Hey, and welcome to the Rezolute Conference Call to review top-line results from the RZ402-201 phase II study in patients with diabetic macular edema. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by 0. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on your telephone keypad. To withdraw your question, please press star, then two. Please note, this event is being recorded. I would now like to turn the conference over to Christen Baglaneas, Senior Director of Corporate Operations at Rezolute. Please go ahead. Thank you, operator. Good afternoon. Before we begin, as a reminder, the information discussed during this call will include forward-looking statements, which represent the company's view as of May 21st, 2024. We undertake no obligation to update or revise any forward-looking statements to reflect new information or future events, except as required by law. Please refer to our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements. With me here today at Rezolute's corporate headquarters in Redwood City, California, is our founder and CEO, Nevan, as well as Dr. Brian Roberts, Chief Medical Officer of Rezolute. In addition, also here with us is Dr. Bob Bhisitkul, Professor of Clinical Ophthalmology and Retinal Specialist at the University of California, San Francisco, and a member of our scientific advisory board. Dr. Bhisitkul has worked in the field for many years, including as an investigator for anti-VEGF therapies for DME, as well as in more than a dozen clinical trials for novel therapies in the retinal space. Nevan will offer some brief comments regarding our study results, and then Dr. Roberts will outline the design of our phase II study and review the results. Dr. Bhisitkul will provide his perspective on the significance of the results and the potential that RZ402 may have in the treatment paradigm, should the therapy continue to demonstrate safety and efficacy in late-stage clinical studies and eventually be approved by regulatory authorities. Following the presentation, the speakers will be available for questions. And now, I would like to turn the call over to Nevan. Thanks, Christen, and good afternoon, everyone. Thank you for taking the time to learn more about the results from our phase II study of RZ402, an oral plasma kallikrein inhibitor, or PKI, that is a potential therapy to treat DME. I am very pleased to announce that our phase II study of RZ402 met its primary endpoint. It was generally safe and well-tolerated, while demonstrating a reduction in swelling at the macula of up to approximately 50-60 microns, and approximately 75 microns in patients with more significant edema at baseline. The magnitude of these reductions is significant in a three-month study. To the best of our knowledge, RZ402 is the first oral agent to demonstrate efficacy in a clinical study in a DME patient population. Now, meeting the primary endpoint in any clinical study, particularly one that is placebo-controlled and double-masked, is always an accomplishment. However, this study and the results that we will discuss with you today are particularly noteworthy, not just because it is the first oral agent to show efficacy in DME, but also because the foundation of this program is based upon what could be considered to be somewhat radical scientific rationale. Namely, that diabetes is a systemic disease caused by excess glucose and the resulting corruption of the microvasculature throughout the body, including at the back of the eye. When we treat other complications associated with diabetes, we do so through systemic medical management. It would follow that maybe DME should be treated the same way. In other words, rather than trying to administer a therapeutic into the eye, as is typically done, perhaps an alternative approach is warranted. Systemic delivery with a DME tablet. It was on the basis of that thesis that RZ402 was developed. Our preclinical studies validated this thesis, and our phase I studies demonstrated that RZ402 was generally safe and likely to provide adequate coverage with a single tablet at predicted doses and concentrations. But until today, it was unknown whether the therapy would actually be generally safe, well-tolerated, and effective in reducing fluid on the macula in patients. The potential implications of an oral therapy to treat DME are very significant, particularly given the notable limitations of the current standard of care and the massive unmet need that exists for thousands of patients in the U.S. and throughout the world. And as you listen to the report of the results from the study today, please keep in the back of your mind the potential target product profile for RZ402. It is not a therapy to be necessarily evaluated against current standard of care. Rather, an oral therapy is a complete potential paradigm shift, introducing the possibility of treating patients much earlier in the disease cascade and preventing vision loss. Now, I'd like to hand the call over to my colleague, Brian. Thank you, Nevan. Good afternoon, everyone. I'm looking forward to taking you through the design and top-line results from our phase II study. But before that, it's worth spending a moment to briefly review the rationale for targeting plasma kallikrein with an oral systemic plasma kallikrein inhibitor as a treatment for DME.... DME is a vascular complication of diabetes. Chronic high glucose levels can impact a number of major organs, including the brain, kidneys, nervous system, cardiovascular system, and as we've been discussing, in particular, the eyes. Tissues with a sensitive microvasculature, such as the retina and kidneys, may be particularly impacted by prolonged glucose exposure, causing endothelial cell dysfunction, inflammation, and fluid hyperfiltration. The loss of integrity of the blood-r etina barrier results in vascular leakage into the back of the eye and the accumulation of fluid in the macula, the part of the retina responsible for high-resolution central vision, which can lead to progressive visual loss and blindness. The Kallikrein-Kinin System is an early upstream mediator of DME and is therefore an attractive therapeutic target. The KKS, also called the contact activation system, is part of the first line of defense against vascular injury, as it closely coordinates processes involved in vascular permeability, inflammatory responses, and coagulation. However, when elevated blood sugars associated with diabetes damage the endothelium of the retinal microvasculature, the KKS system is overactivated, leading to excessive bradykinin production and counterproductive amounts of inflammation and vascular leakage. There is strong evidence suggesting that there are VEGF-independent signaling pathways involved in the progression of DME. Numerous preclinical studies have demonstrated the role of the KKS in VEGF-mediated, as well as VEGF-independent pathways of DME, including kallikrein injection studies, kallikrein knockout studies, and our own studies of RZ402 in animal models of DME. Additionally, and possibly corresponding with often quoted response rates to anti-VEGF therapies, studies have shown that as many as 50% of DME patients have limited to no expression of VEGF in the vitreous when sampled intravitreally, whereas markers of the KKS are nearly universally elevated. RZ402 is a potent and selective small molecule plasma kallikrein inhibitor, which has been extensively characterized in animal pharmacology models of DME, and to our knowledge, is the most advanced and differentiated oral systemic plasma kallikrein inhibitor in development for this indication. Systemic administration of RZ402 consistently inhibits retinal vascular permeability and leakage by up to 90% in animal DME models compared to animal control animal groups. Importantly, RZ402 response correlates with plasma exposure and is not dependent on ocular exposure, which was minimal in tissue distribution studies of RZ402. This highlights the importance of targeting plasma kallikrein inhibition systemically to achieve adequate drug concentrations at the vascular site of action. The effective concentrations from these studies served as our benchmark for target concentrations and dose selection in present phase II study. There is currently a large unmet need to utilize treatment earlier in the disease course, creating an opportunity for an oral kallikrein inhibitor to be employed as a first-line monotherapy. This is the target product profile to which we aligned the clinical study design and strategy. And so with that intro, now let's get into a discussion of the completed study. Our phase II study of RZ402 was a randomized, double-masked, placebo-controlled parallel arm study to evaluate safety, pharmacokinetics, and proof of concept efficacy of RZ402 in patients with DME. It was conducted at approximately 25 sites entirely within the U.S. Our oral route of administration afforded the opportunity to conduct the study in a unique target population and in monotherapy against DME. As an oral therapy, we focused on patients who were treatment naive or those in early stages of disease intervention, which contrasts with what many companies are forced to do when offering a new alternative intravitreal injection as a second-line therapy to failed anti-VEGF treatment. The study is a proof of concept study and is not add-on to anti-VEGF therapy or head-to-head against anti-VEGF. The slide shown provides a schematic of the study design. Patients meeting eligibility criteria were randomized in a 1:1 fashion into one of four parallel arms in the study. The three active RZ402 arms were dose levels of 50, 200, or 400 milligrams, while the fourth arm received matched placebo. All three dose levels were expected to inhibit plasma kallikrein and to reach or exceed target concentrations throughout the 24-hour dosing interval, as per the studies in animal models of DME. Patients were treated with study drug for 3 months and came to the clinic for evaluation at regular intervals for ocular and systemic evaluations, including OCT, or optical coherence tomography scan, BCVA, fundus photography, and safety examinations. After the 3-month treatment period, they completed a 4-week safety follow-up, culminating in an end-of-study visit. With up to 25 participants in each arm of the study, we anticipated enrollment of between 80-100 participants overall and ended up enrolling 94 participants, or between 23-24 per treatment arm. As a phase II study, the sample size was chosen to be adequate to demonstrate proof of concept, and as you've gleaned already, was indeed able to demonstrate both clinically and statistically significant improvements, improvements in macular edema by CST.... With this being the first study of RZ402 in patients with DME, a principal objective was to assess the safety of an oral medication with systemic exposure. Safety was evaluated broadly by assessment of adverse and serious adverse events, ocular safety assessments, and systemic assessments, including electrocardiograms, vital signs, as well as physical examinations. It's worth noting that as a result of RZ402 being an oral agent and not an intravitreal injection, we were not as concerned with ocular safety assessments or complications as compared to patients who received intravitreal injections. Since issues such as infection, bleeding, or retinal detachment are less likely to be observed in this study compared to an intravitreal injection study. Serial measurements of RZ402 blood levels were obtained to evaluate the repeat dose pharmacokinetic profile and modeled concentrations. As far as efficacy endpoints, since this was a three-month study in either treatment-naive or early-stage patients, and this is a timeframe in which applicable anatomic changes in CST could be observed, our main objective and the primary endpoint of the study was to assess macular edema, as measured by the change in CST on an OCT scan compared to placebo. We specifically wanted to see central macular fluid decreases in the study eye of no less than 35 microns, and ideally about 50 microns relative to placebo. Our secondary endpoints included several visual acuity outcomes, and as we stated prior to the commencement of the study, we didn't necessarily expect to see improvements in vision over a short study duration of 3 months, but lack of progression was also an outcome of interest. Likewise, a change in diabetic retinopathy severity score, or DRSS, although not necessarily expected in a 3-month study, was assessed by fundus photography as an exploratory endpoint. Although we qualified and pre-specified a study eye for the primary analysis, considering the oral systemic nature of the medication, we do plan to analyze the effects of RZ402 on the non-study or the fellow eye to the extent it is evaluable and once we're able to dig into the complete data picture. I say to the extent evaluable, because the fellow eye was not required to meet eligibility criteria, and furthermore, the investigators in the study were at liberty to treat the diseased fellow eyes with anti-VEGF injections during the study. For our study, as far as eligibility criteria, we included diabetes patients with stable glycemic control and mild to moderate non-proliferative diabetic retinopathy, or NPDR, with center-involved DME in the study eye. As I mentioned earlier, we targeted patients at a somewhat earlier disease stage and avoided patients with chronic or refractory disease. To achieve this, we sought patients with limited to no history of prior anti-VEGF exposure. Specifically, they had to have 3 or fewer anti-VEGF injections and none within 8 weeks of randomization. As I'll share with you later, a surprising number of enrolled patients were treatment-naive. Given that CST by OCT was the primary efficacy endpoint in the study, male participants had to have a CST of at least 320 microns, and female participants at least 305 microns. All CST values throughout the study, including those used to evaluate the eligibility criteria, were assessed in masked fashion by an independent central reading center. Eligible patients were also required to have at least mild visual compromise, with less than or equal to 78 letters on ETDRS score, which, for context, is equivalent to 20/25 vision by Snellen. Moving into the disposition of the study, we enrolled 94 participants overall, 84 of whom completed. Twelve participants had an eligible fellow eye for the study, which provided us with a total of 106 evaluable eyes, 94 study eyes and 12 fellow eyes. Patients with early-stage DME are known to progress slowly and hence a placebo-controlled monotherapy study and a conservative approach to rescue was justified. Therefore, we carefully pre-specified and standardized the criteria for any intervention to avoid the indiscriminate use of rescue therapy, and our investigators did follow this diligently during the study. As you can see in the table presented here, the use of rescue with anti-VEGF was uncommon overall and accounted for five of the 10 participants who discontinued the study early. The other five who discontinued early withdrew consent for reasons unrelated to efficacy or safety. Key participant demographics and baseline characteristics are reflected on the next slide and in the table shown here. As you can see, the treatment groups were generally well-matched across age, gender, and diabetes history. Remarkably, although the target population had significant macular edema and some vision loss, as evidenced by the average baseline CST and BCVA in the study eye, effectively, the majority of participants, about 75% overall, were naive to anti-VEGF treatment. In short, we exceeded our own expectations in enrolling a relatively untreated target population in the study. Moving to the results. Safety is an important component of any treatment, and particularly a systemic therapy for a chronic and common condition. As shown in the present slide, RZ402 was safe and very well tolerated among the patients in the study.... Adverse events were generally mild and did not occur at a greater rate in RZ402-treated participants compared to the placebo group, and there was no dose response. Therefore, no adverse events were attributed to RZ402 overall. The four serious adverse events experienced by three participants in the study were all attributed to existing medical history and judged by the investigators to be unrelated to RZ402. Notably, RZ402 has a distinct chemical space from PKIs approved or being developed for hereditary angioedema, and we did not observe hepatic enzyme abnormalities or GI intolerance, which has sometimes been attributed to other compounds in the PKI class. Furthermore, unlike ocular routes of administration, ocular adverse events were largely non-existent or due to preexisting conditions. The full analysis of concentrations and derived pharmacokinetic parameters from the study are not yet complete, but results from preliminary bioanalysis of samples for RZ402 show that target concentrations were exceeded at all three dose levels and continue to support once-daily dosing. Across the dose range from 50 mg to 400 mg, there was a dose-dependent increase in concentrations, but the increase was not proportional to dose. Given these preliminary observations, and assuming an equivalent potency translation between our animal models and humans, it's likely that exposure was adequate to achieve sufficient kallikrein inhibition at all three dose levels. This may, in part, explain the absence of a dose response above the 200 mg dose. Now let's move to the efficacy endpoints. We were very pleased to see a clinically and statistically significant improvement in CST at all three dose levels. Consistent with observations from the PK analysis, there were no significant dose responses or differences between the RZ402 treatment groups. At the 200 milligram dose, there may not be additional benefit beyond that. At that dose of 200 milligrams, the primary endpoint was met with approximately a 50-micron improvement after 12 weeks of treatment, which was sustained during the 4-week follow-up period. It was also encouraging to see that the pattern of CST improvement was physiologic and gradual, beginning at about week 4 and continuing its downward trajectory through the end of treatment and even into the follow-up period. In addition to the overall reductions, these observed trends are strongly suggestive of a drug effect and indicate the possibility of even larger improvements with longer-term dosing. We have also looked at the individual participant response data, which reinforces the observed mean responses across the groups, particularly at the 200 milligram dose of RZ402 in comparison to placebo. Most participants who received the 200 milligram dose experienced CST declines, including clinically significant increases, decreases from baseline in more than 20% of participants, compared to no participants in the placebo group, who experienced high rates of worsening. You can also clearly see the significant improvements in macular edema and fluid cysts on these OCT images from one representative patient who received 200 milligrams of RZ402. This brings me to the conclusion of the presentation of the top-line phase II study results of RZ402 in DME. In summary, orally administered RZ402 was safe and well-tolerated and met the primary endpoint of achieving a clinically significant improvement in CST. As far as we know, RZ402 is the first plasma kallikrein inhibitor or oral therapy of any class, other than systemic steroids, to induce a reduction in macular edema in patients with DME. Based on preliminary sub-analysis showing even greater improvements in patients with higher baseline CSTs and in reduction in excess fluid, as well as the declining trajectory of CST values over the course of study, longer duration studies could reasonably be expected to demonstrate even greater improvements in macular edema. Visual acuity changes frequently lag behind changes in macular edema as measured by CST, and vision improvements were not expected or observed over this three-month study. However, visual acuity did remain stable in the present study, and the observed clinically and statistically significant improvements in CST would certainly predict visual improvements in a longer duration study. Furthermore, in a study of appropriate size, duration, and design to more robustly assess bilateral or binocular responses, dual benefit to both eyes might reasonably be expected, given the oral systemic nature of the therapy. The results from this study certainly warrant advancement of RZ402 into late-stage clinical studies, where proof of concept can be definitively evaluated for a lead indication and first filing, and the full potential of RZ402 as a treatment for both eyes under a variety of use scenarios can be fully evaluated in a broad phase III program. With that, I'd like to turn the presentation over to Dr. Bhisitkul to provide commentary on the study results and share his view of the potential implications of RZ402 as an oral therapy for DME. Thanks, Brian. Let me just say at the outset that I and my retina colleagues who have had a chance to see this data are impressed with the results that Brian just summarized from the phase II study for RZ402. Let me give some context for this. For the past 15-20 years, we, retina specialists, have had invasive therapies to treat diabetic macular edema, from laser therapy to intravitreal injections. And in the past, you know, 15-20 years, as you know, our standard therapeutic option has come about with the introduction of anti-VEGF drugs that we inject into the eye. I was an early investigator for the clinical trials for some of these therapies and can say that we achieved good clinical outcomes within those clinical trials, and these are a powerful tool now to treat diabetic macular edema. In my own practice, I probably treat about a third of my patient population on any given day with these anti-VEGF injections. Nonetheless, we have to be frank about the state of standard of care for patients with DME, and we have to acknowledge the current limitations that we have with anti-VEGF therapies, and see that we still have a ways to go to maximize the treatment for this leading cause of blindness in the U.S. and globally. Anti-VEGF therapies have a challenging route of administration. It's an injection into the eye with all that that entails: the discomfort, the risks, the treatment burden, and this compliance with these ongoing injections every month or every 2 months, often for many, many years. The compliance is a significant problem, given the route of the administration. Patients and their physicians are hesitant to start the treatment in some cases, and even after chronic treatment has been underway, patients often stagger the frequency of their injections rather than maintaining the standard of monthly or every other monthly injections. And of course, poor compliance with the treatment regimen leads to poor clinical outcomes. And that's one of the reasons that we see that in the real world, our vision results over time really don't match up to the good results that we see in a formal clinical trial. Receiving an anti-VEGF injection is an involved process with a treatment burden, as I mentioned. The trip to the doctor, taking half a day off or more from work, having a family member or a friend accompany the patient to the appointment. All of these are a burden to the patients that can be very disruptive, and it's, but there's not necessarily a good alternative for these patients. On top of this, please keep in mind that anti-VEGF therapies are effective in about 50%-70% of our patients, so we all recognize patients that never respond or never fully respond to anti-VEGF therapies. In short, while the anti-VEGF drugs have led to improved outcomes for patients, there's still a major unmet need, and it would be ideal if there was another therapeutic option with another mechanism of action. Particularly, one that would allow us to treat patients at an earlier stage of the disease. Our treatment plans are often measured in years for a newly diagnosed patient with the early stages of diabetic macular edema, and so often we watch and wait these patients, trying to defer undertaking the regimen of monthly intravitreal injections, and we hope in this meantime, we hope that things stabilize and that their diabetes can come under control. It's really the only viable option that we have as we are in that waiting and watching period. So an oral therapy would be ideal for these patients with diabetic macular edema. It could be used to treat the disease much earlier because it's much less invasive and could be administered by the patient themselves and initiated by physicians that are beyond just retina specialists. This could be done by general ophthalmologists, general practitioners, or endocrinologists. It could be part of the overall management of the patient's diabetes. Oral therapy would offer a convenience for these patients and would likely have better compliance for a patient to take a pill daily, rather than come in monthly or every other month for these injections, which gives us an opportunity to reach more patients before their disease progresses to the more serious stages that are vision-threatening. An oral therapy would also offer the potential to treat both of the eyes of a patient, since the therapy is delivered systemically, and It's widely the case that diabetic macular edema affects both eyes in a given individual. RZ402 has demonstrated significant potential in this clinical trial, and let me be specific about what I mean. When myself and others were advising Rezolute on the phase II study design, we made it clear that to us, as retina specialists, the most important thing, especially in a three-month study with an oral agent or any agent for that matter, is to, of course, demonstrate safety. But beyond that, the key endpoint for us is a reduction in the diabetic macular edema and the swelling in the macula, and this is measured as a reduction in the central subfield thickness, as measured on OCT. This is the key economic, this is the key anatomic marker that is predictive of whether a therapeutic agent is or will be effective. We wanted to see approximately a 50-micron reduction over this three-month study period, and this was achieved in the study. Importantly, across each of the three dose cohorts, there was an improvement in central subfield thickness, which is proof of target engagement. Like most of my colleagues in retina, in my clinic and in my daily practice, I really put the emphasis on the CST value, on the central subfield thickness and on the appearance of the OCT to determine how a patient is progressing. It's an objective measurement. It doesn't have the same variability, and it's highly reproducible, as opposed to some other outcomes that we use in the clinic, such as the patient's visual acuity, which tends to lag behind improvements in the OCT. Improvement in vision is, of course, important, but it's something that, as I said, follows on from the improvements in the macular edema, and it's not the primary endpoint when evaluating the potential of a new therapy in a three-month study such as this. We wouldn't necessarily expect to see improvement in vision over this time period, especially since we know that vision improvement lags behind the CST improvement on OCT. So this is really in keeping with what we saw in this study. The impressive central subfield thickness reduction is compelling enough to warrant advancing this compound into late-stage development. I see a lot of therapies in early development in my role as an advisor to companies, and unfortunately, most of those don't show the same level of promise that we've seen with RZ402 here. As a next step for RZ402, I'd really like to see a follow-on study of longer duration at one or more dose levels, and based upon what we've seen in the phase II study, I would expect those curves of OCT improvement to continue over time, up to 6 months and 12 months. If the pattern held up along with maintaining this good safety profile that we see in phase II, to me, it would be clear that RZ402 is a logical candidate as a first-line treatment for diabetic macular edema in clinical practice. There are two aspects to my thinking here. One, way before we would think about administering anti-VEGF therapies, we could put patients on an oral drug, RZ402, which is non-invasive, and then we could treat preventatively rather than reactively to benefit the patients before the disease advances and preserve the vision while it's still at a high level. And secondly, with RZ402, there would be a new tool that may be effective improving patients' outcomes in those patients who are incomplete responders or non-responders to standard anti-VEGF therapy. This is actually a significant percentage of patients in my practice, and once we find those patients, there really are very few good alternative treatments to anti-VEGF or intravitreal therapies. In summary, the results from the phase II study are compelling to me, and it's intriguing to consider that we may be on a path toward a commercially available oral therapy with potential to significantly improve outcomes and treat more patients all over the world, including the patients in my own practice. Thanks. Now I'll hand it back to Nevan. Thank you, Bob. Really appreciate you taking the time to share your perspective, perspective with us on the results from the 402 study. In the last few days, our excitement here at Rezolute has grown as we've digested these study results and what this could mean for the treatment landscape for millions of patients and their treating physicians. Developing RZ402 has been a bold endeavor and one worth pursuing. RZ402 has the potential to be a highly disruptive therapy in a landscape that is ripe for the next great leap forward. Our goal in developing this therapeutic has always been to achieve proof of concept with a novel approach to treat a disease that impacts so many lives. And now, as we consider next steps, we need to be thoughtful about how to responsibly advance the program into late-stage clinical development and hopefully commercialization. This program is much bigger than us, much bigger than what a small biotech company that is otherwise focused on rare diseases should advance on its own. On the heels of these study results, we will be thoughtful as we consider alternative paths for the program and explore ways to optimize value for shareholders. In drug development, sometimes the overall mission is lost in the myriad tedious details, unknowns, and frustrations inherent in scientific exploration and clinical development. Our mission is to positively and significantly impact the lives of patients and their families by developing novel therapies. RZ402 has demonstrated that potential to impact the lives of patients who are currently being managed on state-of-the-art care, as well as, and now this is important to us, many others who don't have the resources, access to, or otherwise generally afraid of a treatment paradigm defined by injections into the eye. Hopefully, 402 can make a difference. The prospect of a single daily tablet targeting the preservation of vision as the next new therapy to be introduced as part of the regimen to manage the complications associated with the unfortunate epidemic that we know of as diabetes. I'm proud of the team and want to thank them for their efforts in developing RZ402, in particular, our internal pharmaceutical sciences team, as well as the clinical team. I also want to thank our partners and folks like Bob, who you heard from today, who have been instrumental in guiding us. I would also like to thank the physicians who served as investigators in our Phase II study, as well as the study participants and their families for agreeing to participate, all with the hope that collectively, we can make a difference. Thank you all once again for taking the time today to learn about the RZ402 phase II clinical study results. We will now take any questions that you may have. We will now begin the question and answer session. To ask a question, you may press star, then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. Our first question today is from Maury Raycroft with Jefferies. Please go ahead. Hi, much congrats on these data, and thanks for taking my questions. Maybe to start off, I know it's still early days, but just wondering, was there anything unique about the 20% of patients in the 200 mg dose cohort that saw a response on CST and DRSS? And how does this inform the type of patients that can benefit from treatment with 402? And likewise, is there anything unique about the patients-- Oh, can you hear me or? Yeah, we can hear you. Oh, and then, and likewise, is there anything unique about the patients in the 400 mg cohort to help explain the greater variability in this group? Thanks, Maury. This is Brian. Obviously there's still a lot of data to get into and a lot we can read and learn as we continue to investigate. I would say, you know, to lump those two comments together in terms of response at 200 and maybe slight, somewhat lesser numerically at 400, there's three things to keep in mind. I think, one, as I said during the presentation, we probably had sufficient concentrations at all three dose levels, and RZ402 is potent in vivo, so it may well be that we're not getting much benefit beyond 200, and therefore, the differences that are seen are... And they were not significant, I'll point that out, are likely just due to, you know, group sizes of 20-25 patients and inherent differences between them. What we did observe, as we noted, is that, the CST improvements were more pronounced in patients who had more severe CST, using a cutoff of 400. And it turns out, and again, we will get into the data in more detail, the 200 milligram group had more of those patients, so that may be one explanation. There certainly may be others, and we look forward to diving, you know, more into the data to really learn about the responses and refine our understanding as we go forward. Got it. That's helpful. And maybe one other question, just, you mentioned digging into the data and doing analyses on the fellow eye as well. Can you talk a little bit more about what additional analyses you're gonna be focused on, and when we could see updates, an additional update from the program? Sure. So we had certainly hypothesized, and still do, that the fellow eye, in general, should have similar response to the study eye in a you know real world scenario. This wasn't a real world scenario in the sense that it was a study that defined a study eye and limited you know had strict entry criteria for the study eye and strict criteria for intervening with other therapies that could confound the results in the study eye. So that was the primary analysis, and that was successful. We hoped that, incidentally, the fellow eye would be evaluable. We ended up having, as I said, 12 participants whose fellow eye, incidentally, was both eligible and evaluable, meaning it was not treated with VEGF on study. When we group those patients in and create a sample size, you know, of 94 + 12, here in 6 participants, we see the P values, even just with the increased sample size, get a little bit better. So that definitely supports the notion that if you, you know, in a carefully controlled study, we're seeing a result. The problem is in most cases, the fellow eye was not eligible. It either had no edema, no DME, or it was on the other end of the spectrum, you know, severe chronic and overly treated with VEGF. If it was in a zone that we would have liked, you know, we, again, we didn't limit anti-VEGF use during the study, and so the investigator had the liberty to do so and often did. So we will continue to look at that. As I said in the presentation, we would. There's no reason to think it wouldn't respond similarly, but I don't know that we're gonna be able to gather a tremendous amount of useful information from the fellow eye, just because it was because of the factors I went through. Got it. Is there a medical conference or a venue where you could have additional data from this study this year, or? We'll certainly look to present this at an upcoming medical conference. We're evaluating right now, which is the right conference to present these data at. Understood. Okay, thanks for taking my questions. I'll hop back in the queue. The next question is from Pete Stavropoulos with Cantor Fitzgerald. Please go ahead. Hi, congratulations on the data, and thank you for taking our questions. I guess our first one is, you know, how do the changes in CST sort of impact your view on the patient population you enrolled in the study? You know, do you still believe that earlier treatment is better? And, you know, when you look at the natural history of the type of patients you enrolled, you know, how long does it generally take for them to progress in terms of disease and meaningful vision loss? I'm just trying to understand how long treatment-wise, you know, you may need in order to separate, let's say, 402 from placebo. Yeah. Hi, Pete. I'll take the first part of that question and then maybe ask Dr. Bhisitkul to address the second part. I think we did enroll the right patient group. You know, in a study size of approximately 100 participants, you do get some group differences inherently. So I think it's clear that we observe that more severe CSTs, you know, there's a delta to be shown, and if you're, you know, too close to 300 or 280 or normal, you know, a change in 50 microns is simply not able to be demonstrated. So I would still say that we've learned that when, and it's the right use of an oral therapy to intervene early. I would still characterize this patient population as relatively early and upstream, but we certainly, I think, want to be treating patients with edema. That's clear. And so, you know, we will continue, as I said before, to do sub-analyses and look at responses and responders, seeing who the ideal patient group is. I think we had enrolled the right patient population. In a larger study, we're gonna have patients with more severe edema across the board, and I expect, again, with longer duration treatment to continue to have more pronounced effects. Maybe, Bob, you can touch on the natural progression. Yes. The part of your question was about the natural progression. You know, it's a 3-month study, so your typical patient with diabetic macular edema, you know, as a treating physician, over 3 months, if you do nothing, probably a good portion of those patients are going to worsen. You're hoping that, you know, some portion of them at least just stay stable, and then it's really gonna be just a minority of them that can show any improvement on the OCT with no therapy. You know, the regular trend will be dwindling to worse and worse disease over 3 months, 6 months. So it is an interesting question of, you know, how will we use this in clinical practice? And then a second question of, what's the next patient population to target in the clinical trial? I think as Brian has mentioned, you know, a very similar patient population in the next clinical trial, I think would be one that would have a good chance of showing good effects. But once you put it in our hands as retina doctors, you know, we can use this in a lot of different ways, including intervening, for example, before patients have center- involved diabetic macular edema, or intervening in patients who, you know, have previously been treated. So the clinical population will be broader than the population that we're looking at here for these clinical trials. Okay. Thank you for that. And additional question I have is, you know, so from my understanding, there were three pre-specified rescue criteria. You know, was the rescue criteria triggered in the active arm? And if so, were there any differences in the rate of between rescue and the active group? As for rescue between the active and non-placebo group. Sorry. Yeah, there were small numbers overall, Pete, only 5 total, so it's a little bit, you know, when you have such small numbers in general, hard to see differences. We had a table of that in the presentation. I think it's noteworthy that no patients at 200 met rescue criteria or received anti-VEGF rescue. There was 1 at placebo, 3 at 50, and 1 at 400. So, you know, arguably, I, if you're looking for a dose response, you might say, "Well, the 50 was insufficient," but I don't think those numbers are meaningfully different across the groups. What I would draw attention to more so is that the use of anti-VEGF did not confound the interpretation of the study, and that that's not always been the case of studies like this, where you end up having a fairly indiscriminate use of VEGF, and it makes for a very confusing picture. Okay. Last question I have, you know, take into consideration the mechanism of action of RZ402. You know, can you see RZ402 being leveraged in other ophthalmological indications? I would say most definitely. We're, you know, we thought that DME was the right starting point. Based on the oral route of administration and the mechanism of action, there may certainly be an opportunity for diabetic retinopathy. We also have some preclinical data in models of wet AMD, and there's reason to think it may have utility there, too. So, and that's why I mentioned in the presentation, there's a variety of use scenarios, whether it's monotherapy, early treatment, refractory patients, add-on, where four-oh-two follows or where, sorry, anti-VEGF follows four-oh-two, and certainly in alternate indications as well. So lots to explore. We view this as a potentially large program with a number of label indications, if it were to all pan out. All right. Thank you for taking my questions, and, congratulations once again. Thank you. The next question is from Julian Harrison with BTIG. Please go ahead. Hi, thank you for taking my questions. Let me add my congratulations to these data. I'm curious how many watch and wait DME patients you expect to be receptive to this therapeutic profile. Can you remind us of how large that opportunity is? I can address it just from my experience in the clinic. You know, it's not uncommon that you see a patient who has true DME that you pick up on OCT. They may have some level of vision loss or not vision loss that they quite notice yet, and then you present them with the options, which really are start anti-VEGF injections or do nothing, the wait and watch approach. And a good number of those patients will, especially in the early stages of diagnosis, they'll select the wait and watch. And so we'll say, "Okay, come back and see me in three months, or come back and see me in six months," and we'll reassess. So it's not an uncommon scenario that we have patients that we follow who have diabetic macular edema but are not receiving active treatment. Oh, okay, to follow on, I've been prodded. It's, you know, now those patients, given the same scenario, our options are to give you injections in your eye, wait and watch, or, "Hey, there's this once a day pill that you could take, and it's been shown to be beneficial for patients that aren't receiving injections." And you'll see a lot of hands get raised to take the pill over those other two options. I would just add, just based on the experience during the trial, you know, that's the exact population that came in. And while, you know, we had to ramp up, enrollment, it went pretty quickly in the last few months of the year. And we were surprised, as I said, to see how few patients were on anti-VEGF when we would have allowed many more. The average injection was less than half of an injection, across the groups. And these patients were in turn, willing to sign up for an investigational clinical trial. Okay, great. Thank you. That's very helpful. And then it was great to see the CST improvements continuing to get better through the end of the study in the 200 mg dose group. I'm wondering if you have a good sense for, when you would have expected to see a plateau had the study been longer? It's a good question. I don't know that we know the answer to that. I think it in part depends on how much fluid there is at baseline, and the patients we're enrolling. Based on the data we saw, there's no reason to think you couldn't, you know, that trajectory wouldn't continue and that you couldn't reduce fluid down to a normal level. Yeah, one of the things that struck me looking at the data, and that I mentioned with the group was, you know, that CST curve is sloping downward, and it's still sloping downward at the end, at the end of study visit. So, you know, I'm really looking forward to a study where we can follow it at 3 months, 6 months, 12 months, because I don't think we've come close to the plateau in the context of this 3-month, 4-month study. Very helpful. Thank you, and congrats again. The next question is from Catherine Novack with Jones Research. Please go ahead. Oh, hi, guys. Congrats, congrats on the data. It's really great to see these improvements on CST, but I wonder if we can drill down a little bit into how predictive CST is of future improvements in visual acuity. I guess, you know, what conclusion can we draw from today's data about future BCVA? And then, why was 30 microns considered the lower bound for efficacy before the study? Okay, two parts to the question. The first one is, you know, the relationship between vision and OCT, retinal thickness. And this is something we have recognized now for 10 or 15 years, that, you know, when we get the initial improvements in the macular edema for a given patient, the visual acuity does not always or does not even often track right along with those improvements in the fluid. There can be a, there can be a sort of lag or a delay or a, you know, an uncoupling between the vision improvements and the OCT improvements. But I just keep in mind, what's the disease? The disease is fluid in the retina, along with abnormal thickening of the retina. Any drug that gets rid of that disease, the fluid, and gets rid of the thickening of the retina, that is, you know, by almost by definition, going to have visual benefits for the patient. And again, I think in a 6-month study, in a 12-month study, that would give enough time to the clinical trial to demonstrate that effect, on the visual acuity. The second part of your question was on 30 microns as the endpoint, and this is a pretty standard one across clinical trials in diabetic macular edema. You know, what is an improvement that's outside of the noise? And so here, what was seen here was picked as 30 microns. And for me, it achieved that. But more importantly, the delta between between the two, the 200 milligram group and the placebo was 47, call it 50 microns. And there, you know, especially over a 3-month period, we are definitely seeing something that would be meaningful to the patient, something that would be meaningful to the treating physician to see that delta of 50 microns. Okay, got it. And then on, you know, potential next steps, I understand that this is not something, you know, that you see yourself commercializing per se, but given the hypothesis that you need longer duration of treatment for BCVA improvement, do you, you know, see conducting additional phase II studies in the near term, as well as looking at additional dose levels, since you expect that you, you know, had no dose response at these high doses, maybe go lower in a dose? Yeah, Catherine, this is Nevan. Thanks for the question. We will definitely explore all viable options as a company going forward. It's unlikely that independently we would push forward in the late-stage clinical development. I think there are a variety of things to look at, and there's probably some intriguing things to look at, including, you know, as we've all highlighted here, the 200 milligram dose. But, you know, even under a broader program, you could even explore, over a longer period of time, a lower dose. ... A lower dose may be efficacious somewhere in the hundred, between 100 and even 200. So I think there's a variety of things that can be done. We still have a lot to consider as we think about digesting all of the data, because this really is all about the top line and getting it out to the world today. But all of that, I think, will need to be considered as we think about next steps and what the late-stage clinical development plan would look like. Okay, thanks. That's very helpful. Congrats again, guys. Thank you. The next question is from Douglas Tsao with H.C. Wainwright. Please go ahead. Hi, thanks. Congrats on the data, and thanks for taking the question. I guess people sort of asked it, I guess I'll just ask maybe more specifically. I mean, how quickly would you expect to see BCVA improvements given the CST improvements that you're seeing? I mean, I know you've highlighted 6 and 12 months, and obviously 3 months is too short, but do you think we'd start to see separation sometime between 3 and 6 months? I think that's about right, okay? I think at 6 months, we would start to see the visual acuity effects that follow the macular thickness effects. And if the, you know, in a registration trial, it's gonna have to be 12 months, and I think that's certainly gonna be sufficient to detect the visual acuity benefits from RZ402. Great. I know you mentioned the opportunity for, you know, to go outside of retina specialists. How would you envision that working in terms of just assuring that there is fluid and there is macular thickening that would necessitate treatment with RZ402? Thank you. Yeah. Yeah. You know, here, we're, we're starting to talk about what medicine might look like in 10 years, okay? In five years or 10 years, with, you know, insufficient number of doctors. Retina specialists, we are all drowning in patients right now, you know, we, we have a hard time keeping up. So, you know, this could be a detection that could go on with, you know, a new diabetes patient to treated by their general practitioner or by their endocrinologist. Maybe it would be an optometrist appointment. Optometrists are certainly capable of interpreting, of performing and interpreting retinal imaging studies, including OCT. From there, it could, you know, either get referral for confirmation to a general ophthalmologist or a retina specialist, or maybe that would be sufficient, and that would be enough, once, once that retinal imaging study has been performed, it would be sufficient for a general practitioner to put the patient on this once-a-day pill, just like they would put them on their antihypertensive medication or on their statin drug. Maybe I can add, as an endocrinologist, we already co-manage patients with ophthalmologists and retinal specialists, so they're already involved in the diet, the surveillance and the diagnostic management. So you could, you could, you know, conceive of something where they're still doing that, they're doing the assessments that detect DR, which is already done, as well as DME, and you know, the medical management could be outside of that specialty. I guess maybe not to change topics, because that's the core data wants on this call, but just maybe it'd be helpful to provide some context on the data that you released last week, in terms of the findings with the Brown Norway rat versus the Sprague Dawley for RZ358. Sure. Doug, happy, happy to do so. Yeah, so this is for everyone's benefit in reference to our other program, which is our antibody RZ358 and the partial clinical holds that we have in the U.S. on that program. We continue to collect what we think to be very compelling data, both in vivo and in vitro, that demonstrate that the particular injury that is occurring in the Sprague Dawley rat is specific likely to that rat. So all of the work that we've done over the last year now, looking at liver cells, looking at CD-1 mouse studies where they were super pharmacologically dosed, and we didn't see any findings. And now we've just completed the dosing of the Brown Norway rat, very common rat that we see running around all over the US, and there are no findings as well. So that's pretty compelling, really bookending what we've done. And so we will be rounding out that package for submission to the agency this summer of a complete response, looking for liberalization of those partial clinical holds. We think it's a compelling package with all that we've done, and look forward to that, and we will all see and learn through the course of the summer, how that progresses. Okay, great. Congrats on all the progress with 358 and 402. Thank you. The next question is from Jason Butler with Citizens JMP. Please go ahead. Hi, thanks for taking the questions. The first one, just on the CST change after the end of treatment. Any more thoughts on the, you know, why the 200 milligram cohort seem to continue to trend down, whereas 50 milligram was rebounding? Do you think there's a threshold effect or a dose effect there? Yeah, and then I have a follow-up. Yeah. Hi, Jason. I don't know that we can draw too many conclusions there. T hat there may not be, you know, true differences between the groups. I think that in all groups, the trajectory was downward at week 12. The PK, you know, the half-life of the drug is at least a day, so there are likely some sustained exposure effects. And then biologically, I think it's plausible based on the mechanism of action, it's not just fluid reduction, there's also likely anti-inflammatory effects here. At least there's plausibility for a sustained biologic effect. So differences between the groups, I wouldn't read too much into, other than what I commented before regarding, you know, group sizes and group differences that are somewhat inherent to, you know, relatively small phase II studies. Got it. And then obviously, I understand it's early to ask this question, but when you think about, you know, long-term treatment paradigms, when a physician would think about potentially adding anti-VEGF, is this where you would maybe discontinue 402, or is this a scenario where you would continue to use both anti-VEGF and 402 in combination, given the different mechanisms? Yeah, that's exactly what we're looking forward to. So to move away from this sort of monotherapy approach to diabetic macular edema, so that I have in my hands a couple of different options. And, you know, as I said, once it's there, once you give it to us, we'll use it in many different ways. We'll use it as a standalone therapy and then switch to anti-VEGF therapy for the patients that are more severe. We will use it as a combination therapy. We might use it as start with anti-VEGF and then see if you can get them stable and then switch them over to this. So there's only so many things you can do in a clinical trial, but once it's available in the world, you know, then we'll really be able to learn from our experiences on how to use this drug. And then again, what I really hope for this is that it keeps me out of the injection stage of treatment altogether. So, from what we're seeing here, it's gonna keep a good proportion of those patients from ever needing to progress to have to consider the anti-VEGF.