not block that out.

Nancy S. Lurker: Thanks, Nancy, Ian. Thanks, David.

Jay S. Duker: The issue of neuroprotection, it is a kind of a holy grail, and not just retinal diseases but obviously glaucoma, and we've been looking for agents that will block cell death in the retina for decades. With respect to what A&B specifically, Chronically, many patients lose vision, and they may lose vision because they have recurrent disease with active exudation, fluid, or blood that takes the vision down and They can have progressive geographic action.

Jay S. Duker: But there are other patients who we never really allow to get exudation, and there's no definite geographic atrophy, and the retina just thins. And that's been referred to as macular atrophy, which is kind of a catch word for loss of the retinal tissue. Those are the type of eyes that if we can block that via neuroprotection, we may be able to sustain or even improve.

Jay S. Duker: patients, certainly in the longer term. So that's really what we're looking for a lack of thinning structurally and better stability or improvement in visual acuity from that neuroprotective perspective. As for other TKIs, we really have no data on that.

Jay S. Duker: It certainly could be a class effect, and we're trying to understand better which receptor blockage might affect this. There is one other theoretical possibility here. We know, we've known for years that VEGF in normal levels in the eye is neuroprotective. And there's always been a worry that by completely suppressing VEGF in an eye, you may accelerate the long-term thinning and loss of vision. But that has never really been shown

Jay S. Duker: But because we're not blocking VEGF per se, we're blocking the receptor, it is theoretically possible that the VEGF that remains in the eye may continue to act as a neuroprotective agent. Now, that's not what we looked at in our model, but that theoretically might be a second reason why a receptor blocker might lead to better visual acuity outcomes in the long run. Jay, do you want to comment just And, you know, again, Nancy alluded to the fact that ANCH2 down regulation appears to be beneficial to visual acuity as shown by Fibismo. Tie 2 blockage results in up regulation of ANCH2, and Verolene it doesn't have any activity at all at the levels we're using on TIE2. And so we shouldn't be upregulating the inch.

Daniil V. Gataulin: Thank you very much. That's for your help.

Operator: The next question comes from the Lao, Yijin, from Leit Law and Co. Please go ahead. Good morning and

David Lally: and my congratulations as well.

David Lally: My first question just follows the previous one in a slightly different way.

David Lally: that if I reduce the patient size for the aviote study, was there any information you may not be able to gain, and any perspective you think that will be different if you retain the 100 patients, 105 patients for that study? Sure, Jay.

Jay S. Duker: Yeah, so with a reduction in the end of the Pavia study, I think I kind of alluded to this. I don't think certainly, again, we weren't powering this study to give statistical significance to the non-inferiority against the Shan control. So it's not a matter of statistics per se, but in order to determine the end of the pivotal trials, you want to get a pretty good idea of what the standard deviation is and what your treatment effect is overall.

Jay S. Duker: Until we have the results, I can't really answer the question. But we're still confident, even at the reduced end, that we should be able to plan for the pivotal accordingly, depending on the treatment effect we see with that lower end. And again, everything you do, it's like practicing medicine, risks and benefits. And we think the strategic benefit of getting into the pivotal trial sooner far outweighs the risk here.

David Lally: Okay, great, that's very, very helpful.

David Lally: Question here is that I remember you have developed you are developing new injectors at this point. Any updates on that development?

Nancy S. Lurker: Yeah, let me make one quick comment on that, and Jay's team is responsible for the new injector, but we're pretty excited about that injector. It's proprietary, it'll be patented, and we absolutely believe it's the best-in-class injector. So, Jay, why don't you go into some of the, Yeah, so the ejector is on track, on target development. We expect to use it for the first time in our DME trial, which is slated to start in the first quarter of 2024.

Nancy S. Lurker: Again, the injector, we believe it will be state-of-the-art. We've tested it with retinal specialists and got excellent feedback, and as I said, production is underway, and we're on target. Just to remind everybody, the current injection system is a modified UT conjector that was developed over 15 years ago, and while we're pleased with its function, it's, it works fine. We think that a product like UIP 1901 and eventually Utique deserves a state-of-the-art injector, and that's what we're developing.

Jay S. Duker: The next question comes from Galaochaetana, Golakota, from Heshi Wimbright. Please go ahead. Hey, everyone, congrats on the progress. This is Cheyth on behalf of Yi, Chang.

Chaitanya Gollakota: from a three wind rate. Most of my questions.

Chaitanya Gollakota: have been answered. So I just have one quick question. Have you received

Chaitanya Gollakota: received or garnered any FDFED

Chaitanya Gollakota: on your regulatory plans in NPDR, either before your phase two reduction or even on your early phase three plans. Yeah, so.

Nancy S. Lurker: Yeah, so first of all, let me reiterate. We had a type C meeting with the FDA because we wanted to make sure that our phase two trials were close enough to phase three that we could be confident in the structure. You don't typically want to have big changes in your phase three trials from your phase two because it introduces a lot more risk. So we got very good direction from the FDA at that type C meeting, which was confirmed in the guidelines that they've been subsequently issued for wet A&D clinical trials, that we'll have an end of phase two meeting with the FDA to nail down more specifics, but again, that will happen after we read out on our phase two studies.

Nancy S. Lurker: So we're planning for that as soon as we get those results, we will have a meeting with the FDA. We will get the comments from the honorile design, so we don't expect it to change materially from the guidance, but of course, we'll ask for some more specifics for all trials, but we remain confident right now that we're on the right track and we don't expect any major surprises.

Chaitanya Gollakota: Thank you so much, and one quick one, and I might have missed his.

Chaitanya Gollakota: It is in your earlier remarks, but have you disclosed when the Ralebiobio asset would be in the clinic, or not?

Jay S. Duker: Yeah, Jay, you can answer that question. No, we haven't disclosed it. And as I did say earlier, when we have that type of news, we will certainly announce it. It would be very exciting for us and for Rally Bio and potentially for the patients. And so we will be announcing that when we've got more clarity around it. Thank you so much and congratulations. Thank you.

Chaitanya Gollakota: Let me also just make a comment, which is as to disclosure. In our current W-O-2 trial, if there were any safety signals, we would disclose that, and obviously, we have not disclosed any safety signals. So from that standpoint, we're pretty optimistic right now that EYP191 so far in the trial is showing good safety. Again, if there were any serious safety signals, we would report that, and obviously, we've not been notified of any serious safety issues. So that's all very, very positive.

Julian Reed Harrison: The next question comes from the line of Julian Harrison from BTIG. Please go ahead.

Julian Reed Harrison: Hi, good morning, and congratulations on the progress. You're positioning EYP 1901 as a potential six-month regimen and wet AMD in nine months for MPDR. So I guess I'd like to hear a little more about what gives you confidence in the longer injection intervals for MPDR and how important long intervals are for the MPDR market, generally speaking.

Jay S. Duker: So Jay, why don't you take the, you know, the pharmacologic and clinical questions, and then I'm going to ask Scott just to talk about the marketplace on nine-month NPR. Sure.

Jay S. Duker: So in preclinical and vivo and in vitro studies, we believe YP1901 should release the drug at therapeutic levels in humans for between eight and nine months. And so you might ask why are you going for a six-month interval, and the answer is easy. That's what retina specialists want.

Jay S. Duker: We want to give them the flexibility to dose as often as every six months, but because some patients, and I can remind you, a third of the eyes in our Davio trial went for the full year with no supplement. So they'll have the flexibility to go longer if they choose to.

Jay S. Duker: With respect to NPDR, it is a more slowly moving disease; number one, number two, is the consequence of the disease; a treatment effect, let's call it, wearing off a little bit early is not nearly as serious as what you might see in wet AMD. And so it would be hard pressed, I think, to show in a short term of just a month or two that if the insert were out of medication, it would make any difference. That's more around the PK and understanding the disease process. But again, Scott and I can talk about this.

Scott Jones: We talk to a lot of retina specialists and ask them what they would want in such a therapy. And again, nine months to one year later, see. Yeah, Jay, I would just add to that based on, you know, a number of different data points that we have from, you know, as Jay said, talking with individual physicians, market research, and reviewing some of the previous ASRS Pat survey data points. There's clearly a desire to treat in PDR if there is an appropriate interval.

Scott Jones: And, you know, as Jay mentioned, greater than six months, hopefully out to a year. You know, and again, it's a challenge getting these patients into the office as frequently as an AMDF. patient for treatment, you know, again, younger patients, working age, the ability to have them come back monthly by monthly is just non-existent, which is really why you see very low treatment, very low rates of treatment today in this NPDR group of patients.

Scott Jones: So therefore, you know, we believe there's a tremendous opportunity to grow the market substantially over the number of patients that are treated today. If you have a longer-term product, especially a product that is continuing to provide a daily microdose of product.

Operator: Thank you for the questions. Am I showing no further questions in the queue at this time?

Operator: Ladies and gentlemen, thank you for participating in today's conference. This does conclude your program, and you may now disconnect. Everyone, have a great day!