Good afternoon. I'm Nevan Elam, Rezolute's founder and CEO. 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 today, March 22nd, 2023. 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 risks and risk factors that are there as well that could cause actual results to differ materially from those expressed or implied by these statements. Thank you for joining us today for an in-depth discussion of our program, RZ402, an oral plasma kallikrein inhibitor being studied as a potential therapy to treat diabetic macular edema.
Participating in the discussion, we are fortunate to have Dr. Robert 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 brings a unique and comprehensive perspective on the treatment of DME, having worked in the field for many years, including as an investigator for anti-VEGF therapies for DME, as well as more than a dozen clinical trials for novel therapies. Also joining us from the Rezolute team are Dr. Brian Roberts, our Chief Medical Officer, Dr. Raj Agrawal, a renowned retinal specialist in his own right and our Head of Ophthalmological Clinical Development, and Dr. Jeffrey Breit, our Head of Pharmaceutical Sciences. In today's presentation, Dr. Bhisitkul will review the treatment landscape for DME, as well as providing his own perspective as a physician who treats patients.
Breit will present the scientific rationale for the use of a plasma kallikrein inhibitor, PKI, to treat DME, while Dr. Roberts will discuss how an oral therapy could be used in the treatment cascade, and he will also review the results from our initial clinical studies for RZ402. Finally, Dr. Agrawal will present our phase II clinical study that is currently underway in patients with DME. Following the presentations, all of us, including Dr. Bhisitkul, will be available for questions. Before I hand it off to Dr. Bhisitkul, I'd like to highlight some of the key points of the program and why we here at Rezolute are intrigued about its potential to significantly alter the treatment paradigm. As a result of the true epidemic of diabetes, DME is the leading cause of blindness in the U.S. and in other places in the world.
While DME directly impacts the eye and vision, DME is not a classic eye disease. Like other vascular complications associated with diabetes or excess glucose, DME is a microvascular complication. Typically, when we think of eye disease and disorders such as cataracts, glaucoma, or macular degeneration, we think of treating the eye directly. As you'll hear today, DME is very different, particularly because it is caused by a microvascular injury or insult that occurs at the back of the eye at the retinal interface. We believe that a selective and potent oral compound that bathes the entire vasculature systemically may be the ideal candidate to treat DME. Over the past 40+ years, there have been a variety of approaches used to treat DME, from lasers to intravitreal corticosteroids. In the last 15 to 20 years, we've seen the experimentation and adoption of intravitreal anti-VEGF therapies.
Good news is that these anti-VEGF therapies have provided retinal specialists with a powerful tool to correct and prevent DME. However, we also know that these therapies are only effective in about 50% of patients. The route of administration in injection into the eye is less than ideal and can lead to poor compliance and clinical outcomes. We believe that our oral PKI has the potential to be the next wave, the next advancement in how we treat DME. Not only would an oral therapy lead to better compliance, but it could also be used as an early intervention to help manage the disease. Our preclinical studies have validated the pathway and the importance of targeting the pro-inflammatory kallikrein-kinin system as part of the contact activation system. You can think of the kallikrein-kinin system as an alternative to the VEGF pathway.
In our preclinical models, we've observed up to 90% improvement in retinal leakage with the use of RZ402. Our phase I studies demonstrated that our compound was safe and at predicted doses and concentrations sufficient to provide adequate coverage with a single tablet in daily dosing. Our phase II proof of concept study in DME patients is now underway, where we hope to show improvement in patient outcomes. We here at Rezolute are fortunate to have the opportunity to develop a therapy that has the potential to significantly and meaningfully alter the treatment landscape. We hope that RZ402 successfully navigates its way through the clinic and eventually becomes a true treatment option for patients and physicians. I'd like to hand it over to a true expert, Dr. Bhisitkul, to provide you with his thoughts on DME.
As part of the session today, I want to give a clinical background on diabetic retinopathy and diabetic macular edema in terms of patient care in the clinic, the current treatment landscape, as well as the limitations of anti-VEGF therapy and other available options. From there, we'll look to the unmet needs in diabetic macular edema, and outline what's urgently needed in order for future treatments to expand and improve the long-term management of diabetic retinopathy patients. In this context, we can discuss RZ402 as a promising DME treatment that breaks ground in two ways: as a novel therapeutic mechanism by acting on the plasma kallikrein pathway and also with its novel administration route as a once-a-day oral pill to move beyond the regimen of repeated eye injections that's been our only option for nearly two decades.
I've been a retina specialist for 25 years now. In my practice with diabetic retinopathy and DME, it makes up about a third of the patients that I see every day in clinic. I'll see 10-15 patients with diabetic retinopathy every day. Along with diseases like macular degeneration, I'll do 20-30 intraocular injection treatments a day. This is on a schedule for the patient of every one to two months when they're under active treatment. It's a lot, and it's only going to get worse. There are approximately 6 million people in the United States with diabetic retinopathy. About 1 million of these are at risk for severe vision loss. For example, patients with diabetic macular edema are 25 x more likely to go blind than the average person. This patient population is young and middle-aged.
This is the working age population. Now, with diet and lifestyle risks, especially in the United States, but even globally, the population of patients with diabetes is projected to grow significantly over future decades. Diabetic retinopathy is a disease of microvascular dysfunction. It arises from chronic hyperglycemia and chronic inflammation in the small blood vessels that supply the retina. Over many years of the disease, this leads to vascular insufficiency and leakage. When these damaged micro vessels leak fluid and lipids and protein into the retina, this is what produces diabetic macular edema. In this slide here, we can see the retinal hemorrhages and the yellow hard exudates in the macula. This is the bull's eye of the retina when we say the macula.
On the OCT, we can see in the cross-section the typical thickening and irregularity of the retina and the dark brown cysts within the retina. This is what defines diabetic macular edema. It's this fluid sitting in the macula which leads to progressive vision loss and blindness. Let's look at the current therapeutic landscape for diabetic retinopathy and DME. Here we'll discuss a number of different treatment options. Really, in today's world, it's a monolithic situation, with the class of anti-VEGF drugs being the sole treatment for the vast majority of our patients with diabetic macular edema. We'll start with laser photocoagulation, which is something that arose back in the 70s as a treatment for diabetic macular edema. With grid or focal laser burns were done in the macula, and this was the only treatment option that we had for decades.
The benefits for patients were limited. Mainly, we were trying to reduce by about half the percentage of patients that went on to severe vision loss. We still have our old laser machine in the clinic, but in actuality, for diabetic macular edema, laser can be looked at as an historical treatment. For example, for myself, I never use laser these days. Everything changed with the beginning of the VEGF era in the mid-2000s, first for macular degeneration and then following that for diabetic macular edema. With Lucentis, Avastin, and Eylea, for the first time, DME patients showed dramatic vision gains. At the time, these were seen as miracle drugs. I'll go on today to outline the limitations of this therapy. We can't take for granted how these drugs have extraordinary benefits for patients with diabetic macular edema and diabetic retinopathy.
The well-recognized drawback for our standard of care with anti-VEGF drugs is that these drugs have to be given as an injection into the eyeball every month or two, month after month and year after year for most patients with diabetic retinopathy. It's very hard for the patients, and we, as treating physicians, are overwhelmed with the heavy treatment burden. Study after study shows that in the real world, patients and doctors don't or can't keep up with the frequent and consistent regimen. Over the years, the visual benefits can be very suboptimal for many patients. Options like the Susvimo port device for sustained delivery of Lucentis are aimed at addressing this. In the future, I think this technology will benefit a select subgroup of patients in overcoming the treatment burden and the frequent injections.
Other options that are available are Vabysmo and the upcoming high-dose Eylea. These hold promise to extend treatment durability out to three or four months for some patients. These drugs will be new options for us, but they're still within that same anti-VEGF category. We do have a viable second-line therapy for diabetic macular edema in the case of steroid drugs. For a significant subset of patients who don't fully respond to anti-VEGF therapy, we can try intravitreal Triesence injection into the vitreous, or we can use the Ozurdex pellet or the long-acting Iluvien device. The benefits are not at the same scale with the steroids as they are with the anti-VEGF drugs, and there are the side effects of cataract and glaucoma. These are so common and are severe enough to limit the use of steroid drugs for diabetic macular edema.
We do see patients with DME who do not respond to multiple repeated anti-VEGF injections, and then when switched to, say, the Ozurdex pellet, will completely resolve with a dry macula. This is telling us that DME is a multifactorial heterogeneous disease, and unlike the anti-VEGF drugs, steroids have a broad spectrum of action in DME. It may be this broad activity that explains why some patients with some patients' DME resolves with steroids after they don't respond to multiple anti-VEGF injections. To me, this points how significant benefits may arise with broad anti-inflammation and vascular stability effects from RZ402 kallikrein inhibition, especially when this comes without the well-known ocular toxicities of steroids. Let's take a patient case here, one that illustrates some of the shortcomings of our available treatments for diabetic macular edema.
At first diagnosis, this patient has diffuse and severe DME that you can see here, and this has a chronic appearance to me. It's probably been present for many months at least, or maybe longer. The vision is good, surprisingly, but over a year of treatment, I gave this patient eight Avastin injections over 12 months in this eye. There is no significant resolution of the DME. This patient would fall into the category of a VEGF non-responder. Unfortunately, these type of patients are common in our clinics, and we need alternatives to address the problem of non-response or incomplete response to standard anti-VEGF therapy. The proportion of patients that fall into this non-responder category is not small.
From the first phase III clinical trials of Lucentis for DME, the the OCT results showed us that after two years of treatment, up to 25% of patients did not fully resolve the diabetic macular edema. This is after two years of intensive monthly treatment with 24 Lucentis injections. Now, in the real world, where almost none of us use intensive monthly treatment like this, the proportion of patients who don't resolve their DME with anti-VEGF therapy is estimated to be as high as approximately 50%. This is a major unmet need with our current treatments. What we need for VEGF non-responders and incomplete responders is a treatment that doesn't rely on VEGF, something that is beyond VEGF.
That's a fairly obvious statement, but we've been living in an anti-VEGF world now for 20 years, and the only choice for non-responders to anti-VEGF is often to just keep giving more anti-VEGF. That's what we do in practice. If Lucentis isn't working, for example, we give more Lucentis injections, or we try to switch to Eylea, which is also another anti-VEGF drug. We hope we see something different. Most studies show that the benefit of switching between anti-VEGF drugs is equivocal at best. A drug for DME that has a novel therapeutic mechanism could be used as an alternative to anti-VEGF or as an adjunctive therapy in combination with anti-VEGF. This would expand the number of diabetic macular edema patients that can be successfully treated.
Particularly, by targeting the plasma kallikrein pathway, RZ402 offers a potential broad spectrum of action in anti-inflammation and anti-leakage to rescue VEGF non-responders. This would be analogous to steroid therapy, but without the serious side effects of glaucoma and cataract that makes many of us hesitant to incorporate steroids into our treatment regimens. Beyond better mechanisms, there are shortcomings of our current DME treatments. The heavy treatment burden associated with ongoing intravitreal injections that I mentioned before, we're injecting into the eyeball over and over again for years and years. It's painful for the patient. The eye is red and irritated for a day or two afterwards. There are serious risks of complications like endophthalmitis or retinal detachment. It's a low risk of these bad problems, but the risk accumulates when the patient is getting 50 or 100 injections over time.
The trips to the doctor every month or two, taking half a day off of work, maybe a family member needs to take time off to accompany them. All of this disrupts life for these patients, there's no real finishing point to offer them. This is not to mention that retina doctors are burnt out from doing injections all day every day in clinic. We're trying to find ways to reduce the number of injections that we have to give to these patients to lower our clinic burden. A once-a-day oral drug for DME patients could be a solution for this. If it can reduce or even eliminate the need for anti-VEGF injections, this would have a huge impact in improving vision outcomes and expanding the number of patients who can be consistently and effectively treated.
The treatment burden, the disruption of the patients' lives, the clogged up retina clinic, this could also be greatly improved. An oral drug makes it conceivable that we can begin to treatments for diabetic retinopathy patients at an earlier stage of the disease. Right now, the disease has to be fairly advanced to justify starting these eye injections for a long time. We wait until there is central diabetic macular edema and vision loss, and then we try to recover, or in many cases, just stabilize the situation for these patients. With a non-invasive oral drug, you can imagine we can treat preventatively rather than reactively. In this way, we can benefit patients before the disease gets advanced, and we can preserve vision while it's still good. Now I'll pass the presentation back to the Rezolute team.
Thank you, Bob. Good afternoon, everyone. I'm Dr. Jeffrey Breit. I'm delighted to be able to speak to you today about the scientific rationale for targeting diabetic macular edema with an oral plasma kallikrein inhibitor, RZ402. DME is a vascular complication of diabetes. Elevated glucose associated with diabetes can impact a number of major organs, including the brain, kidneys, nervous system, the heart, and as we've been discussing, particularly the eyes. Tissues with a sense of microvasculature, such as the retina and kidneys, may be particularly impacted by prolonged glucose exposure, causing endothelial cell dysfunction and localized edema in tissues. Chronic glucotoxicity may ultimately lead to inflammation in the back of the eye, caused by disruption of the blood-retinal barrier and subsequent leakage of fluid into the retina.
Chronically high glucose levels associated with diabetes initiates pro-edema and proinflammatory signaling cascades that impact the integrity of the eye vasculature by inducing endothelial cell dysfunction and vascular leakage into the back of the eye. The accumulation of fluid in the macula, the part of the retina responsible for high resolution central vision, can lead to progressive vision loss and blindness. Endothelial and blood vessel dysfunction in the retina of DME patients is initiated by the production of reactive oxygen species, created as a byproduct of energy metabolism in the cell. Reactive oxygen species, such as superoxide, are produced when glucose metabolism is ramped up beyond what is necessary to maintain normal cellular homeostasis. Reactive oxygen species may damage proteins, cellular lipid bilayers, as well as mitochondria and nuclear DNA. These factors may all impact endothelial cell dysfunction and vascular wall integrity in the back of the eye.
The edema and macular thickening observed in DME is a direct result of this endothelial cell dysfunction due to disruption of the retinal blood vessel barrier. Maintaining tight junctions between neighboring endothelial cells is critical to prevent vascular leakage and edema, as well as prevent the flux of water, salts, sugar, and proteins into the back of the eye. This cascade of events can all be tied back to the loss of endothelial cell barrier function in the retinal capillaries. Endothelial cells maintain homeostasis between the vasculature and surrounding tissues. There are metabolically active cells that regulate the transport of nutrients into and out of the retina. VEGF has long been a target for treating DME, but VEGF involved in DME is a downstream mediator of vascular edema into the back of the eye of DME patients.
Though VEGF is an important mediator in many patients, upstream events starting at the endothelial wall of the eye microvasculature are critical to the propagation of DME. If pro-inflammatory processes can be stopped at the endothelial vascular wall, DME may be prevented in early disease progression. The kallikrein-kinin system is an early upstream player in the progression 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. A closely coordinated process is involved in vascular permeability and edema. When acting as intended, the KKS is meant to fight infection and vascular damage by enabling local fluid leakage and inflammatory cell translocation into the microvasculature of damaged tissues.
However, when elevated blood sugars damage the endothelial wall of the eye microvasculature, the KKS is overactivated, which leads to the continued overproduction of the inflammatory mediator bradykinin and subsequent bradykinin signaling through the B1 and B2 receptors, which directly mediate tight junction integrity and vascular permeability. There is strong evidence suggesting that there are VEGF independent signaling pathways involved in the progression of DME. In fact, a substantial number of DME patients have shown limited to no expression of VEGF in the vitreous via intravitreal sampling. Whereas the enzyme plasma kallikrein shows substantial and universal upregulation in these same DME patients. Pre-clinical studies have shown that intravitreal injection of plasma kallikrein induces retinal thickening and DME, analogous to what is observed in DME patients. Importantly, this is prevented by administration of a kallikrein inhibitor, but not anti-VEGF therapies.
As demonstrated in animal and human studies, the KKS is highly implicated in DME. Several studies have shown that the KKS signaling pathway is a separate and VEGF-independent pathway involved in the development of DME. Interestingly, plasma kallikrein knockout mice are protected from VEGF-induced DME, which demonstrates that the effects of VEGF may be in part mediated by the KKS pathway. This may also explain why DME patients with elevated intravitreal VEGF concentrations also have elevated KKS signaling, while the reverse is not true. These combined studies validate that plasma kallikrein is a potential target for treating DME. These data also show the potential for a kallikrein inhibitor to be used as a monotherapy substitute for anti-VEGF therapies, as well as in combination with VEGF therapies, such as in VEGF-independent DME pathophysiology.
RZ402 is a potent and selective small molecule plasma kallikrein inhibitor, which has been extensively characterized in animal pharmacology model DME. To our knowledge, it's the most advanced and differentiated oral systemic plasma kallikrein inhibitor in development for this indication. While RZ402 is potent and traditional in vitro and ex vivo assays, RZ402 is unique in having been extensively studied in animal models of diabetic vascular leakage, as well as other models relevant to the kallikrein-kinin system. In vivo systems have also shown that RZ402 is significantly more potent when tested in animal disease models involving the KKS system than when compared to in vitro potency data. This is evidence of the importance of localizing a plasma kallikrein inhibitor to blood vessel walls, and the propensity for RZ402 to interact with and inhibit the KKS system at its site of action, the vascular endothelium.
We put more relative weight in animal studies of DME than in in vitro and envision assays. We are reassured that RZ402 is highly potent in these models. The highly effective concentrations seen in these studies represent a more relevant benchmark for targeting human concentrations of RZ402. Plasma kallikrein is categorized as a trypsin-like serine protease, which requires activation and is part of a larger family of proteases. Under normal, non-inflammatory conditions, plasma kallikrein remains inactivated, though when activated via factor XII, plasma kallikrein cleaves high molecular weight kininogen. This process creates bradykinin and its byproducts, which are the key mediators of vascular permeability, leakage, and pro-inflammatory responses. The active site of serine proteases such as plasma kallikrein contains three amino acids critical for the recognition and cleavage of high molecular weight kininogen. This group of three amino acids is referred to as a catalytic triad.
RZ402 with high affinity and with high specificity interacts with a catalytic triad and inhibits HMWK from being cleaved, and thereby prevents bradykinin production and subsequently prevents B1 and B2 receptor signaling. The structure activity relationship of plasma kallikrein inhibition by RZ402 has been characterized using computational chemistry models. These CompChem tools have provided us a unique understanding as to how RZ402 interacts with the catalytic triad and a PK binding pocket in general. RZ402 shows vascular enrichment and as a result, has a relatively low volume of distribution. If you look at the RZ402 compound, these added properties are fairly apparent as the high PKI head group in RZ402 is not associated with high cellular internalization. These physical properties are beneficial to targeting disorders associated with the vascular endothelium, like plasma kallikrein rather than intracellular targets.
This slide highlights two rodent models of DME, one being a streptozotocin-induced diabetes model, another being an angiotensin II-induced blood pressure model, both very standard rodent models for DME. As our preclinical data shows, both responsive to kallikrein inhibition. Systemic administration of RZ402 consistently inhibits retinal vascular permeability and leakage by up to 90% in these models compared to control animal groups. These results can be observed by the quantitative bar graphs and also quite clearly in the fluorescein angiography images. RZ402 is effective at reducing retinal leakage in these models, both in preventative or in an interventional fashion, in which treatment for 14-28 days after DME onset reverses the process. In addition to the two models discussed in the previous slide, RZ402 is highly effective in preventing edema in a variety of related animal models of vascular leakage, inflammation, not surprisingly, wet AMD.
Importantly, there's a highly correlated exposure-response relationship, which enables estimation of effective target concentrations in blood that equates to the ability of RZ402 to reduce the retinal vascular leakage in these models. Namely, half inhibition occurs at approximately 10 nanomolar or 3.5 nanogram per ml of RZ402. Ninety percent inhibition occurs at approximately 20 nanomolar or 7 nanogram per ml of RZ402. RZ402 response correlates with plasma exposure and is not dependent on ocular exposure, which is minimal in tissue distribution studies of RZ402. These effective concentrations serve as our benchmark for target concentrations in clinical studies of RZ402. We believe the availability of these in vivo and modeled drug exposure and response estimates using these models increases the likelihood of clinical success in DME relative to relying solely on in vitro assays.
We also believe that our understanding of RZ402 physical properties and enrichment in heavily vascularized tissues facilitates our understanding of how RZ402 works in vivo. These results, combined with the safety and drug exposure data generated from our phase I clinical studies, have enabled the advancement of RZ402 into phase II proof-of-concept studies in DME patients. I will now turn it over to our clinical team to discuss clinical experience with RZ402 to date, as well as the phase II clinical study recently initiated in patients with DME.
Thank you, Jeffrey Breit. Good afternoon, everyone. Before passing the presentation over to Dr. Raj Agrawal, I wanted to share some of my thoughts on the therapeutic approach and drug target, the ideal profile for a plasma kallikrein inhibitor, and the clinical strategy for and clinical experience to date with RZ402 from my perspective as an endocrinologist. Let me start by saying that while an oral therapy would be paradigm changing for DME within conventional retinal practice, I do believe that the management of diabetic retinal vascular disease with an oral therapy earlier in the course of disease would be more in line with the way in which we currently manage other vascular complications of diabetes.
An oral option with a novel mechanism of action has the potential to address the VEGF-independent processes, enhance convenience and compliance, treat DME sooner and in a manner more aligned with the care of other diabetes complications, reach more patients, and therefore achieve better overall outcomes. Jeff has provided a comprehensive review of the scientific rationale for targeting plasma kallikrein and of the supportive non-clinical data with RZ402. In summary, a plasma kallikrein inhibitor is an alternative approach to the anti-VEGF inhibitors for treating DME and targets the excessive production of bradykinin, a mediator of inflammation and vascular permeability caused by diabetes-induced vascular endothelial dysfunction at the retinal microvasculature. Now that we've reviewed the scientific rationale for targeting plasma kallikrein, I would like to Highlight and differentiate the two primary routes of administration, which really do represent two very distinct ways to approach the therapeutic target.
Programs targeting intravitreally delivered PKIs have taken the first step. They have shown proof of mechanism and concept in early clinical studies, thus further validated the kallikrein-kinin system as a target. However, in falling back to conventional ocular treatment paradigms, injection of a PKI into the vitreous of one or both eyes may fail to achieve adequate and sustained plasma kallikrein inhibition to the site of action at the retinal microvasculature behind the eye. In addition to obvious advantages in convenience, adherence, and earlier intervention, oral administration of a plasma kallikrein inhibitor may also be the optimal way to engage the target at its site of action, namely to achieve the PKI concentrations required for sustained inhibition of plasma kallikrein at the retinal microvasculature. It is our belief that adequate and sustained systemic plasma exposure is in fact necessary to unlock the full potential of a PKI.
The KKS is a vascular target for a vascular complication of diabetes. It stands to reason that it would require a systemic vascular approach to treatment. After all, we currently manage analogous renal and other vascular complications of diabetes in this manner, using ACE inhibitors, statins, and antihypertensives by way of example. As Jeff previously mentioned, RZ402 achieves substantial decreases in retinal vascular leakage in animal models using this systemic hypothesis without meaningful drug concentrations in the eye itself. While clinical studies with intravitreal plasma kallikrein inhibitors have shown proof of concept and validated kallikrein as a therapeutic target, the clinical benefit in these studies of second-line intravitreals may be further limited by the necessity to enroll patients who are failing currently available first-line anti-VEGF intravitreal therapies, thus inherently creating a higher hurdle for proof of concept and clinical benefit.
These studies have demonstrated greater effects in patient subsets with less severe DME, which, as you'll hear in greater detail, is the population we're targeting in our phase II clinical study. This can be achieved with an oral PKI, which by virtue of its differentiated route of administration, does not require patients to have failed anti-VEGF treatments. In contrast, a patient who is treatment-naive or new to anti-VEGFs cannot readily be enrolled into a clinical trial with an unproven or investigational therapy with the same intravitreal route of administration. Hence, the targeting of VEGF non-responsive patients with such therapies. There is currently a massive unmet need to utilize treatment earlier in the course of disease when the initiation or ongoing use of anti-VEGF therapies tends to be deferred or avoided by patients and/or prescribers, creating an opportunity for an oral kallikrein inhibitor to be employed as first-line monotherapy.
This is the space we are taking advantage of and operating in with our unique, efficient, and optimized clinical strategy, which does not require us to beat the performance of an anti-VEGF or to demonstrate effectiveness in patients who are resistant to these therapies at this development stage. We intend to also address those populations as part of a late-stage layered clinical program. Unlike second-line therapies, our oral route of administration affords the opportunity to conduct a monotherapy placebo-controlled phase II study in an upstream patient population, as you'll hear about shortly from Dr. Agrawal. To briefly summarize the RZ402 clinical experience to date, we filed an IND in 2021, and our phase I program in healthy volunteers was completed last year and has been presented previously, including by KOLs at various retinal meetings.
To briefly review key highlights from those studies, single doses from 25 to 250 mg were evaluated in the first-in-human single ascending dose study. While in the subsequent multiple ascending dose study with once-oral daily dosing for 14 days, the top dose was increased to 500 mg due to an excellent safety profile at doses tested in the SAD study. Between both studies, a total of 70 participants were enrolled, including 56 who received RZ402 and 14 who received placebo. The main study objectives were to evaluate repeat dose safety, tolerability, and pharmacokinetics. While an exploratory PD endpoint included an ex vivo kallikrein inhibition assay in human plasma to evaluate target engagement. The results of the MAD study in healthy volunteers affirmed the SAD findings while safely exploring even higher exposures over 14 days. More specifically, RZ402 was safe and well-tolerated across the entire dose range.
There were no serious adverse events, adverse drug reactions, or discontinuations due to adverse events in either of the clinical studies. Most of the reported adverse events were clinically mild, represented events that occur with a high background frequency in healthy volunteer clinical trials and/or did not show an imbalance to the placebo-treated group. Therefore, no adverse events emerged as being related to study drug or as a potential side effect of RZ402. Regular assessments of vital signs, ECGs, physical examinations, ophthalmic exams, and safety laboratory assessments was unremarkable. As was previously mentioned, patients with complete genetic deficiencies in kallikrein do not exhibit any adverse clinical consequences. While the knockout of plasma kallikrein in mice was protective against VEGF-induced DME. Furthermore, RZ402 was safely administered to rats and monkeys in toxicology studies at doses that are significantly above the clinically relevant dose range.
Results with respect to the pharmacokinetics demonstrated that RZ402 is bioavailable with dose-dependent increases in systemic blood concentrations being observed. Steady state was achieved with less than twofold accumulation, and the half-life was approximately 20 to 25 hours. Sustained elevated plasma concentrations of RZ402 were achieved that far exceeded target concentrations, both at peak and throughout the intended 24-hour dosing interval, thus supporting the potential for once daily oral dosing. Consistent with the observed human safety, the concentrations were well below safely tested concentrations in the aforementioned animal toxicology studies. The study showed that daily dosing with RZ402 inhibited plasma kallikrein in human plasma at a magnitude that benchmarks comparably to other kallikrein inhibitors that have been developed in the setting of hereditary angioedema.
More importantly, since RZ402 is more potent in vivo, the observed concentrations at all dose levels far exceeded target concentrations that were highly effective across multiple animal models of DME and related conditions. We believe the availability of these in vivo and modeled estimates increases the likelihood of clinical success in DME. These results have enabled the advancement into a phase II study in DME patients, which has been designed with the objective of showing proof of concept that oral delivery of a PKI can favorably impact retinal markers and outcomes, and to inform later stage study endpoints and designs. As such, although the study is robust in size and patient number for this stage, it is not powered to any specific pre-specified primary or secondary endpoints.
We intend to look at the totality of the data across endpoints and the full weight of evidence to evaluate whether the objectives were met, including factors such as safety, plasma exposures to RZ402, effects on CST by OCT scan, BCVA, and DRSS scale. Given the systemic exposure and ability to accurately quantify these levels, we will also take into account aspects that are unique to an oral therapeutic and yield additional proof of concept and or clinically relevant secondary benefits, such as dose response and quantitative exposure response modeling, binocular exposure, in other words, leveraging the potential for a two-for-one ocular benefit, and exploratory effects on non-retinal vascular markers such as renal GFR and albuminuria. I'll turn it over to Dr. Agrawal to discuss the details of the design and rationale for this recently initiated phase II study, as well as the status and timeline for results.
Thank you.
Thanks, Brian. Good afternoon, everyone. My name is Raj Agrawal. Like Dr. Bhisitkul, I'm also a retina specialist with more than 20 years of experience treating retinal diseases with anti-VEGF injections and related therapies. Having seen the frustration in many DME patients and their families with repeat injections over time with no associated improvement in vision, I am personally quite excited about our program, which we anticipate will create a treatment paradigm change in how we manage our patients in the future. With multiple intravitreal injection studies over the years, designing an oral medication study required us to think differently. As an example, an oral drug could favorably impact both eyes simultaneously.
Hence, apart from our team here at Rezolute, we work closely with our scientific advisory board members as well as key KOLs from around the country to help us design the study, accounting for the unique aspects of an oral therapy for diabetic macular edema. Our treatment population in this study is unique. We are not targeting anti-VEGF non-responders. Instead, our focus is on patients who are either treatment naive or those in early stages of the disease. Why are we doing this? This has been alluded to by Dr. Roberts, and I'll explain in some additional detail a bit later. This study compares RZ402 to placebo. Being a proof of concept study and a dose-ranging study, we wanted to make sure we design a clean monotherapy study that will provide us significant potential to evaluate RZ402 in a unique patient population.
For this reason, at this stage, we are not studying RZ402 as an add-on to anti-VEGF therapy or head-to-head against anti-VEGF. I'll be discussing the endpoints in some detail in a later slide, but I wanted to highlight the fact that we are looking at two important outcomes that we focus on in retinal disease clinical studies, including change in CST by OCT and BCVA over time. Since this is a three-month study in either treatment-naive or early-stage patients, and this is a time frame in which anatomic changes in CST are very likely to occur, our main focus is on the potential for RZ402 to affect a change in CST. Although we have pre-specified visual acuity-related endpoints, whether or not this might translate to improvements in visual acuity over the three-month duration of the study is less certain.
It is possible that we may see stability in vision compared to patients in the placebo arm during the course of the study. As I highlighted earlier, considering this is an oral medication, any favorable effects on macular thickening or visual acuity may reasonably be expected to occur bilaterally. Thus, with RZ402 and the study we have designed, there is a potential for benefit in both the predefined study eye as well as a fellow eye, which may have clinically relevant benefit for patients.
Hence, even though we define a study eye and a fellow eye, we will be comprehensively evaluating both eyes for changes in BCVA and CST. While the study eye will follow all the norms, just like in any other clinical study, including rescue criteria, the fellow eye will follow standard of care with the investigators at liberty to treat the fellow eye with anti-VEGF injections if they so choose. No one likes to hear the word rescue in a study. Patients with early-stage DME are known to progress slowly and hence we have a carefully pre-specified and standardized the criteria for any intervention, which we anticipate will also minimize the use of rescue therapy. Our investigators in the study agree with this approach. This slide provides a pictorial representation of the study design.
This is a phase II randomized double masked placebo-controlled parallel arm study in patients with DME. Our objectives in this study are to evaluate safety, efficacy and PK of RZ402 over a 12-week treatment period in patients with DME, followed by a 4-week follow-up safety period. Those patients who meet eligibility criteria will be randomized to one of four parallel arms in the study, with one arm being placebo. A patient who enters the study has a 75% chance to receive one of the three different active doses of RZ402 in the study. Being a masked study, all patients will take matched placebo or RZ402 tablets. The three active RZ402 arms will receive a dose of either 50 mg, 200 mg, or 400 mg. Based on our phase I study outcomes as described by Dr. Roberts.
All doses selected for this trial are likely to be safe and also have the potential to be efficacious. All three dose levels are expected to inhibit plasma kallikrein and to exceed target concentrations throughout the 24-hour dosing interval, as per the studies and animal models of DME. Patients will return to the clinic for evaluation at regular intervals with regular ocular and systemic evaluations planned, including OCT, BCVA and fundus photography. Considering this is an oral medication and not an intravitreal injection study, we are not as concerned with ocular safety assessments or complications as compared to patients who receive intravitreal injections. Since issues such as infection or retinal detachment are less likely to be observed in this study compared to intravitreal injection studies.
With up to 25 participants in each arm of the study, we anticipate a total of 100 patients, in the study, which is not powered within each dosing arm to any specific endpoint in the study. We believe that this is robust enough to demonstrate proof of concept in a phase II study and inform the design and power of late-stage studies. With this being the first study of RZ402 in patients with DME, our main objectives include assessing the safety and pharmacokinetics of the oral medication in patients. Safety will be evaluated broadly by assessment of adverse and serious adverse events and systemic assessments including ECGs, vital signs, as well as physical examinations. The repeat dose pharmacokinetics of RZ402 will be evaluated using population PK modeling, which is a powerful tool to model not only pharmacokinetic parameters, but also exposure-response relationships.
The primary efficacy endpoint of our study is a change in CST assessed by OCT, which is the anatomic marker for change in the disease over time. The rationale for this key endpoint was discussed previously. Our secondary endpoints include several other CST-based outcomes and also several visual acuity outcomes, including the change of BCVA compared to placebo. As discussed previously, improvements in visual acuity may not be expected over three months, but lack of progression is also an outcome of interest. We also have diabetic retinopathy severity score, or DRSS for short, as an exploratory endpoint. Lastly, an important aspect of this study is the effect of RZ402 on the fellow eye.
Considering the oral nature of the medication, we do expect some change in the fellow eye, and hence we plan to evaluate the fellow eye at the same time as the study eye across many of our secondary efficacy endpoints. For our study, we include diabetes patients with stable glycemic control and mild to moderate NPDR with central involved DME in the study eye. As I mentioned earlier, we are targeting patients who are treatment naive or those with early stage disease. For that reason we have set a limit to the number of previous anti-VEGF injections a patient may have received.
As we know, the greater the number of injections received by a patient, the more likely it is that the disease will be chronic and resistant to treatment, which is neither an ideal or a necessary patient population for a dose-ranging proof of concept study for an oral therapeutic, as was discussed previously. Given that CST by OCT is a primary efficacy endpoint in the study, patients must have at least 320 microns of CST, which will vary based on gender or the type of machine used for OCT. All CST values throughout the study, including those used to evaluate eligibility criteria, will be confirmed in a masked fashion by an independent central reading center. Change in BCVA is one of our secondary endpoints and is for patients who can read less than or equal to 78 letters on ETDRS.
Based on our conversations with our scientific advisory board members as well as other KOLs, we wanted to include an option for us to see if BCVA improves by at least five letters in study patients, which is why we have a cutoff of 78 letters on BCVA. We believe RZ402 may have a role to play in diabetic retinopathy management as well, hence we have defined change in DRSS score as another secondary endpoint. DRSS scoring will again be independently performed by a reading center in a masked fashion. As I briefly mentioned earlier, early or treatment-naive DME is slowly progressive, hence it is unlikely that patients in the study will require rescue. To avoid any indiscriminate use of rescue medications and to keep the study as clean as possible, we have set a high bar for rescue. Rescue criteria are pre-specified and standardized across the study.
We have three different rescue criteria. Number one is a loss of more than or equal to three lines in BCVA from compared to baseline. Number two is CST worsening by more than 100 microns from baseline. Number three, which is a combination of both BCVA and CST, the BCVA is worsening by two lines and CST worsening by 50 microns. Considering the systemic aspect of diabetes and the potential for fluctuating glycemic control to impact macular fluid and visual acuity, the criteria of rescue will have to be met at two consecutive visits, at least two weeks apart. The investigator may rescue a patient based on clinical judgment, but we have requested the investigator to discuss with us before he or she rescues the patient. Patients who require rescue intervention will be discontinued from the study.
The statistical methodology for will account for the use of rescue, with rescue use pre-specified as one of the study endpoints. After completing our supporting toxicology studies and tablet manufacture, we initiated the study late last year. Based on the number of patients we require for this study and this being a U.S.-based study, we have 25 sites across the country for the study with leading KOLs as investigators. We chose these sites carefully, making sure all of them are aligned with the study objectives, believe in the oral pathway for treatment in patients with DME, and are proven to be fairly active recruiters in clinical trials of this nature. One very interesting piece of positive feedback we have received from the investigators and the study teams was that patients have been increasingly asking for options other than repeat injections for treatment of DME and other retinal diseases.
We believe that this level of overall engagement will translate to successful enrollment and study execution, and expect to complete the recruitment by September of this year, enabling top-line results by Q1 2024. As I mentioned right at the beginning, this is our first inpatient proof-of-concept study, and hence we have designed the study in a way to maximize our potential to succeed. We are focused on treatment-naive patients or those in early stage of the disease process, primarily because we expect to see relative change in disease characteristics, particularly change in CST and a possible change in BCVA. We did not want to focus on anti-VEGF non-responders because first, we want to maximize our potential to see a positive change, and second, trying to evaluate a relative change in non-responders is challenging, as we have seen with outcomes in other studies.
During this study, we will be able to collect a variety of unique data, in the study, including plasma exposure, relationship of dose and exposure to various responses, and whether there are broader benefits from systemic exposure. For our evaluation of effects on CST, visual acuity, and even DRSS, we will look at the totality of the data we are able to collect and evaluate whether RZ402 leads to clinically meaningful outcomes in the study and how those outcomes inform continued development into later-stage studies. The main goal is to evaluate the study eye, this being an oral medication, as I said earlier, we will also likely see changes in the fellow eye, providing increased study power or the ability to evaluate composite outcomes. We are studying dose and exposure responses as well as directional trends across multiple endpoints.
We will evaluate individual arms of RZ402, as well as pool the data from two or more active treatment arms for additional analyses. Through our systemic assessments, we will explore whether RZ402 has any effects on kidney function, especially in this population. What expectations do we have from the outcomes of this study? This being in first inpatient proof-of-concept study, as I said, we have optimized the study designed to enhance signal detection and favorable outcomes. At this stage, statistical significance is not the main objective of this exercise. What will be this positive signal or signals look like? We believe that a difference of 50 microns in CST by OCT or one line that is five letters of BCVA by ETDRS compared to the untreated placebo-controlled group would represent a cleaning, clinically meaningful outcome for this study.
As previously discussed, with an oral medication and the potential to capture patients at an earlier phase in the disease, we do believe there is a need to demonstrate equivalence to or compare outcomes with anti-VEGF therapies at this stage of development. I would like to end with this thought. As retina specialists, Dr. Bhisitkul and I have treated thousands of patients with DME and other retinal diseases, right from the days of laser photocoagulation in the last century to interval injections that have become standard of care now. As Dr. Bhisitkul pointed out at the beginning, we continue to treat patients with interval injections since we do not have any other way of treating these patients. These, specifically these chronic vision and life-disabling ocular, you know, patients with ocular disease.
With a new mechanism of action that works upstream and with an oral formulation, I believe this drug has a capacity to not only reduce treatment burden for patients, physicians, and the clinics but also make both a qualitative and a quantitative change in the lives of patients. Thank you. I'll pass on back to Nevan for final remarks.
Thanks, Raj. Thank you all once again for taking the time today to join us and to learn more about RZ402. I hope that the session has been informative. As Raj mentioned, we are really looking forward to progression of the phase II study that Raj outlined. In particular, announcing results in the first quarter of 2024. Today, we thought it was really important to spend some time to walk through this program. Given that this program has the potential as an oral therapy to really change the paradigm and to shift the way we think about DME and how we treat DME. As I noted at the outset, we are happy to entertain questions.
In fact, at this point, I'm going to join the rest of the team that's assembled in the conference room next door, and we'll begin Q&A. Thanks again.
We will now begin the question and answer session. To ask a question, you may press star than one on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star than two. At this time, we'll pause momentarily to assemble our roster. The first question will come from Maury Raycroft with Jefferies. Please go ahead.
Hi, everyone. Thanks for doing this event. Thanks for taking my questions. I was gonna ask about the ongoing phase II. Given the early stage patient characteristics, that you're enrolling into the study, can you talk more about what you'd expect in the control arm, during the 12-week treatment period? For any efficacy that you see during the 12 weeks, would you expect that to hold up during the four weeks follow-up?
Sure. This is Brian. Thank you for the question. I'm actually going to refer that question to Dr. Bhisitkul in terms of addressing the kind of expected natural history in the untreated C5 use over the 12-week treatment duration.
Yeah. The question is about, you know, over a relatively short term of three months for this study where the patients are not receiving any on-protocol anti-VEGF therapy. You know, what is the expected course both for the control arm, and for the RZ402 arms? Really, what's the expected natural course? You know, over three months, you would expect that some portion of these patients without receiving any treatment who already have diabetic macular edema are going to have worsening even over that relatively short period of three months. Not all patients, it'll be interesting to look at the percentage of patients that worsen in the control group versus the two treatment arms.
Got it. That makes sense. Then also, if you do I think Dr. Raj Agrawal mentioned that stabilization could be an outcome, could be something that you're interested in seeing as well. If you do see stabilization and maybe not a lot of difference between the control arm and the treatment arm, could there be success on other exploratory outcomes like you mentioned the eGFR and microalbuminuria? Could you potentially win on some of those exploratory measures, and how do you think about that?
This is Brian. I'll start. Then Dr. Bhisitkul and Dr. Agrawal can supplement as necessary. I would say that those parameters are exploratory, and this is not, you know, a renal program, so those may be informative for future studies. We wouldn't consider that victory for the eye indication if those were the only things we saw. Those will certainly be reflective of kind of a comprehensive review of the data, as was mentioned in the presentation. I would say, though, that in terms of lack of progression, we would expect to show a difference from the untreated group. In other words, some measure of progression in the untreated group while the RZ402 treated groups are stable. That's what Dr.
Agrawal highlighted in terms of a difference between the RZ402 treated groups and the placebo groups, whether it be the anatomic change on CST or the visual acuity on the BCVA endpoint.
Got it. That makes sense. I'll ask one more question and then hop back in the queue. I think you mentioned that RZ402 could bathe the systemic vasculature wall, and you showed some data that it enriches in the vascular spaces. Can you talk a little bit more about whether this is a unique attribute of RZ402 relative to systemic kallikrein inhibitors approved for HAE, whether oral or injectable?
I'm gonna ask Dr. Breit to comment on the physical properties of the compound and how that may be a unique attribute of RZ402.
That's great. That's great. Thanks. When thinking about this compound, as mentioned in the head group, it has a benzamide and pKa. Under neutral conditions, we have a fairly high positive pKa, high positive charge. As a result, you know, that sort of feeds into that data you saw from a distribution standpoint in various tissues which align with vessel density in the tissue. We think that's really a property, a physical property-aspect of RZ402 more than anything else. I think that's beneficial as far as where public health results residing, which is based in membrane at the cell junctions, those areas which is sort of where the target is in particular, as was mentioned earlier.
Thanks, Jeff. The only thing I would add to that in addition to the distinct physical properties, we do know that other plasma kallikrein inhibitors used for other indications, in the past, sometimes their in vitro potency has not translated well into clinical efficacy against the target. That might also suggest that from a physical property perspective, that those unique aspects, you know, translate more in vivo.
Got it. Makes sense. All very helpful. Thanks for taking my questions.
The next question will come from Pete Stavropoulos with Cantor Fitzgerald. Please go ahead.
Hi, thank you for holding this call. Very informative. First question for Dr. Bhisitkul. When you look at the diabetic retinopathy, you know, preferred practice pattern guidelines by the American Academy of Ophthalmology, you know, and in particular, when you look at a table, which I'm sure you're familiar with, that provides initial management recommendations, you know, for patients with diabetes. You know, you see that for non-center involved DME, anti-VEGF agents are not recommended for mild non-proliferative diabetic retinopathy, you know, all the way to use, you know, sometimes used in progressive diabetic retinopathy. My question is just for those patients alone, the non-center involved DME, what drives the decision to not use anti-VEGF?
Could an oral agent like RZ402 usher in a new paradigm treatment for that particular patient population?
Yeah, I really like this question. One of the reasons I like it is it's one of the things that we thought about as designing this clinical trial is to actually target those patients that aren't candidates for anti-VEGF, and that being the diabetic macular edema that's not central. I think this, the way this study is set up is ended up being good because it gives us a good common patient population that'll accelerate the recruitment. These patients are in their fairly early stages of diabetic macular edema. You know, it's where we expect the disease to be a little bit more dynamic and responsive.
Now, your other question I like also, and this is sort of, you know, what options do we have for patients with non-central diabetic macular edema right now in the clinic, in the real world? The truth is, if we can find an excuse to not treat a patient with anti-VEGF, we take it. Okay? For those patients right now, we are doing observation, which is another word for saying, doing nothing. We just check them back on a four-month or six-month basis, monitoring for the worsening.
If I had a drug that was safe and beneficial and can be taken as an oral drug, I would see this as a very interesting patient population to initiate that non-invasive therapy at this very early stage of the disease and maybe prevent it from ever getting to the central diabetic macular edema and the vision loss that we know is more risky for the patient.
Okay. Can you, possibly suggest the proportion of patients that have non-central that actually become central, as time progresses, as disease progresses?
This is just, you know, going totally by my gut feeling of what I see in the clinic, but I'd say, you know, at least 50% of the patients that come in this, that have diabetic macular edema, it's non-central. You know, we pick these patients up on screening visits because they don't have any vision problems. They're not coming in because they're losing vision. They're coming in because they're getting their once a year check, or their internist has sent them in to get an eye check. We find on the OCT or on the clinical exam that they do have some diabetic macular edema that's not affecting their central vision yet.
You know, it's just my gut feeling and informal way of estimating it, but I'd say about half the DME patients that I see, it'll be non-central. That's very different from the percentage of patients that we're treating, of course.
Thank you. Very informative. A question for Brian or Raj. You know, for the study, you know, will you focus in on certain patient populations, measured by some type of scale, like the diabetic retinopathy severity scale, you know, to sort of differentiate proliferative from non-proliferative? Because it's my understanding that DME, you know, could occur at any stage of diabetic retinopathy. You know, will you focus in a particular stage of disease?
Yeah. Hi, Pete. Thanks for your questions. I'm gonna ask Dr. Raj to go ahead and respond to that.
Sure. Thanks, Pete, for that question. You know, right now in this study, we are focused on patients who have non-proliferative diabetic retinopathy, early stage disease. The fact that, you know, I think I mentioned in my talk earlier that we don't expect a significant change in DRSS, specifically in this study, primarily because it's a short-term study. That's a good point that we keep in the back of our minds as we move forward, because DRSS change would potentially be helpful for us in terms of getting an additional indication if need be over time.
For this particular study, because we focused on early stage disease, we, I mean, it'll be great if we see some change in DRSS, but it might be difficult to see from the perspective of the outcome study.
All right. Thank you. The last question is, you know, taking into consideration the mechanism of action of 402, can you see it being leveraged in other ophthalmological indications?
I'll also ask, Dr. Agrawal to comment as to whether there may be expanded indications, within ophthalmology.
Again, that's a great question, Pete. Obviously, as I mentioned earlier, we are looking at, we would potentially consider diabetic retinopathy as an additional indication over time. That's definitely one close indication, if I may, to DME. Also, PKI has shown some benefit in animal studies in terms of being a focus for inflammation in the eye, conditions of that nature. There is a likelihood for us to get some pathway to showcase some benefit in those conditions. Obviously, that's for later stage. Right now we want to have, you know, as I mentioned, as everybody has kind of alluded to, we want to get a signal in this particular study.
Based on the outcome from this study, we'll continue to monitor and add potential indications as we move forward.
All right. Thank you very much for, taking my questions.
Thank you.
Again, if you have a question, please press star then one. Our next question will come from Jason Butler with JMP Securities. Please go ahead.
Hey, it's Roy in for Jason. Thanks for taking the questions. I guess to follow up on the, on the patient population question. A couple for Dr. Bhisitkul. Just the lower severity patients that are gonna be studied in this phase II, based on your gut again, I guess, what proportion of the overall DME population do you expect that represents? What's a typical time from diagnosis of diabetes to develop DME in a patient that does? Do you think, maybe going a little bit out on a limb or in the future, but does it make sense to use a drug like RZ402 potentially before, you know, any vision loss and even just after they've been diagnosed with diabetes or something like that? I have a couple for the company.
Yeah, I like your third point a lot, you know. That is a very aspirational indication, the patient, the population of patients with diabetes, whether they have any diabetic retinopathy or not, could this be an early intervention, a preventative drug that can be taken orally, it's safe, it will be sort of like starting them on metformin, and you treat, you know, the overall diabetes population with the goal of reducing the fraction of those patients that will develop, you know, retinopathy and vision loss associated with retinal complications like DME. I like that one. That's very aspirational. The other one is that the, you know, we don't have to wait for diabetic macular edema, we don't have to wait for non-central diabetic macular edema.
Maybe patients with a certain level of just background diabetic retinopathy or non-proliferative diabetic retinopathy, we could capture that whole population, again, take the higher risk group and prevent them from going to more advanced forms of diabetic retinopathy and DME. I like both of those ideas. Again, a safe oral drug allows us to begin thinking about those things, as opposed to monthly needle injections into the eyeball. You know, you can't be so proactive when that's your administration route. I think your earlier question was what % of patients fall into the category of this early stage diabetic macular edema?
Yes, correct.
Yes. Yeah. You, yeah. You know, well, first of all, you have the overall percentage of patients with diabetic retinopathy with no diabetic macular edema. You know that's gonna be 90% of the patients that we see in screen. Of the patients that have some DME but it's not affecting their vision and it's not central yet, you know, again, this is an informal estimate, but I'd say in my screenings it's about 50% of them that will need treatment when they have diabetic macular edema because it's central. Another 50% that I can sort of wait and watch, and see them back again in six months.
I think, again, the question is how long does it take-?
Oh, yeah.
-actually?
Yeah. The second question was, with the diagnosis of diabetes, how long does it take to begin affecting the eye? Some of the numbers that have been shown out there in previous studies have shown, you know, after seven years of the disease, some percentage, I think it's something like 70% of the patients will develop some level of diabetic retinopathy. Once you develop diabetic retinopathy, what percentage of those patients will develop DME? There I don't have solid numbers from the literature, although I'm sure they exist. I think, again, it's gonna be a double-digit percentage of those patients over, say, five or 10 years.
Okay, great. Thank you. Then I-
Maybe, maybe Roy, I would add, this is Brian. Although, when those numbers are quoted in terms of how the percent break down between central and sort of non-central or earlier DME, it's a cross-section, keep in mind. With proper screening, you need all patients, 100% of patients could be identified upstream and early. I think you have to think about it too in terms of how these patients are screened, and when you intervene. If you can intervene earlier, in theory, and this is aspirational as Dr. Bhisitkul said, you can capture many, many more of those patients potentially.
Yeah. I mean, on that, we think there are a lot of patients floating around out there in the world that have diabetic macular edema that's significant.
Because they can compensate with their other eye or just because they're not attuned to their vision symptoms, they're not getting in to see us. They're not getting in to see the optometrist, they're not getting in to see the general ophthalmologist, and they're not getting in to see us as retina specialists. Again, if we can capture more of those patients with a less invasive, with a less invasive approach, we have a way of benefiting a larger population.
Okay, great. Thank you. Then I had a couple more probably for the company. Just wanna make sure I understand the fellow eye and the study eye. The fellow eye is standard of care as this is not being treated with 402, is that correct? The rescue really only applies to the study eye. I guess I'm How likely do you think it's gonna be that you get actually a potentially combo data with the VEGF and the fellow eye in this study? Then I just.
Yeah. Thanks, Roy.
want to be clear what... Okay, go ahead. I have one more.
Yeah, I can respond, and Raj can add to that. Both eyes are, of course, being exposed because it's an oral therapy which gets in the bloodstream. Both eyes are seeing an equivalent amount of RZ402. Only one eye needs to qualify, meet our entry criteria based on CST and BCVA for the study. We identify one study eye, if you will, which is more controlled, meaning, the rescue parameters that Dr. Raj Agrawal went to really apply to that eye, and that's the eye that is the, you know, primary analysis for the key, you know, endpoints across the study. Naturally, the second eye, or what we call the fellow eye, is getting equally exposed to RZ402.
Although, we are, you know, not quite as rigorous with in terms of that eye being managed by standard of care, it can continue to get VEGF therapies over the course of study at the discretion of the investigator. We nevertheless may see some, you know, secondary benefits. Every endpoint that we're looking at for the qualified study eye, we can apply to the non-study eye. You know, depending on sort of the baseline characteristics of that non-study eye, it's possible we may see some, ancillary effects there.
just to add to that.
Okay.
Just to add to that, this is Raj. The issue is, you know, in most patients when they present to the clinic, the two eyes have differing, you know, presentations of the disease, so they may not be similar in most cases. We have to choose the eye that potentially will showcase some benefit. If it's really, let's say, the eye is really badly damaged, so to speak, with diabetic macular edema or diabetic retinopathy, then obviously, you know, it'll be tough for us to include that patient in the study. The other eye potentially can fall into the criteria. As I mentioned earlier, we are looking at early-stage disease, that's the reason why we are choosing a study eye.
We have to define the study eye, as you know, in terms of the clinical pathway, and so, the fellow eye, the non-study eye, is being managed by the investigators as per their discussion.
Okay. I mean, that strikes me as a potentially second way to win. If you see amazing results in patients that are getting VEGF as well as 402, maybe something interesting there. Anyway.
We agree with you, Willie. Yep.
Okay. Then just on the kind of patients that you're getting, it sounds like, you know, you're getting these patients that are not on VEGF or limited VEGF. Is it mostly patients that are afraid of injections, don't wanna do the injections? You know, it sounds like DME, not central, is another criteria. What do you expect the breakdown of the patients that you're gonna get in the trial to mostly be? Thanks.
We're actually, we've kind of predefined a cap to the patients who have had previous VEGF exposure. The majority of patients in the trial will be treatment-naive. The reasons for that won't necessarily be clear to us whether they're newly presenting patients or whether they're patients who are relatively advanced with central DME who otherwise meet the criteria but have refused VEGF therapy. It could be a mixed group there, in terms of, you know, why they haven't gotten VEGF before. The other approximately third of the patients, no more than one-third could have received up to three previous injections of VEGF. You know, they likely fit the category, as Dr. Bhisitkul talked about, of having central DME presenting with some visual changes.
You know, those patients have just started VEGF. It's not to say that they've not responded. In fact, that's the population that we're trying to avoid. They either will, you know, jump at the chance to enter a trial and try something else because they're earlier in their treatment. Or, you know, have gotten a couple injections and aren't finding, you know, benefit yet.
Okay, great. Thanks for taking the call.
Of course.
This concludes our question-and-answer session as well as our conference call for today. Thank you for attending today's presentation. You may now disconnect.