Opus Genetics, Inc. (IRD) Earnings Call Transcript & Summary

Greetings. Welcome to the call today to discuss Ocuphire Pharma's ZETA-1 top line results. [Operator Instructions] Please note this conference is being recorded. I will now turn the conference over to your host, Michael Wood of LifeSci Advisors. You may begin.

Thank you, and good afternoon, everyone. As a note, there are slides accompanying today's call. For those of you who have dialed into the phone lines this afternoon, you'll need to access the company website in order to view the slides. The link is available on the Investor Relations section of the Ocuphire corporate website under News and Events and Future Events. Before we begin, I'd like to draw your attention to the legal disclosures regarding forward-looking statements here on Slide 2. During the course of this conference call and webcast, the company will make forward-looking statements regarding future events, including statements about financial business, clinical milestones, commercialization and plans and strategies anticipated in fiscal 2023 and beyond. We encourage you to review the company's past and future filings with the SEC, which identify specific factors that could cause actual results or events to differ materially from those described in the forward-looking statements. You can find the SEC filings on the EDGAR database at sec.gov or on the Investor Relations section of the corporate website at ocuphire.com. Please note that any comments made on today's call speak only as of today's date, January 25, 2023, and may not be accurate at the time of any replay or transcript rereading. I'd now like to turn the call over to Mina Sooch, CEO and Founder of Ocuphire. Please go ahead, Mina.

Thank you, Michael, for the introduction, and good afternoon, everyone, and thanks for joining us. We are pleased to host this call today to announce the top line results from Ocuphire's ZETA-1 Phase II trial evaluating oral APX3330 in diabetic retinopathy. By now, you will hopefully have the chance to review the press release we issued after the market closed today. The agenda for our call is shown here on Slide 3. We will begin by the overall takeaways and a review of the APX3330 oral molecule. Then we will review the trial design demographics and, of course, the efficacy and safety findings and provide some overall summary thoughts and next steps. With me this afternoon is Dr. Mitch Brigell, our Head of Clinical Development and Strategy; Dr. Charlie Wykoff, Harvard-trained, Board-certified medical and surgical retinal specialists and ophthalmologist and retinal consultant of Texas; Mark Kelley, the founder of Apexion, the discoverer of the Ref-1 target as well as a Professor at the Indiana School of Medicine. And we also have Dr. Jay Pepose, our Chief Medical Adviser and Board member and ophthalmologist at Jay Pepose Institute. So we welcome all of you and them to the call today. So let's get right into it on Slide 4. I just want to say we're going to now describe and share some of the key takeaways. So moving to Slide 5. Nonproliferative diabetic retinopathy is a big problem in over 8 million people today with limited-to-no-treatment options. Our study, ZETA-1, started back in early 2021 with our first patient, first visit, and it was roughly a 2-year trial as we sit here today to share our results. It was our first trial in ophthalmology, the first for an oral APX3330 in this population, and it was designed as a robust randomized, double-masked, placebo-controlled multicenter trial, a true proof of concept, not necessarily often found in early trials in the field. So as many of you know, the purpose of a Phase II is to gather data on the drug's efficacy and safety in order to inform the design of a robust Phase III trial that can support registration. We chose a primary, and then assigned all other efficacy endpoints as secondary. So with that in mind, I think you'll see that ZETA-1 has served its purpose. We have control data, a relevant registration endpoint, and a path forward for APX3330 for a potential approval in diabetic retinopathy. So specifically, the takeaways. Yes, the study did not meet the original planned primary endpoint, which was the percent of subjects with the 2-step improvement in the DRS score at 24 weeks in the qualified study eye. However, as you can see now on the slide, we are happy to share that we have achieved statistical significance on a key prespecified secondary endpoint of preventing clinically meaningful progression of diabetic retinopathy as defined by 3 or more steps of improvement in both eyes on the DRS score after 24 weeks of treatment. And actually, it was very interesting, we saw a trend towards more efficacy at 24 weeks versus 12 weeks, giving us good guidance on a 52-week Phase III trial and hopefully to see a larger signal as more time progresses for those placebo subjects. Number two, the prevention of 3-step worsening binocular, or in both eyes, is a suitable endpoint for an oral systemic drug, and Ocuphire plans to go forward with this potential registration endpoint in Phase III following such confirmation with the FDA in an end-of-Phase-II meeting. Importantly, oral APX3330 demonstrated favorable safety and tolerability. We'll show you more detail, but very exciting for an oral. Three, we've had some early retinal KOL feedback, and it suggests that the slowing of diabetic retinopathy progression with an oral agent would be a very useful treatment of patients with background diabetic retinopathy and good visual function. And if approved, APX3330 could be an important new primary preventative therapeutic option that can be used in a large number of these diabetic patients who are at the earlier stage of their disease. So as I look ahead to Slide 6, I just want to give all of you a quick overview of APX, the molecule that we have just studied and shared the key takeaways. So APX3330 is a first-in-class oral pill with the dual-acting mechanism of action. In diabetic retinopathy, APX3330 works by blocking Ref-1, a transcription factor regulator, specifically REF stands for reduction oxidation effector factor 1, and it is a novel target that Dr. Mark Kelley discovered over 30 years ago at the Indiana University. APX3330 blocks Ref-1 and has downstream effects in both hypoxia and inflammation pathways. And on the left, you can see from the image that inhibiting Ref-1 allows us to block HIF-1-alpha which leads to further down signaling of anti-VEGF effect. On the right side, you can see that we blocked -- by blocking Ref-1, you block NF-kappa B, TNF-alpha and the other subsequent cytokine and inflammatory cytokines. Thus, we have the potential to block 2 important mechanisms that are important and relevant to the progression of disease and diabetic retinopathy, both the VEGF and the anti-VEGF pathway with a single drug. And it's important to note that we lower VEGF and inflammatory cytokines to normal levels. And last point I would like to make is, historically, APX3330 has been a drug that's been studied extensively in multiple conditions, in liver, oncology as well as in healthy subjects. And in this field, the anti-VEGF and the anti-inflammatory mechanisms were both relevant to those prior indication studied of liver and oncology, respectively. So -- and also, since it's been studied previously, that includes 11 prior Phase I and II trials and over 20 in-vitro and animal studies as well, establishing a very great foundation for why we went into a Phase II trial for APX3330. And with that, I'm going to turn over the call to Dr. Mitch Brigell, who will go through the design of ZETA-1 and the safety and efficacy results.

Thank you, Mina. In Slide 8, you can see the trial design for the ZETA-1 study. This is a 24-week Phase II trial of oral APX3330 in patients with diabetic retinopathies. The trial was designed using the example set by the Phase III trial of Eylea, which is a biologic that's injected intravitreally for the same indication. We targeted 90 to 100 subjects and actually enrolled a total of 103 subjects with moderately severe to severe nonproliferative diabetic retinopathy or mild proliferative disease. Subjects were randomized 1:1 to receive either APX3330 orally at 600 milligrams per day BID or placebo for a total of 24 weeks of treatment. As in the Eylea Panorama study, the primary endpoint was the percent of subjects with 2 steps or greater improvement from baseline on the 10-point diabetic retinopathy severity scale at week 24 in the study eye -- single eye. Several secondary endpoints were evaluated as listed on this slide. Importantly, for an oral systemic drug, one of the key secondary endpoints was the percent of subjects with binocular improvement or worsening in DRSS. In other words, we're looking at the status of both eyes with a systemically delivered drug. The next slide shows the eligibility criteria for the subjects enrolled in the study. The trial is open to male and female subjects with diabetes, 18 years of age or older, with at least 1 eye with moderately severe to severe NPDR or mild proliferative disease, defined as a DRSS score of 43, 53 or 61. But the study eyes had to have good -- best corrected visual acuity of 20/63 or better and could not have been treated for diabetic retinopathy or diabetic macular edema within the previous 6 months. Diabetic macular edema was allowed in the fellow eye of these subjects. Other important inclusion and exclusion criteria are noted on this slide. Next slide shows the patient demographics. Here you can see that the study was well balanced across treatment and placebo arms for factors such as age with a mean age of approximately 56 years; sex, race, ethnicity as well as time duration of diabetes of approximately 16 years. The next slide shows the diabetic retinopathy severity score at baseline for subjects in the study. The upper part shows the study eye, and you can see that most of the eyes had moderately severe to severe nonproliferative disease, and only a few had mild proliferative disease, and that this is well balanced across the 2 treatment groups. The fellow eye, which didn't have the same restrictions for eligibility, has a wider range of DRSS scores, with some patients having mild -- very mild or moderate diabetic retinopathy in the fellow eye, and others having more severe proliferative disease. The next slide shows some more baseline characteristics in the study in fellow eye. Subjects had good baseline visual acuity and mean central retinal thickness on OCT within normal limits. Although it should be noted that about 10 of the fellow eyes had center-involved DME. Other baseline parameters such as heart rate, blood pressure, BMI and HbA1c were also well balanced between groups and typical for a diabetic population. I'd now like to go into the efficacy findings in the study. But before going into the results, I want to provide details on the diabetic retinopathy severity scale, or DRSS, which is a standard system for measuring the severity of diabetic retinopathy. This is a 10-step scale and an accepted surrogate endpoint for diabetic retinopathy. It's based on the presence of vascular changes on fundus photographs such as microaneurysms, IRMA, flame hemorrhages, vascular bleeding and vitreous hemorrhages. During clinical trials, the severity of patients' retinopathy over time can be categorized into discreet steps using the scale. I'll draw your attention to the green box around steps 5, 6 and 7, which highlights the 3 levels of disease severity in the patients that were -- in the study eye of the patients that were recruited into the ZETA-1 trial. Monocular changes on this scale. Look at the number of step changes in a single eye, which is the study eye. Whereas binocular changes, some of the change of the 2 eyes. The next slide shows the results for this trial on the primary endpoint. That is the percent of patients with greater than or equal to 2 steps of improvement in the DRSS from baseline at week 24 in the study eye. As you can see from the graph on the left, there was no difference between the APX and placebo group when we evaluated the study eye for this endpoint at 24 weeks. The placebo rate that we observed is similar to prior DR trials at this time point. When we look at the fellow eye on the right that met -- the fellow eye that met eligibility criteria, there were numerically higher number of patients on APX3330 who improved compared to placebo at weeks 12 and 24, but this difference was not statistically significant. The next slide, I'd like to discuss the clinically meaningful endpoint that we plan to move forward with. As Mina discussed in her opening comments, we are happy to share that we successfully met one of the key prespecified endpoint for this study. There has been an opportunity for retinal drugs to be approved based on either the improvement or a prevention of worsening of retinal disease. It was a precedent with intravitreal-injected anti-VEGF drugs that treat only 1 eye to use a monocular 2-step or greater improvement in DRSS as the approval endpoint for the treatment of diabetic retinopathy, both Eylea and Lucentis were approved using this endpoint. In contrast, APX3330 is an oral treatment for diabetic retinopathy. And as such, it treats and benefits both eyes, thus the more relevant measure of efficacy for a systemic drug should consider changes in both eyes. And so we considered a composite score, that is the total change in the study and fellow eye, of 3 steps or more binocular worsening or improvement to be a clinically meaningful outcome. We've had preliminary conversations with the FDA on this, and we'll seek formal confirmation of the use of these end points at our end-of-Phase-II meeting later this year. Dr. Wykoff, would you like to comment on your experience with endpoints and the slowing of progression of -- in DR patients?

Yes, Mitch, thanks for that. Great to be here virtually with everyone, and I really appreciate hearing this data so far and looking forward to the discussion that follow. Related to this specific topic, I think the points that you bring up are critically important, right? This is the sort of first recent proof-of-concept Phase II trial that we're seeing with a systemically delivered agent that is showing a possibly positive signal that could be of clinical benefit. And sort of thinking of the path forward for potential approval is really important at this stage as we digest this data. And it's fascinating historical data that we've used a study eye, a single-eye DRSS change as the approvable end point for, as you point out, aflibercept and ranibizumab. And those bolus anti-VEGF injections have proven to be exceptionally well suited to improve DRSS levels in the eye into which they're being injected. But it's a quite different treatment paradigm to think about now using a systemic agent. And in that context, it makes a lot of clinical sense to think about the eyes holistically, to think about them both, not just a single study eye, but really both eyes become the study eye if you're exposing the patient to an investigational product systemically. And so I think it makes sense to actually consider DRSS changes, again, more holistically here across the eyes, and that's the preliminary feedback that I think that you have received, which I think is quite insightful because certainly, you would want to see directional changes holistically across the patient and not just in 1 eye that would be a study eye. I think this is a valuable development, and the data here is fascinating to put in that context.

Thanks, Charlie. Now let's actually get to the results on this measure. In the ZETA-1 trial, we've set 3 steps or more worsening and improvement of binocular DRSS as a prespecified secondary outcomes. Here are the results for these key endpoints at week 12 and week 24. On the left, you can see that at week 12, 12% of placebo patients had disease progression by this definition, whereas none of the APX3330-treated patients met this criteria and level of progression. At this time point, 4% of placebo patients had binocular improvement compared to 7% of treated -- APX-treated subjects. The important outcome I want to highlight on this graph is in the right. At 24 weeks, you can see that 16% of placebo patients got worse compared to none of the APX3330 patients. This result was statistically significant at a p-value of 0.04. At week 24, 11% of APX3330 patients improved versus 7% on placebo. In the next slide, we focus our attention more on the proposed primary endpoint for Phase III, which is a binocular 3-step or more worsening of DRSS. At 24 weeks, you can see that 16% of placebo-treated patients got worse compared to 0 for APX3330-treated patients. In addition, you can see that the percentage of subjects whose DR severity worsened, increased from 12% to 12 -- at 12 weeks in the placebo group to 16% at 24 weeks, whereas none of the treated subjects worsened at both time points. We would predict that in a 1-year Phase III registration trial that placebo patients may continue to worsen so that approximately 25% of placebo patients might meet this criterion by this -- by 1 year, whereas we would expect to maintain a low level of progression in APX3330-treated patients. Prevention of worsening of DR would be a very meaningful clinical outcome. The next slide shows a waterfall plot of patients who worsened in each treatment group at 24 weeks. You can see we have -- each line represents the change in DRSS score for an individual patient. On the left, we have placebo patients. And you can see that 8 of these patients had a worsening of 3 steps or more on monocular DRSS, whereas none of the APX3330 patients worsened by 3 steps or more. On the next graph, we look at some historic data to illustrate or to try to elucidate the importance of the change in DRSS. In general, the worse the DRSS score at baseline, the higher the risk of vision-threatening complications. The graph on the left shows historical Lucentis data from the open-label extension study of Rise and Ride registration trials for DME. During this extension study, patients were dosed PRN with Lucentis based upon their fluid status and diabetic macular edema. And about half of the patients never received treatment over the course of the year of the extension trial, whereas -- and those are represented in the green bars, whereas other patients received PRN treatment in the gray bar. And what we're plotting here is the percent of patients with change in DRSS over that time period. And what you can see is that 18% of untreated patients had worsening of 2 steps on DRSS scale and 9% had a worsening of 3 steps. So a total of 28% of untreated patients in this trial showed progression similar to what we would predict at 1 year. On the right, this is data from the diabetic control and complication study trial that was performed in over 1,400 type 1 diabetics. And each of these lines represents a different baseline diabetic retinopathy severity going from mild to severe PDR -- NPDR, excuse me. And what we're showing is the cumulative percent of patients who progress to vision-threatening complications of proliferative disease or diabetic macular edema. And you can see that as baseline DRSS increases, the probability of having vision-threatening complication increases. And this is the basis upon which the DRSS became -- accepted as a surrogate end point. Charlie, would you like to make any further comments on the clinical significance of the DRSS scale and the historical trial finding?

Yes, Mitch, thanks. I think that there's a lot to unpack, and I think you did a nice job doing that. I think the key concept to me that's fundamental and actually, I think, really resonates with clinicians here is that historically, with, again, aflibercept and ranibizumab, right, that's what this jewel is kind of built on for the last 5-plus years, is all about DRSS improvements in the study eye. And that's quite relevant because it's been a reliable, approvable endpoint to allow commercial access. But really, if you think about it clinically, what's the value of treating patients early when they have NPDR. And I think many clinicians, myself included, would argue that the value of treatment at that stage, whether it's an anti-VEGF bolus injection in the eye or whether it's a systemic therapy, is actually not to improve the dot-blot hemorrhages. We've heard that repeatedly in the field that patients, they can have great vision. You saw the good baseline visual acuity here, and they don't personally care if they have dot-blot hemorrhages. Doctors don't really care what the DRSS level is when it's NPDR. You don't necessarily need clinically to make the DRSS stage better is what we see. But what is really clinically meaningful, and the reason why I'm such a proponent of earlier intervention with our current therapies and future therapies, is what this slide is trying to show, which is to slow the progression of the disease, to decrease the worsening. That is a very clinically meaningful endpoint: To slow the progression of the disease, to decrease the proportion of patients that transition from NPDR into PDR, for example. And that's what you would be doing if you prevented 3-step changes on a holistic patient level, including both eyes. And then to get into the data on the left side here from the open-label extension following Ride and Rise, it's interesting, we saw the very similar data in the Endurance long-term extension study following the VISTA Phase III trial of aflibercept in DME also. And the point here was that when you transitioned from regular fixed anti-VEGF bolus injections in the study eye to a less frequent dosing regimen, whether it was the open-label extension here with Lucentis or Endurance with Eylea, we saw the same pattern, which was between 20% and 40% of patients, depending on how you looked at it, experience diabetic retinopathy severity worsening of a meaningful degree. And so what that taught us was that you really do need to have consistent bolus anti-VEGF injections to maintain those DRSS improvements that have been achieved with consistent dosing historically for many patients. And so in this context to be able to have a systemic agent that stabilize disease and decrease the probability of progression, I think, would be quite meaningful.

Thanks, Charlie. Now let's move on to the safety findings in this study. APX3330 demonstrated an excellent safety and tolerability profile at 600 milligrams a day BID for 24 weeks in diabetic subjects, which is consistent with 11 prior trials of APX3330 in non-ophthalmic indications. First, serum levels or PK of APX3330 that we measured in this trial were as expected. We are still exploring other biomarkers such as inflammatory cytokines. Second, there was no loss of visual acuity in APX3330-treated subjects, whereas approximately 15% of placebo patients lost 5 letters or more of visual acuity over the 24 weeks of the trial, again, suggesting that the drug is preventing progression of diabetic retinopathy. Third, we observed limited adverse events with no treatment-related serious adverse events. The only AEs that had a meaningful increase in frequency compared to placebo were rash in 6% of treated patients and itching or pruritus in 12% of patient. These AEs are mostly mild and mostly resolved while treatment was maintained. Finally, we saw no effect on liver enzymes or other organs and no changes in clinical labs. The next slide summarizes the -- in a little more depth, the treatment emergent adverse events. In this study, we had a total of 211 adverse events in 64 subjects. Adverse events were more frequent in the placebo group. Of all these 211 adverse events, only 31 were considered to be drug related with a similar frequency of related adverse events in the 2 treatment groups. Only 2 subjects in each treatment group withdrew to an adverse event. And as you can see, there were 14 serious adverse events in 11 subjects, more in the placebo subjects than in the APX-treated subjects, and none of these were considered related to treatment drug. Charlie, any comments on the safety profile?

Yes. I think safety in a disease state such as this with patients with a lot of comorbidities, a lot of other medical challenges, a lot of systemic medications is of paramount importance. And I think it's really encouraging to see such a clean safety profile. I mean they have more treatment-emergent adverse events in placebo patients than the active treated patients, I think, says a lot. So very encouraged by this. We've seen other oral agents and other excavated retinal diseases, not diabetic retinopathy, but other retinal diseases that had a signal systemically but then were not able to move forward because of potential for safety side effects. And so very positive to see such a clean safety profile for this systemic medication.

Thanks, Charlie. So in summary, the safety was as good or better than that seen in placebo. And the benefit risk ratio is very promising for this oral agent. I'd now like to turn it back to Mina.

Great. Thank you, Mitch and Charlie. Let's move to some overall thoughts and summaries. Here on Slide 25, I just wanted to sort of summarize the current snapshot of our product profile for APX3330. If you look to the right, basically, Mitch has just summarized kind of these key points of this very favorable safety profile. And really, what I wanted to share is that we've had 600 mgs now for 6 -- almost 6 months, 24 weeks, in diabetic subjects, and we've been in over 300 other subjects. And we've also had some cancer patients out a year at 600 mg. So we probably have the most extensive human clinical database on safety in retina with this oral program. Number two is everything you don't see here, please pay attention to what's missing, because those are many times side effects with other systemic drugs, other intravitreal drugs, other gene therapy, cell therapy drugs. We don't have other toxicities of interest. And so I'd point you to what's missing on retrospect later. And then just looking at the left in terms of kind of what have we learned out across the 12 trials. I think we're -- through the preclinical and the clinical work that we're excited about the reducing inflammation and reducing abnormal angiogenesis and really the opportunity to treat daily versus episodically, which is what you do with an intravitreal injection. Two, that I think patient compliance can't be underscored. The reason why patients are not getting their optimal treatment, even with good potent anti-VEGF injections but other diseases outside of diabetic retinopathy in the retina, is because of compliance. It's really hard to come in for every other month, every 2 months dosing for life. And I think having a convenient oral dosing, especially of diabetics that are already taking multiple tablets each day. And by the way, in our study, we had very few withdrawals and very high compliance. So I think that bodes well to the tolerability and compliance with an oral program such as APX3330. And last but not least, again, you've heard this now a few times, but we're really excited on our ability to demonstrate slowing the progression of the disease so that you don't lose vision, and we have a real meaningful impact on the patient at these earlier stages that are essentially wait and monitor in practice today. And so with that, let's go to the next slide. And so I just want to reiterate all -- the millions of subjects out there that are both mild nonproliferative diabetic retinopathy, moderate to severe nonproliferative diabetic retinopathy as well as some of the mild PDR subjects, we have an opportunity to go after and have a treatment option for many of these 8 million subjects, really creating a very, very large multibillion revenue opportunity. And that is just the beginning. We believe that proof of concept and approval in diabetic retinopathy really will open up the door to people seeing the benefits because of its anti-inflammatory, its convenient oral method as well as maybe working a bit upstream of other VEGF pathways. So all we want to really highlight is we're focused on diabetic retinopathy. But the expansion potential in practice is quite real. And we look forward to doing the work in diabetic retinopathy with APX3330 oral. But in addition, there are opportunities as well as we expand the platform with potential local delivery of either the lead compound or pipeline compound. And of course, we're still exploring some of the signals in our DME eyes and how it did alongside anti-VEGF treatment. We look forward to sharing some of those results in the future. And so I'll move on to Slide 27 and sort of showcase the landscape of oral or systemic therapies for diabetic retinopathy. And what I want you to notice here is that there were 8 players over the last, I guess, decade to 2 decades. There are actually only 4 currently. The 4 that are no longer were either due to safety or maybe other reasons not known. But ultimately, there are 4 active systemic programs today, all oral. We are the most advanced program completing this very large well-controlled Phase II program. And I want to reiterate that the concept of oral reaching the retina is not where the risk is per se. There are nutraceuticals and other products that showcase the ability of an oral to provide benefit through the delivery of an oral and to the retina. But it's really always been about the safety profile, and that has been what's limiting any program to go from Phase II to Phase III. And as you've heard, we have that in hand. The other thing I want you to note is just the primary endpoints on the column to the right. All of the participants, ourselves included, have always used the precedented DRSS 2-step in a single eye week 24 as our primary endpoint. I think the field will be evolving as we continue to see that actually you need to look at both eyes. And it really obviously makes more sense as an oral is very different than a single injection. And again, we are pioneering the first to move from Phase II into an end-of-Phase-II meeting and into Phase III. So what you're seeing there is a little bit of that pioneering. And with that, maybe I'll open it up to Dr. Wykoff just to see if he wants to make any further comments about the landscape with oral programs and/or the regulatory endpoints. Charlie?

Yes. Thanks, Mina. Absolutely. I think you summarized that well. It's been a busy space over the last 10-plus years. And unfortunately, there have been a lot of agents that haven't proven to be valuable. But I think that the reason it's a busy space is exactly the point they made before, which is there are a lot of patients with this disease state, and it's sort of an obvious clinical intervention. If you can prevent these eyes with nonproliferative disease from developing proliferative disease and/or prevent them from developing DME, the 2 manifestations that ultimately cause vision loss and more blindness in our country in the working age population than anything else, I think it makes a lot of sense. And what's fascinating about this field is that we've already talked about, we have these bolus anti-VEGF agents that are quite effective at slowing progression and reversing diabetic retinopathy severity scales, and yet they're still not used as broadly as one may have anticipated before approval. And really the reason for that is, as we've discussed, it's the challenges. It's the challenges of chronic delivery of an intravitreal injection from -- particularly from a patient perspective when many patients are well sighted to begin with. And so the possibility of a systemic agent that is safe, I think, rings very genuine among clinicians that we are looking for something like this. There have been a lot of failures. And then particularly about this Ref-1 inhibitor, I think it's fascinating data. Of course, it's not ideal that the primary endpoint here was not met. But we must keep in mind that this was not designed to be a registration for the commercial access trial. This was meant to be a proof-of-concept study, and we've learned a lot. We've learned a lot about this agent. We've learned a lot about how to potentially structure a trial to get FDA approval for this agent, and it's a positive signal that makes clinical sense that we're seeing to slow the progression. I guess the last point I would bring in is just the mechanism of action. It's a fascinating upstream mechanism of action that we haven't really seen in diabetic retinopathy or any AMD disease or any retinal disease recently. And I think we need to continue to try to understand what we might be most likely to see with such an upstream target. And maybe it makes most sense mechanistically that we would expect to see slowing of progression rather than a dramatic reversal of the dot-blot hemorrhages that may already be present, sort of quite a different mechanism of action than a bolus anti-VEGF injection. So keeping that in mind, I think this data set seems to fit with what this mechanism action might be.

Thank you so much, Dr. Wykoff. As I move to wrap up here on Slide 28. I think most of these points have actually been made again. What we really want to emphasize is there is a difference in end point between an intravitreal product and a systemic product. And therefore, thinking about preventing progression really is a great place for an oral or systemic treatment. And that, again, these patients are essentially weighed and monitored and also asymptomatic and therefore, an oral convenient option makes a lot of sense. And I think maybe the only other point I'd make here is that we look forward again to taking these data to the FDA shortly. So with that, let me go to Slide 29. And just to summarize, you've heard and seen, we are the most advanced oral program. So as we pioneer, we learn and focus; two, that you've seen a very favorable safety profile, along with statistically significant data on a potential approvable endpoint of binocular 3-step worsening of the DRS score. And really, ultimately, we think there's a huge clinical benefit to slowing the progression of the disease and hopefully avoiding vision loss. The other -- the next steps, just for those interested in kind of where we see the program going. We look forward to continue to analyze the data. It's just a few days. So we look forward to really digging into the data subgroups and eyes, in both eyes as we also look for the insights into our Phase III trial design. All of that in preparation for our planned end-of-Phase-II meeting for the DR indication for oral APX. We actually already have some upcoming data presentations both at Angiogenesis and at Macular Society in the coming weeks. So we look forward to this data and other data being presented. And given the solid foundation of funding through our mITT-LOCF partnership from a few months back, we actually are very excited to continue to advance APX3330, do the GMP manufacturing work, some additional NDA-enabling work and most importantly, design and initiate the first Phase III trial and, of course, all along, continue to look at opportunities, both inside and outside the U.S. from a partnering perspective. What is our end goal? To have a clinically meaningful impact on preventing progression to reduce the likelihood of vision loss in diabetic patients. And that is what this endpoint that we're looking at is suggesting and showing. And with that, for those of you who just might not know the Ocuphire story, I was just going to end with a corporate summary. We have 4 catalysts sort of lined up for this year. The first was this top line results, which we had promised for early 2023, and we're excited to have been able to provide this data here in January. The next will be an end-of-Phase-II meeting where we get the confirmation of our path forward on the APX program. And then we are launching all 3 trials with respect to our Nyxol. This is the drug that reduces the pupil and has multiple indications, including presbyopia and night vision. And of course, we have filed our NDA submission for Nyxol and reversal of mydriasis, and we, again, look forward to confirmation of our PDUFA date, and then, of course, the potential approval later this year. So the point just being is that we, at Ocuphire, remain committed to both of our assets, and we are excited to continue to advance those to help aging and the everyday vision in hundreds to tens of hundreds of millions of people, while also serving the diabetic and the retinal community and focused on vision loss with APX3330. And with that, I'd like to thank you for the attention and open it up to questions.

[Operator Instructions] And our first question comes from the line of Kristen Kluska with Cantor Fitzgerald.

So first, I wanted to ask which endpoints do you believe are most important from the physician perspective, especially as now it seems that they tend to view their prescribing decisions based off of real-world experience versus trials? And should you move forward with the greater-than-3-step binocular endpoint, what do you view as the efficacy bar from standard of care that would compel them to use this therapy?

Thank you, Kristen. I don't know, Charlie, if you'd like to take that question. Thank you.

Sure. Yes, happy to jump in there. Great question. It sort of frames this situation quite well, right? In the field, we've been talking about DRSS improvements for a long time because that's what we saw with bolus anti-VEGF injection sort of most dramatically and most clearly in the panorama data set, which was the Phase III trial for aflibercept that ultimately led to approval of aflibercept for all stages of diabetic retinopathy. And the approval endpoint there was 2 steps of DRSS improvement, and they hit that very easily with these bolus injections. What's interesting is that clinicians don't really think in terms of the DRSS, right? We think in terms of NPDR, PDR, and then certainly different severity levels within those 2 major phenotypes. But when we treat patients in the clinic, we don't really think of, okay, I've achieved a 2-step improvement in this patient, therefore, the patient has a good outcome. Really what we think about, if and when we manage patients with NPDR with bolus injections is, can we stop the disease? Can we slow the disease down? Can we prevent progression? So that's really how physicians are using anti-VEGF injections for diabetic retinopathy today. And what's fascinating about this program is, it sort of brings the perspective of, let's move away from just treating a single eye to treating the patient. Let's treat them more holistically and think about treating both eyes. And in that context, I think the clinical meaningful end point would be, can you prevent development of PDR? Can you slow the development of DME? And both of those are wrapped into this concept of, can you decrease the rate of DRSS worsening? And so I think it's very consistent, this concept of moving towards a prevention of worsening as a potentially approval endpoint to what clinicians are going to think about.

Thank you, Dr. Wykoff. I don't know if anyone else wanted to add anything, Dr. Pepose or Dr. Brigell?

This is Mitch Brigell. I mean I'd just like to comment on if we showed that we could get the 3 steps -- prevent 3-step worsening in 25% compared to a very low percent in treated patients, would that be enough for you to want to use it in all your patients?

Yes, it's a good question. And to talk sort of the specifics of what percentage would be meaningful is tough. I do a couple of numbers out there just of interest, and then I'll give you the best shot I've got, if it's a direct answer. But it's interesting. If you look at Panorama, right, we published that data in GEM ophthalmology, right? What happens to the anti-VEGF treated patients? Well, their rate of progression is not 0, right? The rate of progression there is -- I'm going to round here, but about 10% over a year or 2, and more at 2 years and 1 year of the anti-VEGF-treated patients will progress to PDR or center-involved DME. So with bolus injections a very strong treatment directly into the eye, regularly, you're still seeing some progression. And so I don't think it's -- I think it's unlikely for us to find a drug that has a 0 rate of progression with the drug and then some higher rate of progression in sham. I'm expecting that most programs in the space are going to have some breakthrough. And then one of the points I'd make about that, even in the monthly dosed Ride and Rise program with Lucentis, about 20% of eyes treated with monthly Lucentis develop PDR, despite monthly injections. So we're probably going to see some breakthrough. So in that context, if you had 20% or 25% of patients at 1 year in the control arm progressing and low single digits or maybe even amazingly 0 in the treated arm, I think that would be highly clinically meaningful. And I think even differences that aren't that great could also still be clinically meaningful. But exactly where that threshold is, I don't know.

Thanks, Charlie.

Yes. Thanks. And I was just going to add, I think, again, in terms of, Kristen, to your question, the standard of care is not anti-VEGF injections for NPDR patients. Today, it's when they progress to DME after they've been watched and monitored every 6 months or a year in their visits to the doctor. So really, this is an untreated patient population. So from our perspective, we're thinking through the statistics of different spreads, whether it's 10%, 15% or 20%. And I think that actually gets you a very reasonable sample size, a little bit more than the end of 100 we did here, but it's still not -- it's not a very large number if we're looking at that signal, and that's a step we're seeing binocular endpoint.

It's Jay Pepose. I would point out, for example, in a practice like mine, for example, where we have 2 retina doctors, we have 3 anterior segment surgeons, we have 2 optometrists. These patients with preproliferative diabetic retinopathy are seen by every practitioner. They're sprinkled in with every practitioner. The only time that we internally refer to retina is if they develop proliferative diabetic retinopathy or center-involved DME. And so if there was a drug that had a great safety profile and prevent -- and could be shown to prevent progression or slow down progression, a drug like that would be of interest to, not just the 3,000 retina doctors in the U.S., but ophthalmology, optometry, endocrinology, internal medicine. I mean, I think it will be of very wide interest.