EyePoint Pharmaceuticals, Inc.

good morning my name is leeway and i'll be your conference operator today at this time i would like to welcome everyone to the ipoint pharmaceuticals three quarter 2023 financial source and recent corporate development conference call there will be a question and answer session to follow at the completion of the prepared remarks please the advice of this call is being recorded at the company's request I would now like to turn the call over to George Elston, Executive Vice President and Chief Financial Officer of the I-Point Pharmaceuticals. Please go ahead.

Thank you, and thank you all for joining us on today's conference call to discuss I-Point Pharmaceuticals' third quarter 2023 financial results and recent corporate developments. With me today is Dr. Jay Duker, President and Chief Executive Officer. Jay will begin with a review of recent corporate updates and discuss the ongoing Phase II clinical trials for EYP1901. I will close with commentary on the third quarter 2023 financial results, and we will then open the call for your questions. Earlier this morning, we issued a press release detailing our financial results and recent operational developments. A copy of the release can be found in the Investors tab on the corporate website, www.ipointpharma.com. Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. These include statements about our future expectations, clinical developments and regulatory matters and timelines, the potential success of our products and product candidates, financial projections, and our plans and prospects. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the risk factors section on our most recent annual report on Form 10-K, which is on file with the SEC, and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. I'll now turn the call over to Dr. Jay Duggar, President and Chief Executive Officer of iPoint Pharmaceuticals.

Thank you, George. Good morning, everyone, and thank you for joining us to discuss iPoint's continued execution toward our milestones as we work to bring first-in-class therapeutics and delivery technologies to patients suffering from serious retinal diseases. In the third quarter, we both advanced and expanded our product pipeline with the announcement of positive mask safety data in our ongoing W02 and PAVIA Phase II clinical trials for our lead product candidate, EYP1901, which is the small-molecule virolinib and our proprietary bio-erodible DuraCert E technology, as well as the unveiling of a new preclinical program, EYP2301. EYP2301 delivers a promising Ti2 activator for zooprotafib, formerly known as AKB9778, formulated in DuraCert E to potentially improve outcomes in wet age-related macular degeneration, or wet AMD, and diabetic eye disease, It's an exciting time at iPoint as our EYP1901 clinical trials approach key data events with top-line Phase II W02 trial results anticipated in early December and PAVIA results in Q2 of next year, and as we plan to initiate a third Phase II trial in diabetic macular edema, or DME, in Q1 of 2024. I'll now review our recent program and corporate updates and give an overview of upcoming catalysts. Turning to our lead program, EYP1901 is being advanced as a potentially paradigm-shifting treatment for patients suffering from VEGF-mediated retinal diseases. EYP1901 is delivered with a single intravitreal injection in the physician's office, similar to the current FDA-approved anti-VEGF biologic treatments. EYP1901 is immediately bioavailable, featuring an initial burst of drug, followed by near-constant zero-order kinetic release for approximately nine months. EYP1901 delivers Verolinib, a selective and patent-protected tyrosine kinase inhibitor formulated in a solid insert using our proprietary sustained-release bioerodible Duracert E technology. Verolinib brings a new mechanistic approach to the treatment of VEGF-mediated retinal diseases by acting as a pan-VEGF receptor blocker. blocking all VEGF isoforms. We expect EYP1901 with its new MOA and sustained drug delivery for up to nine months to meaningfully reduce treatment burden in the majority of wet AMD patients while keeping vision and retinal anatomy stable. Virolanib features reduced off-target binding and at clinically relevant doses does not inhibit TIE2, a critical pathway associated with vascular stability. which may result in an improved efficacy. In a rodent model of retinal detachment, ViroLinib demonstrated neuroprotection, and because it blocks PDGF, may also have antifibrotic benefits. We were pleased to present preclinical and clinical data at multiple medical meetings that underscore the promising profile of EYP1901. One highlight was at last month's Retina Society meeting, were a comparison of the anti-angiogenic profile of three TKIs, virolinib, exitinib, and sutinitinib, validated virolinib as a panVEGF receptor inhibitor that effectively blocks the critical pathways of pathologic angiogenesis. Importantly, the data showed that virolinib is differentiated from the other TKIs tested in retinal disease. Unlike sutinitinib, virolinib does not bind to melanin. And unlike accitinib, virulinib is not expected to have a physiologic impact on normal TIE2 function. As a reminder, the fully enrolled W02 trial is evaluating EYP1901 in 160 subjects with previously treated wet AMD as a maintenance therapy with a goal to maintain stable vision and retinal anatomy for the majority of wet AMD patients for six months or longer following a single injection of EYP1901. This could represent a significant improvement compared to the current anti-VEGF treatments that are dosed on average every two months in the United States under a treatment-extend protocol. This lifetime of frequent treatment represents a tremendous burden for patients, physicians, and the healthcare system in general. EYP1901 has the potential to change this treatment paradigm into a treat-to-maintain model by providing sustained delivery of rolinib for approximately nine months, following induction treatment with a large molecule anti-VEGF like Ann Walker. This may allow patients and practitioners the flexibility to reduce the number of visits without sacrificing visual outcomes. The subjects in the W02 trial were randomized to two treatment arms, approximately 2 milligrams or approximately 3 milligrams of EYP1901 or on label of Flibercept as a control. All subjects of the trial received three loading doses of Aflibricep on day one, month one, and month two, followed by dosing a BYP-1901 or a sham injection 30 minutes after the last loading dose. The FDA approval pathway for this program and the primary endpoint for W02 is non-inferiority in the change of best corrected visual acuity, or BCVA, for each of the 1901 arms versus the Aflibricep control arm. The lower limit of non-inferiority margin is defined as minus 4.5 letter loss by the FDA. For perspective, patients do not generally notice a change in vision until they lose five or more letters, which is the equivalent of one line on an eye chart. I'd like to share our perspective in terms of targeted outcomes for the non-inferiority BCVA, as there are both numerical and statistical considerations for this outcome. First, a very successful outcome in Davio 2 would be to mirror the Phase 1 Davio BCVA results that showed an average of 2.5 letter loss six months after EYP1901 was injected. Recall that Davio was an all-comers, open-label, non-randomized Phase 1 trial. Based on learnings from that Phase 1 trial, we modified inclusion and exclusion criteria for the Davio 2 trial. in an effort to exclude eyes that were not responding to standard of care therapy. We presented masked patient demographic data last quarter that reflects the fact that we enrolled a more controlled patient population in W02 than in the phase one trial. Generally, an outcome of minus three letters or better would be a very strong numerical outcome and possibly statistically non-inferior, even in this relatively small trial. If the EYP1901 arms match or better the minus 1.4 letters difference versus the 2 milligram of Flibercept control, which was what was seen in the 16-week 8 milligram ILEA arm in the PULSAR trial, this would represent an outstanding outcome from a single injection of EYP1901. In addition to stable BCVA, it is critical that the EYP1901 continues to show a favorable safety profile consistent with the interim mass safety update through October 1st, 2023 across all of the EYP1901 clinical trials. As of October 1st, approximately 170 patients have received EYP1901 with a minimum of four months follow-up post-injection from the ongoing Phase II PAVEA and W02 clinical trials and the completed Davio Phase I trial with no reported drug-related ocular SAEs and no reported drug-related systemic SAEs. This continues to give us confidence in the results of this crucial endpoint. Although change in best corrected visual acuity is the primary endpoint, reduction in treatment burden will also be a critical secondary outcome to consider, giving the unmet need in this patient population for more durable therapies. For a clinically meaningful outcome, we believe that one or both EYP1901 arms need to result in a reduction in treatment burden of a minimum of 50% or better for the six months following EYP1901 injection at week eight. In addition, we also believe that 50% or greater of the EYP1901 treated eyes should be supplement-free up to the week 32 visit, along with a relatively stable anatomy as measured by OCT. Based on our market research and KOL interactions, these endpoints will be meaningful to retina specialists who treat wet AMD patients. We plan to host a virtual call with renowned retinal specialists Dr. David Boyer and Dr. David Lally on November 9th at 8 a.m. Eastern Time to discuss their perspectives on the current treatment landscape and the W02 outcome considerations that I just reviewed. We hope that you will all join us for this informative presentation and Q&A. And you can find the link to that call in the investor tab of our website. Looking ahead to the potential phase three pivotal trials for EYP1901 as maintenance therapy in wet AMD, our current plan is to initiate the first trial by the fourth quarter of 2024. This initial trial will be largely in the US and Canada. We hope to initiate a second pivotal trial several months later. The second phase three trial will be largely outside of the US. The Phase II W02 trial of EYP1901 was designed to mirror the anticipated design of the Phase III trials based on our type C meeting with the FDA and other interactions with the agency. The key differences are that the Phase III trials will feature redosing of EYP1901 every six months, and the primary efficacy endpoint will be non-inferior change in visual acuity to approximately one year instead of eight months, as it is in W02. We expect to share more details about this trial in the coming months. Now let me turn to our second indication, NPDR. In June, we reported that enrollment of the Phase II PAVEA clinical trial was complete. PAVEA is a randomized controlled Phase II trial evaluating EYP1901 as a potential nine-month treatment for moderate to severe NPDR. Similar to the DAVIO2 trial, our PAVEA trial saw significant investigator and patient interest during enrollment. The trial enrolled 77 patients, exceeding the 60-patient target. Patients were randomly assigned to one of two doses of EYP-1901, approximately two milligrams or approximately three milligrams, or to the control group that received a sham injection. As in the wet AMD trials, EYP-1901 is delivered with a single intravitreal injection in the physician's office. As a reminder, NPDR is a very common retinal disease that affects almost one-third of diabetic adults over the age of 40. and it's projected to impact over 14 million Americans by 2050. In NPDR, blood vessels are weakened, potentially leading to swelling of the macula, which is called diabetic macular edema, or DME, and may eventually result in abnormal blood vessel growth, which is called proliferative diabetic retinopathy, or PDR. Both DME and PDR can ultimately result in severe visual loss. It is important to note that there remains a great unmet need for a safe, efficacious, and convenient treatment for NPDR that proactively reduces the risk of progressing to a site-threatening complication over the long term. Approximately 90% of patients with NPDR currently receive no course of therapy, apart from observation by their eye doctor, until their disease progresses to DME and or PDR. EYP1901 in our Phase II PAVEA trial could potentially reduce the risk of progressing to these complications with a less intrusive treatment protocol. Recently, we reported an interim analysis of mass safety data from the Phase II PAVEA clinical trial in NPDR, which showed that as of October 1, 2023, EYP1901 was well-tolerated with no reported drug-related ocular or drug-related systemic SAEs. demonstrating EYP1901's excellent safety profile in NPDR for the first time. Top-line data from the PAVIA trial remains on track for the second quarter of 2024. As mentioned earlier, we plan to initiate a Phase II trial evaluating EYP1901 and DME in the first quarter of 2024, which we are calling the Verona trial. We will share details of that trial at a future date. goal of the Verona trial is to gain experience with EYP1901 in this potentially large indication. In September, we disclosed a new preclinical program called EYP2301. EYP2301 is tied to agonist razoprotafib, formerly known as AKB9778, which we have formulated to work in DuraCert E. This has the potential to provide intravitreal sustained delivery over six months or longer to improve the treatment of wet AMD and diabetic eye disease. Previous preclinical and clinical studies show that raciprotafib delivered subcutaneously demonstrated proof of concept in diabetic eye disease. And we believe that delivering EYP2301 intravitrally has the potential to offer new site-saving treatment for patients with severe retinal disease, either alone or in combination with anti-VEGFs. Finally, we were delighted to announce that I-Point expanded its board of directors with the appointment of Stuart Doody, a seasoned biopharmaceutical financial executive who brings more than 25 years of experience to the role. We also strengthened our executive leadership team with a promotion of our CFO, George Elston, to the additional role of executive vice president. George's wealth of experience, financial acumen, and strategic guidance has been a tremendous asset to our iPoint team. On behalf of the entire leadership team, we welcome Stuart and congratulate George, and we are grateful for their valuable leadership at iPoint as we continue to build value for our shareholders during this active time in the company's growth. I'd like to thank the entire iPoint team for an incredibly productive quarter. And I will now turn the call over to George to review the financials. George?

Thank you, Jay. As the financial results for the three months ended September 30, 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 third quarter ended September 30, 2023, total net revenue was $15.2 million, compared to 10 million for the quarter ended September 30, 2022. Net product revenue for the third quarter was 0.8 million compared to net product revenues for the third quarter ended September 30, 2022 of 9.7 million. Consistent with the exit from the commercial business, the decline in revenue resulted from the sale of the UT franchise in May 2023, along with the discontinuation of marketing activity for the Dexecu franchise this year due to the loss of pass-through reimbursement by CMS effective 1-1-23. Net revenue from royalties and collaborations for the third quarter ended September 30, 2023, totaled $14.4 million, compared to $0.3 million in the corresponding period in 2022. The increase was primarily due to a recognition of deferred revenue from the sale of UTiQ, which will be recognized over a two-year period, which began in Q2 of this year. Operating expenses for the third quarter ended September 30, 2023, totaled $29.6 million versus $28.4 million in the prior year period. This increase was primarily driven by higher R&D spending on EYP 1901 clinical trials, partially offset by lower sales and marketing expense. Non-operating expense net totaled $1.8 million, and net loss was $12.6 million, or 33 cents per share. compared to a net loss of 18.4 million or 49 cents per share in the prior year period. Cash and investments at September 30th, 2023 totaled 136 million compared to 144.6 million at December 31, 2022. We expect the cash, cash equivalents and investments on September 30th, 2023 will enable us to fund our current and planned operations into 2025. In conclusion, We are pleased with iPoint's progress in the third quarter and year to date and are well capitalized to advance our product pipeline to key value inflection points. I will now turn the call back over to Jay for closing remarks.

Thank you, George. We believe EYP1901 is a potentially paradigm shifting treatment for patients suffering from serious retinal diseases, providing unique benefits that may include delivery of virolinib consistently over approximately nine months, a new mechanism of action to treat retinal disease beyond anti-VEGF ligand blockade, the potential for neuroprotection and antifibrosis, and a proven delivery technology with a positive safety profile. I will close by recapping key upcoming catalysts, including the top-line data from our Phase II W02 clinical trial anticipated in early December, the dosing of the first patient in the Phase II Verona clinical trial of EYP1901 and DME in the first quarter of next year, and top-line data released from our Phase II Pavia clinical trial in the second quarter of 2024. This remains an incredibly exciting time for iPoint, as we are well-positioned to execute on our upcoming milestones and continue to transform the treatment landscape with innovative, long-term solutions to improve both the vision and the lives of patients with serious retinal diseases. Thank you all very much for listening this morning. I will now turn it over to the operator for questions.

Thank you so much, presenters. Our first question comes from the line of Tyler Van Vuren of TB Commons. Your line is now open.

Good morning. Congrats on the progress. Thanks very much for the call. I have a couple questions for you. First one is, You know, I appreciate how transparent you guys have been with respect to your BCVA outcome scenario ranges for the W02 trial ahead of the data, but were these constructed in accordance with KOLs, and can you elaborate on what the KOL feedback has been regarding what they need to see from the trial, perhaps a preview of sorts of the upcoming KOL event? And then the second question is, upon positive data, can you talk about how quickly you would be able to start the Phase III program and Is it possible to get to top line data in an accelerated fashion, or should we think of it being a more traditional WET-AMD phase three program timeline?

Thanks, Tyler. Appreciate the questions and your interest. First of all, with respect to the BCVA ranges, so there's really kind of three ways to look at this. And the first way is, what does the FDA want? uh and that's pretty clear uh not the non-inferiority margins got to be minus 4.5 letters you can't cross it with your confidence intervals uh and depending on your end of your study and your the standard deviation you could come pretty close to 4.5 and get a result but the second part of what you asked is what is what does the kols want and interestingly when you ask them and i'm sure you have uh They're generally fine with a good efficacy profile, good safety profile, as long as the numerical change is in the range of three to four letters. It's interesting that I think that they believe in general that that type of change in vision is not noticeable to the patient. On the other hand, We, as a company, look at it as a combination of both of those, and so that kind of minus three range or better, I think based on what we anticipate the standard deviation of the trial might be, in a pivotal trial would likely be non-inferior and meet the KOL's expectations. Of course, we don't know what the results are yet. We'll know in approximately a month, but there's reasons to believe that we could do considerably better than that. Second question was on the start of the phase three. With good to great data, we believe we can start the first phase three trial in the second half of next year. It may be closer to the fourth quarter. We haven't really zeroed in on that. Suffice it to say, the company has been really focused on phase three prep for basically the last nine months. And there's a lot to do to get ready. And we continue to be on track. for our goal to start it in the second half of next year. From an accelerated perspective, I think the trouble with unmasking early is you penalize yourself with a higher end. And, you know, cost and speed is critical here. And if our statistics suggest we can do the phase threes with relatively low ends, I think it's best to get them done right and get them done fast as opposed to, you know, be penalized for an early look. I hope that was sufficient. Anything else?

No, that's clear. Thank you very much.

Thank you so much. Your next question comes from the line of Yadin Suneha of Guggenheim. Your line is now open.

Thank you for taking my question. So Jay, you just mentioned that, you know, you're focused on obviously delivering this data, but also in the phase three. So my question to you is, and it also has to do with the competitor is, you know, how does the ILEA induction relate to the mechanism of TKIs in wet AMD? And then can you maybe just talk about why you think it is necessary for patient to do that induction when your competitors are doing a, superiority study with just a single-dose effluent receptor as a comparison. I'd love to get your thoughts there.

Thanks, Yatin. Those are two great questions. Let me start with the induction. First of all, from a scientific perspective, it's unclear if the induction offers anything to the patients treated with EVIP-1901. We have pretty good preclinical data that shows that our drug is bioavailable in the cord of animals within minutes of injection and reaches therapeutic levels in hours. On the other hand, we've set out from the beginning to use EYP1901 as a maintenance therapy for previously treated wet AMD patients. The decision to do the reinduction is something that came up with our discussions with the FDA around the structure of the Phase III pivotal trials. When we had our Type C meeting, the FDA was certainly agreeable to us using ILEA as our control in the Phase III. And when we discussed on-label ILEA, the FDA's response was, Yes, after you reinduce the patients, you can go to every other month on label ILEA. And the rationale was the patients you enroll in that trial may be undertreated. And therefore, before you allow them to go to every other month, you've got to reinduce them. Made sense. And then we had to re-engage the FDA and said, well, if we're going to make an assumption that some of these eyes are undertreated in the real world, which we think is probably true, we'd like to re-induce all the patients in the study. And they were agreeable to that. What that did, however, is you may be aware, you can have a nine-month efficacy endpoint in a wet AMD study. But our nine months doesn't start ticking until after the reload of ILEA. So what it was, the trade-off here was we needed to do, in our pivotal trial, the efficacy endpoint out approximately one year. We thought that was a fair trade-off to be able to level the playing field and make sure that we weren't allowing relatively undertreated patients to flood the EYP in 1801 arms. So it really isn't a scientific reason. I'd say it's a regulatory reason and a de-risking reason that we're reinducing. So that, I think, gets into the second question. You know, why induction? Again, I think I've covered that. Our decision to do this you know, I think more typical non-inferiority phase three is, again, it comes out of our discussions with the FDA and a de-risking. We think that this is the fastest and least risky pathway to FDA approval.

Yeah, I remind you that, remember, we had a type C meeting with FDA laying out the phase two plans, which would inform phase three. And so that's also a big driver of focus going into the phase threes next year.

Very helpful. Just one more question, if I may. Could you talk about the dose response? There are two doses in this study. So just curious, what would you expect? Should we expect any dose response? And then, you know, if let's say if there is no dose response, just curious, like how you will decide on the dose to take forward?

Yep, that's another great question, Yachton. And we really don't know if there will be a dose response, because it's certainly possible that our two milligram dose will work efficiently to shut down the receptor for up to nine months. And therefore, any additional drug may not give you additional benefit. So I would say we're, as a company, a little bit agnostic to that. I mean, it's nice to show a dose response. And there's some validation to that, understandably. On the other hand, if both our two milligram dose and our three milligram dose work great, and they're essentially the same, we would opt to go with the two milligram dose approximately in our pivotal trial against a lower dose, most likely around one milligrams. What that would do, of course, is enable us, if successful, to have fewer inserts in the eye and lower the cogs.

Thank you so much.

Thank you so much. Your next question comes from the line of Jennifer Kim of Cantor Fitzgerald. Your line is now open.

Thanks for taking my questions. I have two. The first is just touching on the BCBA question. Jay, I think in your prepared remarks, you said a BCVA letter change difference of three letters or better would be good. And I think investors are generally aligned with that. The most pushback I've gotten is on the minus three to minus four letter scenario. So I was curious to see if you have any thoughts on that scenario. Is the base case or the hope that it would be better than that? And similar to that, in this scenario where you get a minus three letter difference, would STAT-SIG have to assume a standard deviation better than what we've seen with, say, PDS? Thanks.

Sure. Great questions, Jennifer. Thanks. So, the best corrected visual acuity of three or less difference really would be, I think, kind of a clear pathway in everybody's mind if we can replicate that in the pivotal trials. Minus three to minus four is kind of a theoretical range where one could argue that with a minus, let's say, three and a half letter difference and a large enough N and a small enough standard deviation that that could be statistically non-inferior. But then you're getting into a point here where would it be commercially successful? So while it would meet that first bar of FDA approval, it may not meet the second bar of what the KOLs want and perhaps, as you say, what the investment community might want to see as a result. So I would say, you know, again, centering on the three letters are better. I think that beats everybody's test for success here. I remind everyone that, you know, we were minus 2.5 letters in the phase one at six months after the 1901 was injected. And one would expect, and of course we don't know this yet, but one would expect the ILEA control arm to be relatively stable after the load between, you know, weeks 8 and week 32. And if it is, and we can replicate minus 2.5 again, I think that that would be really an outstanding result. So the words, again, you know, base case, and, you know, it's, again, I think a lot of this depends on what the view of what we need to do to advance the drug into, you know, pivotal trials. And one could see with a very tight standard deviation that even minus three letters would be statistically significant. So you mentioned the PDS standard deviations, and again, if you go back and look at the pivotal trials and wet AMD, I think basically every one since ILEA was approved was done on a non-inferiority basis in treatment-naive patients and generally had standard deviations to the change in visual acuity of around 12 letters. That's because they're treatment-naive. Some eyes respond, some eyes don't. The PDS phase 3 enrolled previously treated patients. like we did, but they limited the length of time to diagnosis to nine months prior. So some of those eyes were still relatively early in their treatment and still perhaps being treated and extended. They weren't at a stable kind of pace of their disease yet. They had 7.1 letter standard deviation. So we have reasons to believe that because of our enrollment of eyes that had the disease longer than nine months, are suggesting they'd be more stable, that our standard deviation could be lower than that. Does that answer the question?

Yeah, it does. If I could add one more. Your competitor announced that they received an agreement under their superiority trial design this morning. Net-net, this seems like good news for the overall space, given the post-draft guidance world we're in. But I'm wondering if you have any takes on that.

Well, yeah, and again, that was just announced this morning with no details. But at a high level, this is great news. It's great news for all of the TKI companies because it shows that the FDA is willing to work with us to advance this new paradigm into the clinic. And as we know, it's great for the space. You know, when investors see that there's a clear pathway to approval, then things are de-risked. From our perspective, we're very comfortable with our phase two design. And if we get good to great results at this point, I think our phase three design, which the FDA has already seen and commented on and through our type C meeting, I think that still would represent the fastest, least risky way to get approval for our drug. Again, last comment about this, though, is once we are able to see the details of the SPA that Okta was received, we will, like any company should do, is take a look at our program and see if there's any learnings from what they're doing. But I have to, again, state we're very comfortable with our approach to the pivotal trials in Pathway to Approval.

Okay, that's helpful. Thanks for taking my question.

Thank you.

Thank you so much. Your next question comes from the line of Colleen . Your line is now open. Colleen, your line is now open. You may ask your question.

Maybe we could go back to Colleen after the next one.

All right. Your next question comes from the line of . Please go ahead.

I couldn't hear. I thought that was my name that was called. Yeah, thank you for taking the question. I have a quick one on 2301. I wanted to ask for the rationale for this product and specifically how does it fit with 1901 strategy, given that there could be some overlapping indications? Thank you.

Thanks, Daniel. That's a great question. 2301 is based around a molecule that's been studied into phase two by a company called ARPO. We've acquired their assets, and their lead product, AKB9778, was delivered subcutaneously for diabetic macular edema and for diabetic retinopathy. And it showed really promising anatomic results, although the visual results did not enable the company to really go forward into pivotal trials. This drug activates TIE2, and by activating TIE2, you stabilize blood vessels, and you down-regulate angiopoietin 2, or ANCH2. Now, you may be aware that Vabizmo is a bispecific that blocks VEGF and blocks ANG2. So that pathway of ANG2 blockage is validated. And we believe that AKB9778, now EYP2301, may be a better way to block that pathway by activating TIE2. Secondly, we can now deliberate sustained release. So these bispecific molecules still require relatively frequent injections. And we believe we can deliver at therapeutic levels for over six months with a single injection of 2301. So how does it fit in? Well, that remains to be seen. I think that we could develop it and test it in a non-inferiority fashion to get a label against the standard of care for either wet AMD or DME or both. Or we could choose to go for a superiority trial using it in conjunction with an anti-VEGF. That, of course, would be perhaps riskier because the anti-VEGFs are so effective. It sets a really high ceiling. On the other hand, if one is successful with that approach, you would likely have a multi-billion dollar product because doctors would relish the opportunity to do even better than anti-VEGF alone. How would it fit into EYP 1901? Highly speculative, because we've got a long pathway to go with 2301, shorter pathway with 1901, but you could envision a day when both have approval as standalone and as combo, and one could do it one of each in a single injection. Obviously, there's a long pathway to that and a lot of permutations that we're going to look at. But in a nutshell, what we believe we can do with 2301 is activate the TIE2 pathway, secondarily inactivate ANG2, and to do it in a sustained release fashion with a de-risk molecule. All right. Got it. Thank you.

Thank you so much. Your next question comes from the line of Sean Kim of Jones Reading. Please go ahead.

Thank you for taking my questions. I just have a couple of quick ones. So I guess for the WET-AMD program, following the W-2 readout, would you be requesting an end of phase two trial with FDA to further guide the phase three trial design?

That's our plan. In fact, we would plan currently on having both a clinical end to phase two and a CMC end to phase two to gain alignment in both those areas.

Okay. Gotcha. And the potential timing of that meeting?

I would say late in the first quarter of next year may bleed into early second quarter of next year, depending, again, tables from W2 in a format that we can submit.

Okay, great. Thank you.

That's a really great limiting step here.

Okay, gotcha. And what RallyBio complement inhibitor collaboration, what updates should we be expecting from that program in 2024? Okay.

Thanks for that question, Sean. You know, that's a good question. And the answer is, as we kind of said before, we're really excited about the collaboration. We're really excited about the molecule. Getting complement inhibitors to last several months at therapeutic levels in the eye is a challenge. If it wasn't a challenge, you'd see them already. However, we've made great progress. And we remain optimistic that we will be able to sustain release of complement inhibitor. But until we have really are confident in our formulation and our ability to do this consistently, we're not going to make any public statements around that. So I would say that, again, we're still working on it. We have made great progress. We have some really great scientists working on this. But it's not an easy task to accomplish.

Yeah, Sean, maybe I can add to that because if you look at how we, you know, our cadence on disclosure, you know, we just disclosed 2301 this past quarter because we've gotten it to a point where it formulates and we're in a position to move it into those preclinical programs. And I think you should think the same for the complement space as well. Once we get that formulation that we know works and has the right window, we'll start talking about it a little more publicly on what that pathway looks like.

Okay, I got you. Thank you. And last one from me is about the cash runway into 2025. Does that include potential Pivotal 3 Phase 3 trials in WebMD as well, now that you're looking to start in second half?

Yeah, thanks for that question, Sean. So our cash guidance into 2025 includes the ongoing Phase 2s, the planned Phase 2. in DME, which is the Verona trial, which we expect to start in Q1, along with a significant amount of phase three prep to be in a position to start the trials sometime second half of next year. It does not include the actual clinical trial cost for the Pivotals. And as we've talked previously, that's something that we're going to look to a range of options to fund, which includes potential equity raise, we've got strong strategic partner interest and some other levers that we can pull. And we'll be talking about that over the coming months on our plans to fund that really after phase two results.

Okay. Thank you again for taking my question.

Good question. Thank you.

Thanks so much. Your next question comes from the line of Yale, Janus Label & Company. Your line is now open.

questions, and my question probably will be focusing on the potential future Phase III study. The first one is that in one of your latest presentations, you have laid out four scenarios in terms of the Phase III of different BCVA outcomes. I'm just curious, based on those assumptions, what might be your thoughts in terms on the scenario, what the Phase III study size might be. Then I have a follow-up. You're talking about on the BCVA measures? Right, from 1.0 all the way to minus 4.

Yeah. Yeah, if I may, those actually were our interpretation of the Phase II outcomes of where they might land. and what they might mean for those outcomes. Without knowing the standard deviation of the change in visual acuity, we can't predict the size of the trials. But, you know, you can run it into a statistics package, and we've certainly done that. If we're minus one letter worse than the ILEA control, and the standard deviation is seven or less, we could do pivotal trials that might involve as few as 250 to 300 patients. So it's fluid because we don't know those results yet. But there's a second consideration, I think, for most of these trials that when you're doing treatment naive patients, when the standard deviation is larger, companies end up doing 500, 600, 700 patient trials. But that's because not only the standard deviation, but because the FDA requires a certain number of patients for safety. So the FDA requires that you submit, and you're able to submit with one-year efficacy data of your second trial. You don't need a two-year safety to submit. But at the one year, you need to have 300 patients treated with your go-to-market dose or higher Ultimately, you need approximately 400 patients treated with your go-to-market dose or higher for safety. So that's another consideration for the end of the trial. And that might suggest that we would maybe not do a one-to-one-to-one randomization in the pivotals and have more patients in the higher dose to reach those safety measures, knowing that the statistics would allow a smaller number. As I've said already, you know, our view is to do this as quickly, as safely, as de-risked, and as less expensive as possible. And that's how we are going to view all the options in the pivotal trials.

Okay, great. That's very, very helpful. And you mentioned earlier that the Phase III also incorporates the retreatment options or costs. Could you elaborate a little bit more in terms of at least what you proposed, the retreatment, any details on that?

Sure. Yeah. Thanks. And I think we've been very consistent from the start. Even though we have in vivo and in vitro evidence that these EYP19-1 inserts will release at therapeutic levels for approximately nine months, we've done enough tox studies to show that even if we re-inject earlier than that, we're in a very safe area for toxicity of virolinib and number of inserts. In fact, we have not found the maximally tolerated level of virolinib in animal eyes. So from a safety perspective, it's not a problem. Why did we choose six months? I think it's simple. That's what retina specialists want. They want flexibility to dose drugs when they want to dose them. while it's clear that some eyes can go longer than six months, remember in our phase one trial, rather, we had a third of the eyes made it a year without supplement. We're going for the label of every six months because we want to give the doctors flexibility to dose that often should they choose to.

Okay, great. That's helpful. And maybe just add one more that regarding spots from the competitors' news this morning. Was that something you guys also consider, or it still depends?

Well, yeah, again, I think I did address this earlier, but I'll reiterate. We have what we believe is an agreement with the FDA that's in writing that we have an acceptable protocol for our pivotal trials. If that is the fastest, least risky way to proceed, that's our plan. And we've seen nothing at this point to alter that. Obviously, it's dependent on good to great data from W02. But there may be learnings from other companies' approach. and we'll be studying that to see if there are any learnings for us. So until the details are out, I really can't make any comment on that except to reiterate once more, we are very comfortable with where our program is at right now.

Okay, great. And congrats on the other progress and look forward in early December.

Thank you so much. Your next question comes from the line of Yi Chen of HA BrainWise and Company. Your line is now open.

Thank you for taking my question. So my question is, by positioning 1901 as a maintenance therapy, while your competitor seems to target treatment-naive patients in their phase three trial, does that mean you could potentially lose part of the market in the future? I mean, could you use 1901 for treatment-naive patients as well? Thank you.

So If we get a label for maintenance therapy and the label includes follow use of 19-1 after induction with ILEA or any anti-VEGF, let's say, hypothetically. I think doctors, knowing the retina specialist community the way I do, I think doctors will try it earlier than after three induction doses in some cases. If we're safe, effective, and tolerable, I think the argument might be why not use it after a second induction or first induction dose? Will it be used as solo therapy initially? I think data needs to be shown that it's effective that way. So again, the market share depends on a lot of things. And once again, one of the things we just talked about was reinjection. And the hope and expectation is we would get a label for every six months reinjection. The FDA was clear that if we wanted a label for reinjection, we needed to test reinjection in the pivotal trials. And so I think that if that is the way our label reads eventually, I think that will have an advantage also. So it's hard to predict. I would certainly admit that. But once again, we are very comfortable with where our program is at and the approach that we're taking. And the retina community that we've talked to, I think, is in favor of the approach that we're taking. And if we get that label, I think retina specialists will figure it out.

Yeah. And you, maybe if I can add to that, just keep in mind, the vast majority of the market is previously treated patients. And the fact that we are going to be able to read those every six months is going to be meaningful on our label. And, um, you know, I think ultimately physicians will have the opportunity to use it sooner, but as we think about our approach and the market approach, you know, we're, we're addressing a very significant portion of a $10 billion plus market. So, you know, we're, we're comfortable with our pathway.

And I could add one more, George. You know, that was an excellent point you made about, you know, for every newly diagnosed patient, a retina specialist probably has a dozen or more previously treated patients in their practice. So once again, from a recruitment perspective and from speed to filling a trial, there's a lot more maintenance therapy patients out there than there is newly diagnosed. And that's one of the many reasons why we've chosen this pathway, speed to approval.

Thank you.

Thank you. Could we see if Colleen is still on the line and wants to ask a question?

Yeah, she responded. She's having issues with a number of calls this morning, so we'll find her later. Great.

All right. And we actually don't have any further questions in the queue at this time. So, ladies and gentlemen, thank you for participating in today's conference. This does conclude your webcam on your program. You may now disconnect. Everyone, have a great day.

Thanks, everybody.