Surrozen, Inc./DE — Call Transcript 2025

Good morning, everyone. Welcome to Guggenheim Healthcare Innovation Conference. My name is Yatin Suneja, one of the senior biotech analysts here at the firm. It is my pleasure to welcome our next presenting company, Surrozen. From the company, we have two executives here. We have Craig Parker, who's the Chief Executive Officer, and we have Chuck Williams, who used to be CFO, but he took a new role here. Gentlemen, thank you so much for your time. Craig, why don't you maybe make some opening comments? Tell us about the story of Surrozen, where you are, what you're doing, what are some of the key milestones that we should be focusing on, and then we'll go into the Q&A that I have prepared for you. Okay, great. I mean, we have an hour, right? Yes, we'll try. Thanks, everyone, for being here. Thanks for the invitation to participate in the conference. Surrozen was founded in 2016 by the scientific luminaries in the field of Wnt biology. I'll tell you a little bit more about what that is. The company was started on some breakthroughs that really opened the opportunity to activate this pathway for tissue regeneration with multispecific antibodies. Now, the Wnt pathway, it stands for Wingless and Integrated One Site, is really one of the fundamental pathways in cell biology that's involved with stem cell renewal, cell fate, tissue organization, and importantly, for therapeutics, tissue homeostasis or regeneration or response to injury. This pathway has been known for some time to be potentially a really exciting therapeutic target for a number of reasons we don't have time to go into. It's been very difficult to drug, but a key breakthrough in some of the structural biology around the pathway and the receptors and ligands led to the formation of the company and this concept of being able to activate the pathway with multispecific antibodies that bind some of the signaling receptors that are involved in the pathway. There are many, many different tissue types where Wnt is known to play a critical role. We're now exclusively in ophthalmology for a number of reasons. One, there's clinical proof of concept that activating the pathway has a large clinical benefit. Merck acquired a molecule that was our one direct competitor several years ago that's had some compelling clinical proof of concept data in diabetic macular edema. Indeed, the magnitude of that benefit activating Wnt signaling is about as large as with VEGF inhibition, like with Eylea. Really, no other single mechanism has been able to achieve that magnitude of benefit. IL-6 alone, Ang-2 alone, some of these other targets that have been combined do not really do as much as Wnt seems to. We have these multispecific antibodies now that both combine activating this key pathway, Wnt, with inhibiting other pathways that we know are contributors to the pathology of retinopathies like VEGF and IL-6. It is probably worth also highlighting this is one of the few areas in Wnt biology where there is really important genetic evidence of the role of this pathway in disease. There is a set of very rare childhood diseases that are mutations in Wnt signaling where kids are born with, it is very heterogeneous, but some of them are born with actually vision loss and retinas that look like the retina of a 70-year-old with wet AMD. We know that Frizzled is critical for the retinal vascular function and integrity, which is why we and others have targeted it for retinopathies. Got it. Very helpful. Thank you for that context. Maybe just on a high level, you mentioned that this is a pathway which is difficult to drug. I think particularly there have been some challenges around safety. What is your approach to addressing some of the challenges of Wnt agonist therapy? There actually is a Wnt agonist on the market today which is extraordinarily safe. It is a bone-selective Wnt agonist. It is an Amgen molecule called Evenity or Romosozumab. It is approved for postmenopausal osteoporosis. It actually builds bone, so it is an anabolic agent, and it is extraordinarily safe. There have not actually been clinical safety signals with the few Wnt agonists that in this case are either on the market or have been in clinical trials. Merck did not disclose any really notable safety issues with their intravitreal injection of a Wnt agonist. Also, just the fact of giving an intravitreal injection versus a systemic injection is a theoretical way to, if there were systemic liabilities, to manage those liabilities because the drug, while it leaks out of the eye over time, is largely, in terms of the concentration, only high when it is in the eye. Got it. I mean, we do observe that there is an excitement around Wnt biology, specifically as it relates to retinal disease, as you mentioned, or Merck. Roche is also in the program. Can you maybe contextualize for us at least what we have seen at clinical level and preclinical level from your competitor, and how does that make you either more comfortable or more confident in going into some of these retinal diseases? Yeah. As I mentioned, I think it really starts in terms of the biology story with the human genetics, that this pathway is critical to the function and structure of the retinal vasculature. What we've seen preclinically, and it's very differentiated from other approaches like VEGF or IL-6 or Ang-2 preclinically, these are mouse models of retinopathy. What we see is not only that you can prevent vessel leakage, which is what VEGF inhibition does, but we can normalize the retinal vessels in parts of the eye that can become ischemic or are missing vessels in these mouse models. If you talk to people in the field today and say, "What's the way to really differentiate a molecule in multiple retinopathies?" people tell you, "It's drying the retina," which is, if you could normalize the vasculature, you shouldn't have any leakage. It's both directly blocking the leakage that we see preclinically and also potentially this normalization of vessels. That's what we see preclinically. The inventor of the Merck molecule did not publish any data. With that actual molecule, they published with a precursor tool molecule. They did not have nearly the magnitude of effect on those as we've had in preclinical models. Clinically, what we've seen from Merck is what looks to be a VEGF-like clinical benefit in visual acuity and in something called central subfield thickness, which is a measurement of fluid in the retina. It seems to have a VEGF-like benefit on visual acuity, a VEGF-like benefit on drying. I mean, that's in a very small set of diabetic macular edema patients. Thank you. Maybe going back to the preclinical comment you made, what are these models? Are these the OIR model and the CNV model? Yes. How good are they from a translation perspective into human? I mean, I think you have to be cautious in stating categorically that any animal model is translational or is translatable to human data. What we know is Eylea, for example, works in both these models. I'll tell you a little bit more about the multiple models that we've looked at. Works in those models, works in humans. IL-6, it's difficult to say that because it doesn't cross-react with mouse IL-6, most people's IL-6 antibodies. These are models of either more of a diabetic macular edema phenotype or a wet AMD phenotype. There is something called oxygen-induced retinopathy. You expose the mice to high oxygen concentration, then you lower the oxygen concentration. It creates a diabetic macular edema-like phenotype. It is thought to more closely be translatable to DME. In this model, we actually see synergy of our molecule, which is combining VEGF inhibition with Wnt agonism, synergy compared to just Eylea alone or just Wnt alone. Something about combining those pathways into a single molecule seems to confer about tenfold greater potency. That is a DME model. We have done multiple versions of that. I will not go into the details where you can treat later, allow the disease in the animal to be more progressed or more damage or more leakage. We still see a large benefit that is greater than you can achieve with Wnt agonism alone or VEGF inhibition alone. There is a model that is more translatable to wet AMD, which, as you mentioned, is a CNV. We have done two versions of that. You can laser the back of the eye. There is actually a spontaneous mouse model that develops CNV, and we have done that. We have done similar to OIR where you look early, treat early, and then look later, treat later, trying to mimic a more advanced stage of disease or a more progressive stage of disease. In those, we have a larger treatment effect than Eylea alone. Got it. So one more high-level question, then I'll go into your programs. In terms of the biology for Wnt, the matrix or Wnt agonist, is it more sensitive to one type of a retinal disease, let's say DME versus AMD? Where are you on that? Because I think the data that we are seeing, at least in the clinic, seems to be pointing more towards DME. Yeah. We still see a large treatment effect in both models. I think the field, and the field right now is us, Merck, and probably Roche, but I think the field has prioritized DME over wet AMD because there is just a clearer line of the biology in retinal vessels than there is in what are called choroidal vessels. If you think about the back of the retina, the retinal vessels are parallel to the back of the retina. The choroidal vessels penetrate down into the layer where the photoreceptors reside. Those choroidal vessels do not actually have their own tight junctions. One of the effects of Wnt biology is to upregulate tight junction proteins like Zo1. We do see an effect in the choroid. It is called the choriocapillaris, but it is probably mediated by other cell types like RPE cells, for example. The biology is just really, really clear-cut in retinal vessels. That's why the field has prioritized DME. As you probably know, Merck has started a wet AMD study. There's no reason to not pursue wet AMD. The biology is, I would just say, a little maybe one cell type removed from the actual vessel. Got it. Got it. Very helpful. Now tell us about the assets that you have, your molecule. You have a partnership with Boehringer Ingelheim. I think they are supposed to file an IND relatively soon. What have you done for that molecule? How is that molecule differentiated with the two molecules that you have that you're holding on? The molecule we licensed to BI, I would say, looks to be a better version of RESTRA, the Merck molecule. The pharmacology is similar. It binds the same receptors. I will not go into the people always ask about the epitopes there. We do not think it really matters much. In vitro, the BI molecule is about twice as potent in activating Wnt signaling as RESTRA. Does that mean it is going to be clinically different? We do not know that. That is the principal difference between what we licensed to BI and RESTRA, potency in activating Wnt signaling. That is just the Wnt business end of our molecule. Our molecule 8141 combines that actual sequence that we licensed to BI with VEGF trap sequences. It is multifunctional. It is inhibiting VEGF and activating Wnt signaling. It's activating Wnt signaling with the same targets and the same potency as the BI molecule, which again is more than RESTRA and has the VEGF inhibition and has another modification that were there to be any systemic liabilities or toxicities, we would have mitigated because we put a mutation in a portion that's called the FcRn portion that accelerates the clearance from the circulation. Faricimab has the same sequence. Okay. Good. What work you did on the BI, and where is that partnership? Are you doing any work? I mean, they are your competitor, or you are their competitor now? Maybe I'll let Chuck address that. Yeah. The initial phase of the collaboration ended when they nominated a lead candidate last year. Now it's just a straight-out license. In terms of where they are and the type of information we get from them, it's pretty limited. We obviously do compete with them. It's not entirely clear when they might initiate a phase one clinical trial. Got it. Just simplistically looking, Boehringer Ingelheim has basically a better version of Merck molecule. You have what Boehringer Ingelheim have, but added on top of it is the trap and maybe IL-6 and some mutations. Correct. Okay. We have shown preclinically that there is synergy in combining those into one molecule because we get asked, "Why would not a patient potentially just get RESTRA, the Merck molecule, plus an injection of Eylea, for example?" Yeah. We have done that experiment in the mouse. First of all, the patients are not going to want that in multiple injections at the same time. We have done that experiment in the mouse model. We are not sure the mechanism behind this, but doing it all with one molecule is better than giving separate injections in the same mouse eye of Eylea plus 413. Absolutely. I think you're going after Wnt biology, which is obviously a little bit novel here. VEGF is very well understood, but I think we are seeing a little bit more data on the IL-6 side. Could you put that data in context, what you're seeing, because you do incorporate IL-6 in one of your assets? Yeah. Yeah. Our next molecule after 8141 is 8143, which is trifunctional. It is Wnt agonism, VEGF inhibition, IL-6 inhibition. The data you're referring to, I think, is the Roche DME data with a combination of IL-6 plus a separate VEGF injection in DME. We can talk about UME separately. In DME, we are really encouraged that there's clearly an additive benefit with multiple mechanisms. I think faricimab was some evidence of that. I think if you look at the data, which you can access on ClinTrials now for that DME study, there's very convincing additive benefit on visual acuity and retinal drying in both treatment experienced and treatment naive DME patients. I think that's our approach is obviously to see that additive benefit with multiple mechanisms. We're really seeing that now come true in the clinic with IL-6. Now, IL-6 alone doesn't seem to do much. So we're really encouraged that Wnt alone does as much as VEGF alone. VEGF plus IL-6 does more than just VEGF. So it's just sort of first-order logic now. We're obviously hopeful that Wnt, which has VEGF-like monoactivity and VEGF, will have an even greater additive benefit than some other combinations like VEGF and IL-6. Got it. Got it. Very good. For your two molecules, 8141 and 8143, where exactly are you? Which one is more advanced? When should we expect an IND? What preclinical work do you still need to do in order to facilitate an IND? 8143 is months behind 8141. It's not a year behind, but we haven't given any precise guidance on the interval between those. We've said that we'll file an IND for 8141, Wnt, VEGF in 2026. When we get closer and have a more precise date, we'll update that guidance. We're doing all the typical with 8141, CMC scale-up and toxicology sort of activities right now. We haven't given any more details on the timing of that. Okay. IND next year, at least for 8141. How should we think about your strategy? What type of patients you will go after first? Would you run a study where you actually end up getting both DME and AMD and also talk about the injection frequency? Yeah. So I think we would, we'll give more details on the actual protocol and trial design, but I think likely do both DME and wet AMD. We're still discussing with our clinical advisors, do you just do treatment naive patients because it's a little easier to interpret the data because it's pretty well known how they should respond, like to Eylea, for example. You can do a cross-study comparison, but that's still to be determined whether we do maybe some treatment experienced patients in that. It's likely both DME and wet AMD in a phase one B2A, not unlike what others like IBIO have done. Yeah. I see. Frequency, we do not know all the PK right now. I'd say we have a pretty good idea that we will not need to be more frequent than every other month. I do not know that there is a benefit ultimately to being like every four months or less frequent because the retinal specialists want to see patients more frequently than that. I think 8-12 weeks is probably the sweet spot. Doing a Vabysmo-like study is probably the right phase three where you give people a range of dosing frequency depending on how dry the retina is, and you get reimbursed for all those, which is key. Yeah. I think if you can push the efficacy, I think even the eight week would be fine because I think in this disease category, we have just seen the plateau with almost every new mechanism right now. You still get VEGF-like. Okay. In terms of the, so you go into these two areas, but most likely next year, right? We're going to get data from hopefully Merck. They're running two studies, Brunello and Barolo. They're both good wines. Next year, what would be your expectations for? I'm trying to figure out how you one-up Italian wine names for your study acronym. There is another company that has, they're running four phase three studies, all are Italian names, but they're by cities. I point, I follow them, Como, Capri, Lugano, Lucia. I don't know why. What's the Italian angle here? I don't know. Yeah. What would be your expectation? Because that for sure will have read-through with the whole Wnt biology space. Yeah. I mean, maybe first and foremost, we're obviously hopeful that there's really excellent safety with agonizing Wnt in the eye. There didn't seem to be any safety signal in the IBIO phase I/II, but that was a limited experience, something like 30 patients total for a couple of months. The requirement for any intravitreal injection for these diseases is exceptional safety, right? You can't have endophthalmitis or other serious complications or retinal vasculitis. I think having VEGF-like efficacy would be really encouraging. Again, we think there's a good argument for an additive benefit. With Wnt alone, if you can get VEGF-like efficacy, I still think that leaves an opportunity for improvement. It could be the improvement is on drying. It could be that it's on visual acuity. I think if you ask a retinal specialist, they would say, "Don't have high expectations that you can improve visual acuity anymore," but no one's had any kind of an additive effect yet, so. What is the frequency of RESTRA? Monthly. That'd be monthly. We think that that's limited by how they can concentrate it. There is just a simple math challenge with intravitreal injections, which is you can only put about 50-70 microliters in the eye without potentially damaging the eye or causing an increase in intraocular pressure. If you calculate what is required for the concentration of your drug, it has to be about 100 ml per ml. If you have like a typical IV injection for an oncology ADC, for example, people are doing like 15 ml per mil. This is like very highly concentrated protein, and not all proteins can be stable at that concentration. We think because we have made RESTRA, that might be one of the limitations that they have experienced is they just cannot concentrate it enough to put more in the eye. They have to give a monthly injection. Very interesting. What are you hearing from physicians or the expert as it relates to either, as it relates to the Wnt biology? What is the feedback? I think we have a really great opportunity to convey that we are really the scientific experts in this field. No one's really tried to do that with any of the KOLs yet. We are. We were founded by two scientists who won the Breakthrough Prize in Life Sciences for Wnt biology, a Nobel laureate. I think we've got good cred and chops to be the scientific experts for Wnt. I think there's a great opportunity to reinforce that. There's awareness of the pathway, but not knowledge of the pathway, which I think is also a great opportunity for us to educate people on the role of the pathway in the retina. In terms of the clinical benefit they would like to see from a novel mechanism, I think it's good retinal drying. You'll hear people refer to this as an anatomic effect. It can be measured by central subfield thickness. It can be measured by a % of patients with no intraretinal or subretinal fluid. That's where faricimab has done well. I think there's still headroom for improvement. I think most retinal specialists would tell you that, that not everyone responds to VEGF inhibition or Ang-2, and you can do better drying the retina. The belief is ultimately that's going to translate to visual acuity benefits or preserving vision, visual function. That's where our mechanism, I think, plays well. What we see preclinically is this normalization of the retinal vasculature, reduction of areas of non-perfusion, no pathologic leaky vessels. Hopefully, that connection will be true in humans. Yeah. Yeah. One clarification. The IND that you're filing is in the U.S. for next year, or? Yes. Okay. Maybe a couple of questions for Chuck. In your new role, what are some of the things that you are thinking about or that you will be doing? If you also can touch on the IP. Yeah, sure. I think in terms of some of the enterprise strategy, in terms of what indications and how to co-position 8143 and 8141, I mean, one of the things we're thinking about while we haven't finalized these plans for 8143 is do we do an initial indication in MESI? Because one, it's a more streamlined development pathway, and two, it's a shorter endpoint, six months. Presumably you could catch up with 8143. In the context of having seen the Roche data, VEGF, IL-6 combination, it does give us, it's really encouraging to see that the combination of those two is better than VEGF alone. That we have to take into consideration. Your second question around IP. We were issued, so we've been issued a patent in the US, Europe, and Japan that claims multivalent antibodies targeting Frizzled LRP5 or 6. The reason that's important is it's a fairly broad patent that would actually, where Merck and Roche would be infringing. In fact, post the Merck acquisition, the patent office cited this application at the time of ours as prior art. We have a pretty good intellectual property position as we've been the leaders in the field. We were the first to file. We'll see how that plays out over time with our competitors of Merck and Roche and any others that might be working in this field. Great. Maybe final question. How is the cash position, burn rate, and the funding? Sure. So we did a $175 million pipe earlier this year, split into two tranches. The first tranche of about $75 million gets us a couple of quarters post having the IND clearance. The second tranche of approximately $100 million would get us some cushion post having reported out data for both 8141 and 8143 in the phase one B2A studies that we plan to conduct. Got it. Maybe final question. To the best of your understanding, the RESTRA, Brunello, and Barolo studies are reading out next year. Yes. We understand that it's probably Q3 is what we've been hearing for the first one. For the first one. Okay. Yes. They probably will read out the wet AMD study next year as well because they just initiated that. Got it. Got it. Very good, gentlemen. Thank you so much. Thanks for having me. Appreciate it. Thank you.

Speaker 2: Good morning, everyone. Welcome to Guggenheim Healthcare Innovation Conference. My name is Yatin Suneja, one of the senior biotech analysts here at the firm. It is my pleasure to welcome our next presenting company, Surrozen. From the company, we have two executives here. We have Craig Parker, who's the Chief Executive Officer, and we have Chuck Williams, who used to be CFO, but he took a new role here. Gentlemen, thank you so much for your time. Craig, why don't you maybe make some opening comments? Tell us about the story of Surrozen, where you are, what you're doing, what are some of the key milestones that we should be focusing on, and then we'll go into the Q&A that I have prepared for you. Good morning, everyone. good morning everyone Welcome to Guggenheim Healthcare Innovation Conference. welcome to guggenheim healthcare innovation conference My name is Yatin Suneja, one of the senior biotech analysts here at the firm. my name is yatin suneja one of the senior biotech analysts here at the firm It is my pleasure to welcome our next presenting company, Surrozen. it is my pleasure to welcome our next presenting company surrozen From the company, we have two executives here. from the company we have two executives here We have Craig Parker, who's the Chief Executive Officer, and we have Chuck Williams, who used to be CFO, but he took a new role here. we have craig parker who's the chief executive officer and we have chuck williams who used to be cfo but he took a new role here Gentlemen, thank you so much for your time. gentlemen thank you so much for your time Craig, why don't you maybe make some opening comments? craig why don't you maybe make some opening comments Tell us about the story of Surrozen, where you are, what you're doing, what are some of the key milestones that we should be focusing on, and then we'll go into the Q&A that I have prepared for you. tell us about the story of surrozen where you are what you're doing what are some of the key milestones that we should be focusing on and then we'll go into the q&a that i have prepared for you

Speaker 1: Okay, great. I mean, we have an hour, right? Okay, great. okay great I mean, we have an hour, right? i mean we have an hour right

Speaker 2: Yes, we'll try. Yes, we'll try. yes we'll try

Speaker 1: Thanks, everyone, for being here. Thanks for the invitation to participate in the conference. Surrozen was founded in 2016 by the scientific luminaries in the field of Wnt biology. I'll tell you a little bit more about what that is. The company was started on some breakthroughs that really opened the opportunity to activate this pathway for tissue regeneration with multispecific antibodies. Now, the Wnt pathway, it stands for Wingless and Integrated One Site, is really one of the fundamental pathways in cell biology that's involved with stem cell renewal, cell fate, tissue organization, and importantly, for therapeutics, tissue homeostasis or regeneration or response to injury. This pathway has been known for some time to be potentially a really exciting therapeutic target for a number of reasons we don't have time to go into. Thanks, everyone, for being here. thanks everyone for being here Thanks for the invitation to participate in the conference. thanks for the invitation to participate in the conference Surrozen was founded in 2016 by the scientific luminaries in the field of Wnt biology. surrozen was founded in 2016 by the scientific luminaries in the field of wnt biology I'll tell you a little bit more about what that is. i'll tell you a little bit more about what that is The company was started on some breakthroughs that really opened the opportunity to activate this pathway for tissue regeneration with multispecific antibodies. the company was started on some breakthroughs that really opened the opportunity to activate this pathway for tissue regeneration with multispecific antibodies Now, the Wnt pathway, it stands for Wingless and Integrated One Site, is really one of the fundamental pathways in cell biology that's involved with stem cell renewal, cell fate, tissue organization, and importantly, for therapeutics, tissue homeostasis or regeneration or response to injury. now the wnt pathway it stands for wingless and integrated one site is really one of the fundamental pathways in cell biology that's involved with stem cell renewal cell fate tissue organization and importantly for therapeutics tissue homeostasis or regeneration or response to injury This pathway has been known for some time to be potentially a really exciting therapeutic target for a number of reasons we don't have time to go into. this pathway has been known for some time to be potentially a really exciting therapeutic target for a number of reasons we don't have time to go into It's been very difficult to drug, but a key breakthrough in some of the structural biology around the pathway and the receptors and ligands led to the formation of the company and this concept of being able to activate the pathway with multispecific antibodies that bind some of the signaling receptors that are involved in the pathway. There are many, many different tissue types where Wnt is known to play a critical role. We're now exclusively in ophthalmology for a number of reasons. One, there's clinical proof of concept that activating the pathway has a large clinical benefit. Merck acquired a molecule that was our one direct competitor several years ago that's had some compelling clinical proof of concept data in diabetic macular edema. Indeed, the magnitude of that benefit activating Wnt signaling is about as large as with VEGF inhibition, like with Eylea. It's been very difficult to drug, but a key breakthrough in some of the structural biology around the pathway and the receptors and ligands led to the formation of the company and this concept of being able to activate the pathway with multispecific antibodies that bind some of the signaling receptors that are involved in the pathway. it's been very difficult to drug but a key breakthrough in some of the structural biology around the pathway and the receptors and ligands led to the formation of the company and this concept of being able to activate the pathway with multispecific antibodies that bind some of the signaling receptors that are involved in the pathway There are many, many different tissue types where Wnt is known to play a critical role. there are many many different tissue types where wnt is known to play a critical role We're now exclusively in ophthalmology for a number of reasons. we're now exclusively in ophthalmology for a number of reasons One, there's clinical proof of concept that activating the pathway has a large clinical benefit. one there's clinical proof of concept that activating the pathway has a large clinical benefit Merck acquired a molecule that was our one direct competitor several years ago that's had some compelling clinical proof of concept data in diabetic macular edema. merck acquired a molecule that was our one direct competitor several years ago that's had some compelling clinical proof of concept data in diabetic macular edema Indeed, the magnitude of that benefit activating Wnt signaling is about as large as with VEGF inhibition, like with Eylea. indeed the magnitude of that benefit activating wnt signaling is about as large as with vegf inhibition like with eylea Really, no other single mechanism has been able to achieve that magnitude of benefit. IL-6 alone, Ang-2 alone, some of these other targets that have been combined do not really do as much as Wnt seems to. We have these multispecific antibodies now that both combine activating this key pathway, Wnt, with inhibiting other pathways that we know are contributors to the pathology of retinopathies like VEGF and IL-6. It is probably worth also highlighting this is one of the few areas in Wnt biology where there is really important genetic evidence of the role of this pathway in disease. There is a set of very rare childhood diseases that are mutations in Wnt signaling where kids are born with, it is very heterogeneous, but some of them are born with actually vision loss and retinas that look like the retina of a 70-year-old with wet AMD. Really, no other single mechanism has been able to achieve that magnitude of benefit. really no other single mechanism has been able to achieve that magnitude of benefit IL-6 alone, Ang-2 alone, some of these other targets that have been combined do not really do as much as Wnt seems to. il-6 alone ang-2 alone some of these other targets that have been combined do not really do as much as wnt seems to We have these multispecific antibodies now that both combine activating this key pathway, Wnt, with inhibiting other pathways that we know are contributors to the pathology of retinopathies like VEGF and IL-6. It is probably worth also highlighting this is one of the few areas in Wnt biology where there is really important genetic evidence of the role of this pathway in disease. we have these multispecific antibodies now that both combine activating this key pathway wnt with inhibiting other pathways that we know are contributors to the pathology of retinopathies like vegf and il-6. it is probably worth also highlighting this is one of the few areas in wnt biology where there is really important genetic evidence of the role of this pathway in disease There is a set of very rare childhood diseases that are mutations in Wnt signaling where kids are born with, it is very heterogeneous, but some of them are born with actually vision loss and retinas that look like the retina of a 70-year-old with wet AMD. there is a set of very rare childhood diseases that are mutations in wnt signaling where kids are born with, it is very heterogeneous but some of them are born with actually vision loss and retinas that look like the retina of a 70-year-old with wet amd We know that Frizzled is critical for the retinal vascular function and integrity, which is why we and others have targeted it for retinopathies. We know that Frizzled is critical for the retinal vascular function and integrity, which is why we and others have targeted it for retinopathies. we know that frizzled is critical for the retinal vascular function and integrity which is why we and others have targeted it for retinopathies

Speaker 2: Got it. Very helpful. Thank you for that context. Maybe just on a high level, you mentioned that this is a pathway which is difficult to drug. I think particularly there have been some challenges around safety. What is your approach to addressing some of the challenges of Wnt agonist therapy? Got it. got it Very helpful. very helpful Thank you for that context. thank you for that context Maybe just on a high level, you mentioned that this is a pathway which is difficult to drug. maybe just on a high level you mentioned that this is a pathway which is difficult to drug I think particularly there have been some challenges around safety. i think particularly there have been some challenges around safety What is your approach to addressing some of the challenges of Wnt agonist therapy? what is your approach to addressing some of the challenges of wnt agonist therapy

Speaker 1: There actually is a Wnt agonist on the market today which is extraordinarily safe. It is a bone-selective Wnt agonist. It is an Amgen molecule called Evenity or Romosozumab. It is approved for postmenopausal osteoporosis. It actually builds bone, so it is an anabolic agent, and it is extraordinarily safe. There have not actually been clinical safety signals with the few Wnt agonists that in this case are either on the market or have been in clinical trials. Merck did not disclose any really notable safety issues with their intravitreal injection of a Wnt agonist. Also, just the fact of giving an intravitreal injection versus a systemic injection is a theoretical way to, if there were systemic liabilities, to manage those liabilities because the drug, while it leaks out of the eye over time, is largely, in terms of the concentration, only high when it is in the eye. There actually is a Wnt agonist on the market today which is extraordinarily safe. there actually is a wnt agonist on the market today which is extraordinarily safe It is a bone-selective Wnt agonist. It is an Amgen molecule called Evenity or Romosozumab. It is approved for postmenopausal osteoporosis. it is a bone-selective wnt agonist. it is an amgen molecule called evenity or romosozumab. it is approved for postmenopausal osteoporosis It actually builds bone, so it is an anabolic agent, and it is extraordinarily safe. it actually builds bone so it is an anabolic agent and it is extraordinarily safe There have not actually been clinical safety signals with the few Wnt agonists that in this case are either on the market or have been in clinical trials. there have not actually been clinical safety signals with the few wnt agonists that in this case are either on the market or have been in clinical trials Merck did not disclose any really notable safety issues with their intravitreal injection of a Wnt agonist. merck did not disclose any really notable safety issues with their intravitreal injection of a wnt agonist Also, just the fact of giving an intravitreal injection versus a systemic injection is a theoretical way to, if there were systemic liabilities, to manage those liabilities because the drug, while it leaks out of the eye over time, is largely, in terms of the concentration, only high when it is in the eye. also just the fact of giving an intravitreal injection versus a systemic injection is a theoretical way to if there were systemic liabilities to manage those liabilities because the drug while it leaks out of the eye over time is largely in terms of the concentration only high when it is in the eye

Speaker 2: Got it. I mean, we do observe that there is an excitement around Wnt biology, specifically as it relates to retinal disease, as you mentioned, or Merck. Roche is also in the program. Can you maybe contextualize for us at least what we have seen at clinical level and preclinical level from your competitor, and how does that make you either more comfortable or more confident in going into some of these retinal diseases? Got it. got it I mean, we do observe that there is an excitement around Wnt biology, specifically as it relates to retinal disease, as you mentioned, or Merck. i mean we do observe that there is an excitement around wnt biology specifically as it relates to retinal disease as you mentioned or merck Roche is also in the program. roche is also in the program Can you maybe contextualize for us at least what we have seen at clinical level and preclinical level from your competitor, and how does that make you either more comfortable or more confident in going into some of these retinal diseases? can you maybe contextualize for us at least what we have seen at clinical level and preclinical level from your competitor and how does that make you either more comfortable or more confident in going into some of these retinal diseases

Speaker 1: Yeah. As I mentioned, I think it really starts in terms of the biology story with the human genetics, that this pathway is critical to the function and structure of the retinal vasculature. What we've seen preclinically, and it's very differentiated from other approaches like VEGF or IL-6 or Ang-2 preclinically, these are mouse models of retinopathy. What we see is not only that you can prevent vessel leakage, which is what VEGF inhibition does, but we can normalize the retinal vessels in parts of the eye that can become ischemic or are missing vessels in these mouse models. If you talk to people in the field today and say, "What's the way to really differentiate a molecule in multiple retinopathies?" people tell you, "It's drying the retina," which is, if you could normalize the vasculature, you shouldn't have any leakage. Yeah. yeah As I mentioned, I think it really starts in terms of the biology story with the human genetics, that this pathway is critical to the function and structure of the retinal vasculature. as i mentioned i think it really starts in terms of the biology story with the human genetics that this pathway is critical to the function and structure of the retinal vasculature What we've seen preclinically, and it's very differentiated from other approaches like VEGF or IL-6 or Ang-2 preclinically, these are mouse models of retinopathy. what we've seen preclinically and it's very differentiated from other approaches like vegf or il-6 or ang-2 preclinically these are mouse models of retinopathy What we see is not only that you can prevent vessel leakage, which is what VEGF inhibition does, but we can normalize the retinal vessels in parts of the eye that can become ischemic or are missing vessels in these mouse models. what we see is not only that you can prevent vessel leakage which is what vegf inhibition does but we can normalize the retinal vessels in parts of the eye that can become ischemic or are missing vessels in these mouse models If you talk to people in the field today and say, "What's the way to really differentiate a molecule in multiple retinopathies?" people tell you, "It's drying the retina," which is, if you could normalize the vasculature, you shouldn't have any leakage. if you talk to people in the field today and say "what's the way to really differentiate a molecule in multiple retinopathies?" people tell you "it's drying the retina," which is if you could normalize the vasculature you shouldn't have any leakage It's both directly blocking the leakage that we see preclinically and also potentially this normalization of vessels. That's what we see preclinically. The inventor of the Merck molecule did not publish any data. With that actual molecule, they published with a precursor tool molecule. They did not have nearly the magnitude of effect on those as we've had in preclinical models. Clinically, what we've seen from Merck is what looks to be a VEGF-like clinical benefit in visual acuity and in something called central subfield thickness, which is a measurement of fluid in the retina. It seems to have a VEGF-like benefit on visual acuity, a VEGF-like benefit on drying. I mean, that's in a very small set of diabetic macular edema patients. It's both directly blocking the leakage that we see preclinically and also potentially this normalization of vessels. it's both directly blocking the leakage that we see preclinically and also potentially this normalization of vessels That's what we see preclinically. that's what we see preclinically The inventor of the Merck molecule did not publish any data. the inventor of the merck molecule did not publish any data With that actual molecule, they published with a precursor tool molecule. with that actual molecule they published with a precursor tool molecule They did not have nearly the magnitude of effect on those as we've had in preclinical models. they did not have nearly the magnitude of effect on those as we've had in preclinical models Clinically, what we've seen from Merck is what looks to be a VEGF-like clinical benefit in visual acuity and in something called central subfield thickness, which is a measurement of fluid in the retina. clinically what we've seen from merck is what looks to be a vegf-like clinical benefit in visual acuity and in something called central subfield thickness which is a measurement of fluid in the retina It seems to have a VEGF-like benefit on visual acuity, a VEGF-like benefit on drying. it seems to have a vegf-like benefit on visual acuity a vegf-like benefit on drying I mean, that's in a very small set of diabetic macular edema patients. i mean that's in a very small set of diabetic macular edema patients

Speaker 2: Thank you. Maybe going back to the preclinical comment you made, what are these models? Are these the OIR model and the CNV model? Thank you. thank you Maybe going back to the preclinical comment you made, what are these models? maybe going back to the preclinical comment you made what are these models Are these the OIR model and the CNV model? are these the oir model and the cnv model

Speaker 1: Yes. Yes. yes

Speaker 2: How good are they from a translation perspective into human? How good are they from a translation perspective into human? how good are they from a translation perspective into human

Speaker 1: I mean, I think you have to be cautious in stating categorically that any animal model is translational or is translatable to human data. What we know is Eylea, for example, works in both these models. I'll tell you a little bit more about the multiple models that we've looked at. Works in those models, works in humans. IL-6, it's difficult to say that because it doesn't cross-react with mouse IL-6, most people's IL-6 antibodies. These are models of either more of a diabetic macular edema phenotype or a wet AMD phenotype. There is something called oxygen-induced retinopathy. You expose the mice to high oxygen concentration, then you lower the oxygen concentration. It creates a diabetic macular edema-like phenotype. It is thought to more closely be translatable to DME. I mean, I think you have to be cautious in stating categorically that any animal model is translational or is translatable to human data. i mean i think you have to be cautious in stating categorically that any animal model is translational or is translatable to human data What we know is Eylea, for example, works in both these models. what we know is eylea for example works in both these models I'll tell you a little bit more about the multiple models that we've looked at. i'll tell you a little bit more about the multiple models that we've looked at Works in those models, works in humans. works in those models works in humans IL-6, it's difficult to say that because it doesn't cross-react with mouse IL-6, most people's IL-6 antibodies. il-6 it's difficult to say that because it doesn't cross-react with mouse il-6 most people's il-6 antibodies These are models of either more of a diabetic macular edema phenotype or a wet AMD phenotype. these are models of either more of a diabetic macular edema phenotype or a wet amd phenotype There is something called oxygen-induced retinopathy. there is something called oxygen-induced retinopathy You expose the mice to high oxygen concentration, then you lower the oxygen concentration. you expose the mice to high oxygen concentration then you lower the oxygen concentration It creates a diabetic macular edema-like phenotype. it creates a diabetic macular edema-like phenotype It is thought to more closely be translatable to DME. it is thought to more closely be translatable to dme In this model, we actually see synergy of our molecule, which is combining VEGF inhibition with Wnt agonism, synergy compared to just Eylea alone or just Wnt alone. Something about combining those pathways into a single molecule seems to confer about tenfold greater potency. That is a DME model. We have done multiple versions of that. I will not go into the details where you can treat later, allow the disease in the animal to be more progressed or more damage or more leakage. We still see a large benefit that is greater than you can achieve with Wnt agonism alone or VEGF inhibition alone. There is a model that is more translatable to wet AMD, which, as you mentioned, is a CNV. We have done two versions of that. You can laser the back of the eye. There is actually a spontaneous mouse model that develops CNV, and we have done that. In this model, we actually see synergy of our molecule, which is combining VEGF inhibition with Wnt agonism, synergy compared to just Eylea alone or just Wnt alone. in this model we actually see synergy of our molecule which is combining vegf inhibition with wnt agonism synergy compared to just eylea alone or just wnt alone Something about combining those pathways into a single molecule seems to confer about tenfold greater potency. something about combining those pathways into a single molecule seems to confer about tenfold greater potency That is a DME model. that is a dme model We have done multiple versions of that. we have done multiple versions of that I will not go into the details where you can treat later, allow the disease in the animal to be more progressed or more damage or more leakage. i will not go into the details where you can treat later allow the disease in the animal to be more progressed or more damage or more leakage We still see a large benefit that is greater than you can achieve with Wnt agonism alone or VEGF inhibition alone. we still see a large benefit that is greater than you can achieve with wnt agonism alone or vegf inhibition alone There is a model that is more translatable to wet AMD, which, as you mentioned, is a CNV. We have done two versions of that. there is a model that is more translatable to wet amd which as you mentioned is a cnv. we have done two versions of that You can laser the back of the eye. There is actually a spontaneous mouse model that develops CNV, and we have done that. you can laser the back of the eye. there is actually a spontaneous mouse model that develops cnv and we have done that We have done similar to OIR where you look early, treat early, and then look later, treat later, trying to mimic a more advanced stage of disease or a more progressive stage of disease. In those, we have a larger treatment effect than Eylea alone. We have done similar to OIR where you look early, treat early, and then look later, treat later, trying to mimic a more advanced stage of disease or a more progressive stage of disease. we have done similar to oir where you look early treat early and then look later treat later trying to mimic a more advanced stage of disease or a more progressive stage of disease In those, we have a larger treatment effect than Eylea alone. in those we have a larger treatment effect than eylea alone

Speaker 2: Got it. So one more high-level question, then I'll go into your programs. In terms of the biology for Wnt, the matrix or Wnt agonist, is it more sensitive to one type of a retinal disease, let's say DME versus AMD? Where are you on that? Because I think the data that we are seeing, at least in the clinic, seems to be pointing more towards DME. Got it. got it So one more high-level question, then I'll go into your programs. so one more high-level question then i'll go into your programs In terms of the biology for Wnt, the matrix or Wnt agonist, is it more sensitive to one type of a retinal disease, let's say DME versus AMD? in terms of the biology for wnt the matrix or wnt agonist is it more sensitive to one type of a retinal disease let's say dme versus amd Where are you on that? where are you on that Because I think the data that we are seeing, at least in the clinic, seems to be pointing more towards DME. because i think the data that we are seeing at least in the clinic seems to be pointing more towards dme

Speaker 1: Yeah. We still see a large treatment effect in both models. I think the field, and the field right now is us, Merck, and probably Roche, but I think the field has prioritized DME over wet AMD because there is just a clearer line of the biology in retinal vessels than there is in what are called choroidal vessels. If you think about the back of the retina, the retinal vessels are parallel to the back of the retina. The choroidal vessels penetrate down into the layer where the photoreceptors reside. Those choroidal vessels do not actually have their own tight junctions. One of the effects of Wnt biology is to upregulate tight junction proteins like Zo1. We do see an effect in the choroid. It is called the choriocapillaris, but it is probably mediated by other cell types like RPE cells, for example. Yeah. yeah We still see a large treatment effect in both models. we still see a large treatment effect in both models I think the field, and the field right now is us, Merck, and probably Roche, but I think the field has prioritized DME over wet AMD because there is just a clearer line of the biology in retinal vessels than there is in what are called choroidal vessels. i think the field and the field right now is us merck and probably roche but i think the field has prioritized dme over wet amd because there is just a clearer line of the biology in retinal vessels than there is in what are called choroidal vessels If you think about the back of the retina, the retinal vessels are parallel to the back of the retina. if you think about the back of the retina the retinal vessels are parallel to the back of the retina The choroidal vessels penetrate down into the layer where the photoreceptors reside. the choroidal vessels penetrate down into the layer where the photoreceptors reside Those choroidal vessels do not actually have their own tight junctions. those choroidal vessels do not actually have their own tight junctions One of the effects of Wnt biology is to upregulate tight junction proteins like Zo1. one of the effects of wnt biology is to upregulate tight junction proteins like zo1 We do see an effect in the choroid. It is called the choriocapillaris, but it is probably mediated by other cell types like RPE cells, for example. we do see an effect in the choroid. it is called the choriocapillaris but it is probably mediated by other cell types like rpe cells for example The biology is just really, really clear-cut in retinal vessels. That's why the field has prioritized DME. As you probably know, Merck has started a wet AMD study. There's no reason to not pursue wet AMD. The biology is, I would just say, a little maybe one cell type removed from the actual vessel. The biology is just really, really clear-cut in retinal vessels. the biology is just really really clear-cut in retinal vessels That's why the field has prioritized DME. that's why the field has prioritized dme As you probably know, Merck has started a wet AMD study. as you probably know merck has started a wet amd study There's no reason to not pursue wet AMD. there's no reason to not pursue wet amd The biology is, I would just say, a little maybe one cell type removed from the actual vessel. the biology is i would just say a little maybe one cell type removed from the actual vessel

Speaker 2: Got it. Got it. Very helpful. Now tell us about the assets that you have, your molecule. You have a partnership with Boehringer Ingelheim. I think they are supposed to file an IND relatively soon. What have you done for that molecule? How is that molecule differentiated with the two molecules that you have that you're holding on? Got it. got it Got it. got it Very helpful. very helpful Now tell us about the assets that you have, your molecule. now tell us about the assets that you have your molecule You have a partnership with Boehringer Ingelheim. you have a partnership with boehringer ingelheim I think they are supposed to file an IND relatively soon. i think they are supposed to file an ind relatively soon What have you done for that molecule? what have you done for that molecule How is that molecule differentiated with the two molecules that you have that you're holding on? how is that molecule differentiated with the two molecules that you have that you're holding on

Speaker 1: The molecule we licensed to BI, I would say, looks to be a better version of RESTRA, the Merck molecule. The pharmacology is similar. It binds the same receptors. I will not go into the people always ask about the epitopes there. We do not think it really matters much. In vitro, the BI molecule is about twice as potent in activating Wnt signaling as RESTRA. Does that mean it is going to be clinically different? We do not know that. That is the principal difference between what we licensed to BI and RESTRA, potency in activating Wnt signaling. That is just the Wnt business end of our molecule. Our molecule 8141 combines that actual sequence that we licensed to BI with VEGF trap sequences. It is multifunctional. It is inhibiting VEGF and activating Wnt signaling. The molecule we licensed to BI, I would say, looks to be a better version of RESTRA, the Merck molecule. the molecule we licensed to bi i would say looks to be a better version of restra the merck molecule The pharmacology is similar. the pharmacology is similar It binds the same receptors. I will not go into the people always ask about the epitopes there. it binds the same receptors. i will not go into the people always ask about the epitopes there We do not think it really matters much. we do not think it really matters much In vitro, the BI molecule is about twice as potent in activating Wnt signaling as RESTRA. in vitro the bi molecule is about twice as potent in activating wnt signaling as restra Does that mean it is going to be clinically different? does that mean it is going to be clinically different We do not know that. we do not know that That is the principal difference between what we licensed to BI and RESTRA, potency in activating Wnt signaling. that is the principal difference between what we licensed to bi and restra potency in activating wnt signaling That is just the Wnt business end of our molecule. that is just the wnt business end of our molecule Our molecule 8141 combines that actual sequence that we licensed to BI with VEGF trap sequences. our molecule 8141 combines that actual sequence that we licensed to bi with vegf trap sequences It is multifunctional. It is inhibiting VEGF and activating Wnt signaling. it is multifunctional. it is inhibiting vegf and activating wnt signaling It's activating Wnt signaling with the same targets and the same potency as the BI molecule, which again is more than RESTRA and has the VEGF inhibition and has another modification that were there to be any systemic liabilities or toxicities, we would have mitigated because we put a mutation in a portion that's called the FcRn portion that accelerates the clearance from the circulation. Faricimab has the same sequence. It's activating Wnt signaling with the same targets and the same potency as the BI molecule, which again is more than RESTRA and has the VEGF inhibition and has another modification that were there to be any systemic liabilities or toxicities, we would have mitigated because we put a mutation in a portion that's called the FcRn portion that accelerates the clearance from the circulation. it's activating wnt signaling with the same targets and the same potency as the bi molecule which again is more than restra and has the vegf inhibition and has another modification that were there to be any systemic liabilities or toxicities we would have mitigated because we put a mutation in a portion that's called the fcrn portion that accelerates the clearance from the circulation Faricimab has the same sequence. faricimab has the same sequence

Speaker 2: Okay. Good. What work you did on the BI, and where is that partnership? Are you doing any work? I mean, they are your competitor, or you are their competitor now? Okay. okay Good. good What work you did on the BI, and where is that partnership? what work you did on the bi and where is that partnership Are you doing any work? are you doing any work I mean, they are your competitor, or you are their competitor now? i mean they are your competitor or you are their competitor now

Speaker 1: Maybe I'll let Chuck address that. Yeah. The initial phase of the collaboration ended when they nominated a lead candidate last year. Now it's just a straight-out license. In terms of where they are and the type of information we get from them, it's pretty limited. We obviously do compete with them. It's not entirely clear when they might initiate a phase one clinical trial. Maybe I'll let Chuck address that. maybe i'll let chuck address that Yeah. yeah The initial phase of the collaboration ended when they nominated a lead candidate last year. the initial phase of the collaboration ended when they nominated a lead candidate last year Now it's just a straight-out license. now it's just a straight-out license In terms of where they are and the type of information we get from them, it's pretty limited. in terms of where they are and the type of information we get from them it's pretty limited We obviously do compete with them. we obviously do compete with them It's not entirely clear when they might initiate a phase one clinical trial. it's not entirely clear when they might initiate a phase one clinical trial

Speaker 2: Got it. Just simplistically looking, Boehringer Ingelheim has basically a better version of Merck molecule. You have what Boehringer Ingelheim have, but added on top of it is the trap and maybe IL-6 and some mutations. Got it. got it Just simplistically looking, Boehringer Ingelheim has basically a better version of Merck molecule. just simplistically looking boehringer ingelheim has basically a better version of merck molecule You have what Boehringer Ingelheim have, but added on top of it is the trap and maybe IL-6 and some mutations. you have what boehringer ingelheim have but added on top of it is the trap and maybe il-6 and some mutations

Speaker 1: Correct. Correct. correct

Speaker 2: Okay. Okay. okay

Speaker 1: We have shown preclinically that there is synergy in combining those into one molecule because we get asked, "Why would not a patient potentially just get RESTRA, the Merck molecule, plus an injection of Eylea, for example?" Yeah. We have done that experiment in the mouse. First of all, the patients are not going to want that in multiple injections at the same time. We have done that experiment in the mouse model. We are not sure the mechanism behind this, but doing it all with one molecule is better than giving separate injections in the same mouse eye of Eylea plus 413. We have shown preclinically that there is synergy in combining those into one molecule because we get asked, "Why would not a patient potentially just get RESTRA, the Merck molecule, plus an injection of Eylea, for example?" Yeah. we have shown preclinically that there is synergy in combining those into one molecule because we get asked "why would not a patient potentially just get restra the merck molecule plus an injection of eylea for example?" yeah we We have done that experiment in the mouse. we have done that experiment in the mouse First of all, the patients are not going to want that in multiple injections at the same time. first of all the patients are not going to want that in multiple injections at the same time We have done that experiment in the mouse model. we have done that experiment in the mouse model We are not sure the mechanism behind this, but doing it all with one molecule is better than giving separate injections in the same mouse eye of Eylea plus 413. we are not sure the mechanism behind this but doing it all with one molecule is better than giving separate injections in the same mouse eye of eylea plus 413

Speaker 2: Absolutely. I think you're going after Wnt biology, which is obviously a little bit novel here. VEGF is very well understood, but I think we are seeing a little bit more data on the IL-6 side. Could you put that data in context, what you're seeing, because you do incorporate IL-6 in one of your assets? Absolutely. absolutely I think you're going after Wnt biology, which is obviously a little bit novel here. i think you're going after wnt biology which is obviously a little bit novel here VEGF is very well understood, but I think we are seeing a little bit more data on the IL-6 side. vegf is very well understood but i think we are seeing a little bit more data on the il-6 side Could you put that data in context, what you're seeing, because you do incorporate IL-6 in one of your assets? could you put that data in context what you're seeing because you do incorporate il-6 in one of your assets

Speaker 1: Yeah. Yeah. Our next molecule after 8141 is 8143, which is trifunctional. It is Wnt agonism, VEGF inhibition, IL-6 inhibition. The data you're referring to, I think, is the Roche DME data with a combination of IL-6 plus a separate VEGF injection in DME. We can talk about UME separately. In DME, we are really encouraged that there's clearly an additive benefit with multiple mechanisms. I think faricimab was some evidence of that. I think if you look at the data, which you can access on ClinTrials now for that DME study, there's very convincing additive benefit on visual acuity and retinal drying in both treatment experienced and treatment naive DME patients. I think that's our approach is obviously to see that additive benefit with multiple mechanisms. We're really seeing that now come true in the clinic with IL-6. Yeah. yeah Yeah. yeah Our next molecule after 8141 is 8143, which is trifunctional. our next molecule after 8141 is 8143 which is trifunctional It is Wnt agonism, VEGF inhibition, IL-6 inhibition. it is wnt agonism vegf inhibition il-6 inhibition The data you're referring to, I think, is the Roche DME data with a combination of IL-6 plus a separate VEGF injection in DME. the data you're referring to i think is the roche dme data with a combination of il-6 plus a separate vegf injection in dme We can talk about UME separately. we can talk about ume separately In DME, we are really encouraged that there's clearly an additive benefit with multiple mechanisms. in dme we are really encouraged that there's clearly an additive benefit with multiple mechanisms I think faricimab was some evidence of that. i think faricimab was some evidence of that I think if you look at the data, which you can access on ClinTrials now for that DME study, there's very convincing additive benefit on visual acuity and retinal drying in both treatment experienced and treatment naive DME patients. i think if you look at the data which you can access on clintrials now for that dme study there's very convincing additive benefit on visual acuity and retinal drying in both treatment experienced and treatment naive dme patients I think that's our approach is obviously to see that additive benefit with multiple mechanisms. i think that's our approach is obviously to see that additive benefit with multiple mechanisms We're really seeing that now come true in the clinic with IL-6. we're really seeing that now come true in the clinic with il-6 Now, IL-6 alone doesn't seem to do much. So we're really encouraged that Wnt alone does as much as VEGF alone. VEGF plus IL-6 does more than just VEGF. So it's just sort of first-order logic now. We're obviously hopeful that Wnt, which has VEGF-like monoactivity and VEGF, will have an even greater additive benefit than some other combinations like VEGF and IL-6. Now, IL-6 alone doesn't seem to do much. now il-6 alone doesn't seem to do much So we're really encouraged that Wnt alone does as much as VEGF alone. so we're really encouraged that wnt alone does as much as vegf alone VEGF plus IL-6 does more than just VEGF. vegf plus il-6 does more than just vegf So it's just sort of first-order logic now. so it's just sort of first-order logic now We're obviously hopeful that Wnt, which has VEGF-like monoactivity and VEGF, will have an even greater additive benefit than some other combinations like VEGF and IL-6. we're obviously hopeful that wnt which has vegf-like monoactivity and vegf will have an even greater additive benefit than some other combinations like vegf and il-6

Speaker 2: Got it. Got it. Very good. For your two molecules, 8141 and 8143, where exactly are you? Which one is more advanced? When should we expect an IND? What preclinical work do you still need to do in order to facilitate an IND? Got it. got it Got it. got it Very good. very good For your two molecules, 8141 and 8143, where exactly are you? for your two molecules 8141 and 8143 where exactly are you Which one is more advanced? which one is more advanced When should we expect an IND? when should we expect an ind What preclinical work do you still need to do in order to facilitate an IND? what preclinical work do you still need to do in order to facilitate an ind

Speaker 1: 8143 is months behind 8141. It's not a year behind, but we haven't given any precise guidance on the interval between those. We've said that we'll file an IND for 8141, Wnt, VEGF in 2026. When we get closer and have a more precise date, we'll update that guidance. We're doing all the typical with 8141, CMC scale-up and toxicology sort of activities right now. We haven't given any more details on the timing of that. 8143 is months behind 8141. 8143 is months behind 8141 It's not a year behind, but we haven't given any precise guidance on the interval between those. it's not a year behind but we haven't given any precise guidance on the interval between those We've said that we'll file an IND for 8141, Wnt, VEGF in 2026. we've said that we'll file an ind for 8141 wnt vegf in 2026 When we get closer and have a more precise date, we'll update that guidance. when we get closer and have a more precise date we'll update that guidance We're doing all the typical with 8141, CMC scale-up and toxicology sort of activities right now. we're doing all the typical with 8141 cmc scale-up and toxicology sort of activities right now We haven't given any more details on the timing of that. we haven't given any more details on the timing of that

Speaker 2: Okay. IND next year, at least for 8141. How should we think about your strategy? What type of patients you will go after first? Would you run a study where you actually end up getting both DME and AMD and also talk about the injection frequency? Okay. okay IND next year, at least for 8141. ind next year at least for 8141 How should we think about your strategy? how should we think about your strategy What type of patients you will go after first? what type of patients you will go after first Would you run a study where you actually end up getting both DME and AMD and also talk about the injection frequency? would you run a study where you actually end up getting both dme and amd and also talk about the injection frequency

Speaker 1: Yeah. So I think we would, we'll give more details on the actual protocol and trial design, but I think likely do both DME and wet AMD. We're still discussing with our clinical advisors, do you just do treatment naive patients because it's a little easier to interpret the data because it's pretty well known how they should respond, like to Eylea, for example. You can do a cross-study comparison, but that's still to be determined whether we do maybe some treatment experienced patients in that. It's likely both DME and wet AMD in a phase one B2A, not unlike what others like IBIO have done. Yeah. yeah So I think we would, we'll give more details on the actual protocol and trial design, but I think likely do both DME and wet AMD. so i think we would we'll give more details on the actual protocol and trial design but i think likely do both dme and wet amd We're still discussing with our clinical advisors, do you just do treatment naive patients because it's a little easier to interpret the data because it's pretty well known how they should respond, like to Eylea, for example. we're still discussing with our clinical advisors do you just do treatment naive patients because it's a little easier to interpret the data because it's pretty well known how they should respond like to eylea for example You can do a cross-study comparison, but that's still to be determined whether we do maybe some treatment experienced patients in that. you can do a cross-study comparison but that's still to be determined whether we do maybe some treatment experienced patients in that It's likely both DME and wet AMD in a phase one B2A, not unlike what others like IBIO have done. it's likely both dme and wet amd in a phase one b2a not unlike what others like ibio have done

Speaker 2: Yeah. I see. Yeah. yeah I see. i see

Speaker 1: Frequency, we do not know all the PK right now. I'd say we have a pretty good idea that we will not need to be more frequent than every other month. I do not know that there is a benefit ultimately to being like every four months or less frequent because the retinal specialists want to see patients more frequently than that. I think 8-12 weeks is probably the sweet spot. Doing a Vabysmo-like study is probably the right phase three where you give people a range of dosing frequency depending on how dry the retina is, and you get reimbursed for all those, which is key. Frequency, we do not know all the PK right now. frequency we do not know all the pk right now I'd say we have a pretty good idea that we will not need to be more frequent than every other month. i'd say we have a pretty good idea that we will not need to be more frequent than every other month I do not know that there is a benefit ultimately to being like every four months or less frequent because the retinal specialists want to see patients more frequently than that. i do not know that there is a benefit ultimately to being like every four months or less frequent because the retinal specialists want to see patients more frequently than that I think 8-12 weeks is probably the sweet spot. i think 8-12 weeks is probably the sweet spot Doing a Vabysmo-like study is probably the right phase three where you give people a range of dosing frequency depending on how dry the retina is, and you get reimbursed for all those, which is key. doing a vabysmo-like study is probably the right phase three where you give people a range of dosing frequency depending on how dry the retina is and you get reimbursed for all those which is key

Speaker 2: Yeah. I think if you can push the efficacy, I think even the eight week would be fine because I think in this disease category, we have just seen the plateau with almost every new mechanism right now. You still get VEGF-like. Okay. In terms of the, so you go into these two areas, but most likely next year, right? We're going to get data from hopefully Merck. They're running two studies, Brunello and Barolo. They're both good wines. Next year, what would be your expectations for? Yeah. yeah I think if you can push the efficacy, I think even the eight week would be fine because I think in this disease category, we have just seen the plateau with almost every new mechanism right now. i think if you can push the efficacy i think even the eight week would be fine because i think in this disease category we have just seen the plateau with almost every new mechanism right now You still get VEGF-like. you still get vegf-like Okay. okay In terms of the, so you go into these two areas, but most likely next year, right? in terms of the so you go into these two areas but most likely next year right We're going to get data from hopefully Merck. we're going to get data from hopefully merck They're running two studies, Brunello and Barolo. they're running two studies brunello and barolo They're both good wines. they're both good wines Next year, what would be your expectations for? next year what would be your expectations for

Speaker 1: I'm trying to figure out how you one-up Italian wine names for your study acronym. I'm trying to figure out how you one-up Italian wine names for your study acronym. i'm trying to figure out how you one-up italian wine names for your study acronym

Speaker 2: There is another company that has, they're running four phase three studies, all are Italian names, but they're by cities. I point, I follow them, Como, Capri, Lugano, Lucia. I don't know why. What's the Italian angle here? I don't know. Yeah. What would be your expectation? Because that for sure will have read-through with the whole Wnt biology space. There is another company that has, they're running four phase three studies, all are Italian names, but they're by cities. there is another company that has they're running four phase three studies all are italian names but they're by cities I point, I follow them, Como, Capri, Lugano, Lucia. i point i follow them como capri lugano lucia I don't know why. i don't know why What's the Italian angle here? what's the italian angle here I don't know. i don't know Yeah. yeah What would be your expectation? what would be your expectation Because that for sure will have read-through with the whole Wnt biology space. because that for sure will have read-through with the whole wnt biology space

Speaker 1: Yeah. I mean, maybe first and foremost, we're obviously hopeful that there's really excellent safety with agonizing Wnt in the eye. There didn't seem to be any safety signal in the IBIO phase I/II, but that was a limited experience, something like 30 patients total for a couple of months. The requirement for any intravitreal injection for these diseases is exceptional safety, right? You can't have endophthalmitis or other serious complications or retinal vasculitis. I think having VEGF-like efficacy would be really encouraging. Again, we think there's a good argument for an additive benefit. With Wnt alone, if you can get VEGF-like efficacy, I still think that leaves an opportunity for improvement. It could be the improvement is on drying. It could be that it's on visual acuity. Yeah. yeah I mean, maybe first and foremost, we're obviously hopeful that there's really excellent safety with agonizing Wnt in the eye. i mean maybe first and foremost we're obviously hopeful that there's really excellent safety with agonizing wnt in the eye There didn't seem to be any safety signal in the IBIO phase I/II, but that was a limited experience, something like 30 patients total for a couple of months. there didn't seem to be any safety signal in the ibio phase i/ii but that was a limited experience something like 30 patients total for a couple of months The requirement for any intravitreal injection for these diseases is exceptional safety, right? the requirement for any intravitreal injection for these diseases is exceptional safety right You can't have endophthalmitis or other serious complications or retinal vasculitis. you can't have endophthalmitis or other serious complications or retinal vasculitis I think having VEGF-like efficacy would be really encouraging. i think having vegf-like efficacy would be really encouraging Again, we think there's a good argument for an additive benefit. again we think there's a good argument for an additive benefit With Wnt alone, if you can get VEGF-like efficacy, I still think that leaves an opportunity for improvement. with wnt alone if you can get vegf-like efficacy i still think that leaves an opportunity for improvement It could be the improvement is on drying. it could be the improvement is on drying It could be that it's on visual acuity. it could be that it's on visual acuity I think if you ask a retinal specialist, they would say, "Don't have high expectations that you can improve visual acuity anymore," but no one's had any kind of an additive effect yet, so. I think if you ask a retinal specialist, they would say, "Don't have high expectations that you can improve visual acuity anymore," but no one's had any kind of an additive effect yet, so. i think if you ask a retinal specialist they would say "don't have high expectations that you can improve visual acuity anymore," but no one's had any kind of an additive effect yet so

Speaker 2: What is the frequency of RESTRA? What is the frequency of RESTRA? what is the frequency of restra

Speaker 1: Monthly. Monthly. monthly

Speaker 2: That'd be monthly. That'd be monthly. that'd be monthly

Speaker 1: We think that that's limited by how they can concentrate it. There is just a simple math challenge with intravitreal injections, which is you can only put about 50-70 microliters in the eye without potentially damaging the eye or causing an increase in intraocular pressure. If you calculate what is required for the concentration of your drug, it has to be about 100 ml per ml. If you have like a typical IV injection for an oncology ADC, for example, people are doing like 15 ml per mil. This is like very highly concentrated protein, and not all proteins can be stable at that concentration. We think because we have made RESTRA, that might be one of the limitations that they have experienced is they just cannot concentrate it enough to put more in the eye. They have to give a monthly injection. We think that that's limited by how they can concentrate it. we think that that's limited by how they can concentrate it There is just a simple math challenge with intravitreal injections, which is you can only put about 50-70 microliters in the eye without potentially damaging the eye or causing an increase in intraocular pressure. there is just a simple math challenge with intravitreal injections which is you can only put about 50-70 microliters in the eye without potentially damaging the eye or causing an increase in intraocular pressure If you calculate what is required for the concentration of your drug, it has to be about 100 ml per ml. if you calculate what is required for the concentration of your drug it has to be about 100 ml per ml If you have like a typical IV injection for an oncology ADC, for example, people are doing like 15 ml per mil. if you have like a typical iv injection for an oncology adc for example people are doing like 15 ml per mil This is like very highly concentrated protein, and not all proteins can be stable at that concentration. this is like very highly concentrated protein and not all proteins can be stable at that concentration We think because we have made RESTRA, that might be one of the limitations that they have experienced is they just cannot concentrate it enough to put more in the eye. we think because we have made restra that might be one of the limitations that they have experienced is they just cannot concentrate it enough to put more in the eye They have to give a monthly injection. they have to give a monthly injection

Speaker 2: Very interesting. What are you hearing from physicians or the expert as it relates to either, as it relates to the Wnt biology? What is the feedback? Very interesting. very interesting What are you hearing from physicians or the expert as it relates to either, as it relates to the Wnt biology? what are you hearing from physicians or the expert as it relates to either as it relates to the wnt biology What is the feedback? what is the feedback

Speaker 1: I think we have a really great opportunity to convey that we are really the scientific experts in this field. No one's really tried to do that with any of the KOLs yet. We are. We were founded by two scientists who won the Breakthrough Prize in Life Sciences for Wnt biology, a Nobel laureate. I think we've got good cred and chops to be the scientific experts for Wnt. I think there's a great opportunity to reinforce that. There's awareness of the pathway, but not knowledge of the pathway, which I think is also a great opportunity for us to educate people on the role of the pathway in the retina. In terms of the clinical benefit they would like to see from a novel mechanism, I think it's good retinal drying. You'll hear people refer to this as an anatomic effect. I think we have a really great opportunity to convey that we are really the scientific experts in this field. i think we have a really great opportunity to convey that we are really the scientific experts in this field No one's really tried to do that with any of the KOLs yet. no one's really tried to do that with any of the kols yet We are. we are We were founded by two scientists who won the Breakthrough Prize in Life Sciences for Wnt biology, a Nobel laureate. we were founded by two scientists who won the breakthrough prize in life sciences for wnt biology a nobel laureate I think we've got good cred and chops to be the scientific experts for Wnt. i think we've got good cred and chops to be the scientific experts for wnt I think there's a great opportunity to reinforce that. i think there's a great opportunity to reinforce that There's awareness of the pathway, but not knowledge of the pathway, which I think is also a great opportunity for us to educate people on the role of the pathway in the retina. there's awareness of the pathway but not knowledge of the pathway which i think is also a great opportunity for us to educate people on the role of the pathway in the retina In terms of the clinical benefit they would like to see from a novel mechanism, I think it's good retinal drying. in terms of the clinical benefit they would like to see from a novel mechanism i think it's good retinal drying You'll hear people refer to this as an anatomic effect. you'll hear people refer to this as an anatomic effect It can be measured by central subfield thickness. It can be measured by a % of patients with no intraretinal or subretinal fluid. That's where faricimab has done well. I think there's still headroom for improvement. I think most retinal specialists would tell you that, that not everyone responds to VEGF inhibition or Ang-2, and you can do better drying the retina. The belief is ultimately that's going to translate to visual acuity benefits or preserving vision, visual function. That's where our mechanism, I think, plays well. What we see preclinically is this normalization of the retinal vasculature, reduction of areas of non-perfusion, no pathologic leaky vessels. Hopefully, that connection will be true in humans. It can be measured by central subfield thickness. it can be measured by central subfield thickness It can be measured by a % of patients with no intraretinal or subretinal fluid. it can be measured by a % of patients with no intraretinal or subretinal fluid That's where faricimab has done well. that's where faricimab has done well I think there's still headroom for improvement. i think there's still headroom for improvement I think most retinal specialists would tell you that, that not everyone responds to VEGF inhibition or Ang-2, and you can do better drying the retina. i think most retinal specialists would tell you that that not everyone responds to vegf inhibition or ang-2 and you can do better drying the retina The belief is ultimately that's going to translate to visual acuity benefits or preserving vision, visual function. the belief is ultimately that's going to translate to visual acuity benefits or preserving vision visual function That's where our mechanism, I think, plays well. that's where our mechanism i think plays well What we see preclinically is this normalization of the retinal vasculature, reduction of areas of non-perfusion, no pathologic leaky vessels. what we see preclinically is this normalization of the retinal vasculature reduction of areas of non-perfusion no pathologic leaky vessels Hopefully, that connection will be true in humans. hopefully that connection will be true in humans

Speaker 2: Yeah. Yeah. One clarification. The IND that you're filing is in the U.S. for next year, or? Yeah. yeah Yeah. yeah one One clarification. one clarification The IND that you're filing is in the U.S. for next year, or? the ind that you're filing is in the u.s for next year or

Speaker 1: Yes. Yes. yes

Speaker 2: Okay. Maybe a couple of questions for Chuck. In your new role, what are some of the things that you are thinking about or that you will be doing? If you also can touch on the IP. Okay. okay Maybe a couple of questions for Chuck. maybe a couple of questions for chuck In your new role, what are some of the things that you are thinking about or that you will be doing? in your new role what are some of the things that you are thinking about or that you will be doing If you also can touch on the IP. if you also can touch on the ip

Speaker 1: Yeah, sure. I think in terms of some of the enterprise strategy, in terms of what indications and how to co-position 8143 and 8141, I mean, one of the things we're thinking about while we haven't finalized these plans for 8143 is do we do an initial indication in MESI? Because one, it's a more streamlined development pathway, and two, it's a shorter endpoint, six months. Presumably you could catch up with 8143. In the context of having seen the Roche data, VEGF, IL-6 combination, it does give us, it's really encouraging to see that the combination of those two is better than VEGF alone. That we have to take into consideration. Your second question around IP. We were issued, so we've been issued a patent in the US, Europe, and Japan that claims multivalent antibodies targeting Frizzled LRP5 or 6. Yeah, sure. yeah sure I think in terms of some of the enterprise strategy, in terms of what indications and how to co-position 8143 and 8141, I mean, one of the things we're thinking about while we haven't finalized these plans for 8143 is do we do an initial indication in MESI? i think in terms of some of the enterprise strategy in terms of what indications and how to co-position 8143 and 8141 i mean one of the things we're thinking about while we haven't finalized these plans for 8143 is do we do an initial indication in mesi Because one, it's a more streamlined development pathway, and two, it's a shorter endpoint, six months. because one it's a more streamlined development pathway and two it's a shorter endpoint six months Presumably you could catch up with 8143. presumably you could catch up with 8143 In the context of having seen the Roche data, VEGF, IL-6 combination, it does give us, it's really encouraging to see that the combination of those two is better than VEGF alone. in the context of having seen the roche data vegf il-6 combination it does give us it's really encouraging to see that the combination of those two is better than vegf alone That we have to take into consideration. that we have to take into consideration Your second question around IP. your second question around ip We were issued, so we've been issued a patent in the US, Europe, and Japan that claims multivalent antibodies targeting Frizzled LRP5 or 6. we were issued so we've been issued a patent in the us europe and japan that claims multivalent antibodies targeting frizzled lrp5 or 6 The reason that's important is it's a fairly broad patent that would actually, where Merck and Roche would be infringing. In fact, post the Merck acquisition, the patent office cited this application at the time of ours as prior art. We have a pretty good intellectual property position as we've been the leaders in the field. We were the first to file. We'll see how that plays out over time with our competitors of Merck and Roche and any others that might be working in this field. The reason that's important is it's a fairly broad patent that would actually, where Merck and Roche would be infringing. the reason that's important is it's a fairly broad patent that would actually where merck and roche would be infringing In fact, post the Merck acquisition, the patent office cited this application at the time of ours as prior art. in fact post the merck acquisition the patent office cited this application at the time of ours as prior art We have a pretty good intellectual property position as we've been the leaders in the field. we have a pretty good intellectual property position as we've been the leaders in the field We were the first to file. we were the first to file We'll see how that plays out over time with our competitors of Merck and Roche and any others that might be working in this field. we'll see how that plays out over time with our competitors of merck and roche and any others that might be working in this field

Speaker 2: Great. Maybe final question. How is the cash position, burn rate, and the funding? Great. great Maybe final question. maybe final question How is the cash position, burn rate, and the funding? how is the cash position burn rate and the funding

Speaker 1: Sure. So we did a $175 million pipe earlier this year, split into two tranches. The first tranche of about $75 million gets us a couple of quarters post having the IND clearance. The second tranche of approximately $100 million would get us some cushion post having reported out data for both 8141 and 8143 in the phase one B2A studies that we plan to conduct. Sure. sure So we did a $175 million pipe earlier this year, split into two tranches. so we did a $175 million pipe earlier this year split into two tranches The first tranche of about $75 million gets us a couple of quarters post having the IND clearance. the first tranche of about $75 million gets us a couple of quarters post having the ind clearance The second tranche of approximately $100 million would get us some cushion post having reported out data for both 8141 and 8143 in the phase one B2A studies that we plan to conduct. the second tranche of approximately $100 million would get us some cushion post having reported out data for both 8141 and 8143 in the phase one b2a studies that we plan to conduct

Speaker 2: Got it. Maybe final question. To the best of your understanding, the RESTRA, Brunello, and Barolo studies are reading out next year. Got it. got it Maybe final question. maybe final question To the best of your understanding, the RESTRA, Brunello, and Barolo studies are reading out next year. to the best of your understanding the restra brunello and barolo studies are reading out next year

Speaker 1: Yes. We understand that it's probably Q3 is what we've been hearing for the first one. Yes. yes We understand that it's probably Q3 is what we've been hearing for the first one. we understand that it's probably q3 is what we've been hearing for the first one

Speaker 2: For the first one. Okay. For the first one. for the first one Okay. okay

Speaker 1: Yes. They probably will read out the wet AMD study next year as well because they just initiated that. Yes. yes They probably will read out the wet AMD study next year as well because they just initiated that. they probably will read out the wet amd study next year as well because they just initiated that

Speaker 2: Got it. Got it. Very good, gentlemen. Thank you so much. Got it. got it got Got it. got it Very good, gentlemen. very good gentlemen Thank you so much. thank you so much

Speaker 1: Thanks for having me. Thanks for having me. thanks for having me

Speaker 2: Appreciate it. Thank you. Appreciate it. appreciate it thank you Thank you. thank you