All right. Welcome, everyone, to H.C. Wainwright's sixth annual Ophthalmology Investor Conference. My name is Matthew Caulfield. I'm a senior biotech analyst here at H.C. Wainwright. We're very grateful to be joined by Sprozen and CEO Craig Parker. Craig, thank you very much for joining us. Always great to speak about the platform together.

Thanks for the invitation. Look forward to talking with you.

Yeah, absolutely. So a key component for the Wnt platform has been targeting FCD4 or Frizzled 4 and anti-VEGF. Can you walk us through the rationale behind the Frizzled 4 therapeutic target for retinal diseases?

Yeah. So this is a key receptor that's involved in modulating Wnt signaling. Frizzled and LRP is the co-receptor. You know, actually going back to the early 90s, there were some genetic studies of some pediatric diseases, retinal vascular diseases that led to the identification of Frizzled 4 mutations and Frizzled 4 signaling as a contributor to these, you know, quite rare childhood retinal vascular diseases. Subsequent studies and experiments showed that there were mutations in both the Frizzled 4 receptor, one of the ligands for the receptor, Norin, and LRP, this co-receptor, that result in a loss of function of Wnt signaling in these kids in retinal vascular endothelial cells. And that led to leaky vessels, poorly developed vessels. And while these diseases don't look exactly like wet AMD or diabetic macular edema, they have some overlapping pathologies of leaky vessels and importantly for the Wnt signaling pathway, poorly functioning blood retina barrier tight junction proteins. So that's what led us and others to be interested in pursuing Frizzled 4, mediated Wnt signaling for retinal vascular diseases, was really compelling human genetics that this was a critical pathway for retinal vessel development and retinal vessel function.

That's very helpful. And then the clinical asset SCN413 was previously licensed to Boringer-Ingelheim as a bispecific Wnt agonist antibody. And then from there, the separate development proceeded for preclinical candidate 8141, which includes targeting Frizzled 4 and anti-VEGF.

How do you think about the internal pipeline differentiation and positioning presently? yeah so i mean you you follow obviously the area closely and you know that one of the evolving themes in the area is to pursue um multifunctional antibodies or other modalities where you're targeting multiple contributors to the pathology of the disease so um you know we know frizzled for mediated wind signaling is really important i think you know the merck molecule and data has shown that Wnt agonism alone could have VEGF-like clinical benefit, but we also know there are other contributors to this disease. And as I said, you know, you follow this closely, you know that the field's now identified not just VEGF and now not just Wnt, but IL-6 and potentially other contributors to the disease. So that was really the foundation of our approach, you know, coming from a background of Wnt biology was to see this evolving landscape of trying to target multiple contributors to the disease. And obviously, VEGF is foundational therapy, is extremely effective in improving visual acuity and reducing leakage of retinal vessels. But there are clearly other contributors. And we think the data today points to Wnt and VEGF being the most attractive targets in the area. But I know we'll talk about our other molecule 8143, but there are potentially other contributors to the disease. But the foundation of our approach was this idea of multiple contributors to the pathology and in one molecule targeting multiple pathways that are contributing to the disease pathology.

That's very helpful. So kind of along those lines, the pipeline additionally includes preclinical asset SCN8143, which targets frizzled-4, anti-VEGF, and anti-IL-6, as you just mentioned. How are the tri-specific approach and the IL-6 blockade relevant for targeting inflammatory signaling, and specifically any related retinal edema?

Yeah, so there were observations, actually going back to systemic use of IL-6 in immune patients who also had, you know, what's called uveatic macular edema. And physicians treating those patients observed that their retinal phenotype was improving. You know, I don't know if it was exactly at the same time, but there were parallel observations in patients with retinal vascular diseases looking for biomarkers of disease where people observed that IL-6 was elevated in some diseases like UME and diabetic macular edema. And so the observations sort of came together and resulted in people pursuing IL-6 inhibition initially alone for diseases like uveatic macular edema, where there is clearly an inflammatory component. That's also now led people like us and others to take this multifunctional approach and, you know, really continue to improve clinical benefit for patients, targeting more than just, in our case, WIND and VEGF. And so, you know, we think that there's compelling data from others that IL-6 is a contributor to UME and now to DME. You probably saw this data and also Bardina's data that's been presented on the combination of VEGF and IL-6 showing that IL-6 has an additive benefit. in DME. And there's also obviously evolving data in UME. So again, you know, we sort of built on this foundation of what disease entities have multiple contributors and where is there good clinical evidence that there are multiple contributors. And I think UME really stands out as one where there is clear evidence that IL-6 is a contributor. But I think there's now data that, that in DME, at least in some patients, there's an inflammatory component and antagonizing IL-6 on top of at least, you know, no one else has done wind VEGF yet other than us, but on top of VEGF has an additive benefit. So, so that was, that was, you know, what, what really propelled us trying to make this, you know, quite complex, large antibody that inhibits VEGF, inhibits IL-6 and activates wind signaling and preserves each of those individual elements, at least in terms of its individual potential efficacy, meaning we have the same VEGF inhibition as other VEGF inhibitors. We have the same IL-6 inhibition as other IL-6 inhibitors, and we think we have the best-in-class wind activation.

Well, very exciting. So kind of looking at the data side of things, at Arvo this year, the team highlighted the preclinical efficacy looking back to SCN 8141. Can you discuss the key takeaways there from the preclinical OIR and or CNV mouse models and possible benefit from the Wnt and VEGF dual mechanism that you're seeing?

Yeah, I mean, I think the short answer is there appears to be synergy combining Wnt agonism and VEGF inhibition. Maybe I'll just take a minute to describe the experiment because I think it was a very rigorous way to explore what the individual contributors and what the combined molecule can do in these models. As you said, one of these is a DME model, oxygenopathy. The other is a model of wet AMD, a choroidal neovascularization model. So what we did is we took 8141, which is Wnt activation and VEGF inhibition. And for one control molecule, we knocked out the VEGF inhibition part of it. So it's still the whole 8141, but doesn't inhibit VEGF. So that's what we call Wnt agonist in the poster. Took 8141, knocked out the Wnt part of it. So it's still the whole 8141, but in this case, it just inhibits VEGF. And then we mix those together in one mouse eye in an experiment. And then in another arm, we gave 8141. And what that showed in the OIR model, which, again, is a model of diabetic macular edema that affects the retinal vessels in these animals, is if you look at the same concentration in each of those experimental cohorts, there's significantly better efficacy in the 8141 than there is in Wnt alone or VEGF alone. and that's not surprising i don't think given that we know that you know that these are both contributors um to the phenotype what's really exciting is that the mixture of the wint agonist and the veg f antagonist is not as good as 8141 so there's some intrinsic benefit it may be a proximity effect um or there may be some other biology involved that putting them together in one molecule has a synergistic effect on, in this case, reducing what's called the avascular area. So the phenotype in these mice is that they get leaky vessels, and they also have areas where there are no vessels. There's a clinical correlate to this, which is called retinal non-perfusion in DME. You probably know from studying the field, this is an area of very high unmet need, uh, VEGF drugs, as well as they work on leakage and improving visual acuity, they don't really do anything to these areas of retinal non-perfusion, which are known to be associated with, um, um, um, um, more, um, uh, uh, uh, uh, uh, uh, active disease and disease progression. So that was a very unique finding was the synergy. And, you know, we had previously shown that Wnt agonism alone can reduce these areas of non-perfusion or avascular areas, but the combo does it in a really compelling and synergistic way.

Very exciting, very helpful as well. So obviously an important part of the Wnt pathway validation was Merck's prior acquisition of iBio. They have their current phase 2b3 clinical development of Restorate and DME. So it's important to note cirrosin's 8141 adds the VEGF inhibition to the Frizzled-4 targeting. What do you believe could be the best ways to differentiate 8141 from other WENT pathway therapies? Obviously, you mentioned the retinal non-perfusion impact. What are the best ways that 8141 could carve out its own space in WENT?

Yeah, I think the ways to win in retinal vascular diseases, and I think this is particularly true in DME, are to at least be a better drying agent. So I think, you know, there are a number of ways to measure that, you know, as you know, in these studies and in clinical practice, optical coherence tomography is used to image the back of the retina. You can directly observe fluid. There are multiple ways to measure that like central subfield thickness or, you know, defining absence of macular edema based on a certain cutoff or just looking for the complete absence of fluid. And so these are outcomes that are typically measured in a study. And I think being a better drying agent on those outcome measurements would be differentiating and be really clinically meaningful. That other area that I just mentioned though of retinal non-perfusion, I think would be something that would really, really change the field. Um, and because the VEGFs don't really have an effect on that. So I think if you were both a better drying agent, you'd be the best biologic injectable in the market. And then if you also achieve, um, um, this reperfusion of these areas of, of retinal non-perfusion, you know, that would, that would really be transformative for the field. So I think our preclinical data suggests that's possible um these are mice so of course everyone always says how translatable is the model and i think the answer is you know it's been very translatable for the approved drugs they've all shown an effect in these animal models they're validated you know i think well accepted models but you know this until we see that dual effect of better drying and reperfusion. It's hard to say that the animal models are translatable, but they point to that being the opportunity for 8141.

Okay. Well, that's very helpful. And then when you talk about the retinal non-perfusion areas, the goal there obviously is then facilitating or laying down healthy vasculature, right?

Yeah. So again, there are some well-established methods for measuring this as you said they're they're actually just literally related to the area of non-perfusion so you can image that measure it just the surface area of that and the objective would be to reduce that by storing blood flow to existing vessels that don't have flow or stimulating new blood vessel growth in those areas and in the animals it's a little difficult to know exactly which of those you're doing. But we're clearly, we're clearly reperfusing these areas.

Right. Very interesting. So one question that comes up sometimes is obviously with Merck's registrational progress, do you have any considerations on the ideal mix for treatment naive versus previously treated DME patients? Obviously, the less treated patients are the earlier stage of disease progression, the more they, I guess, conceptually could benefit from interventional therapy. Do you have any sense of kind of where they could be optimally positioned or where you yourself in later stage development would like to see that split between treatment IE versus previously treated?

Yeah, I mean, I think it turns out that that's actually a really important, interesting, but also complex question. So there's a regulatory answer to that question. And then there's a sort of clinical practice and how are the drugs?

The real world, yeah.

The technology of providers perspective. right now the only regulatory path is for treatment naive patients and so that's why you see these phase three studies will have a preponderance maybe not exclusively but a preponderance you know 75 ish percent of treatment naive patients because that's what's required for for registration it's also you know i think a retinal specialist would describe it as the cleanest population to observe a treatment effect in, because there aren't complicating factors, there isn't any issue of, you know, a prior response, and what does refractory mean? So I think, you know, as of right now, that's the, in terms of registrational study, you would expect to have like 75, I'm talking about DME now, 75% of patients be treatment naive, the others would really be to expedite enrollment and, you know, and maybe make some observations about how did your drug behave in someone who had had prior ILEA or Vibismo, but you would have a lost period in these studies. So it's not like it's a crossover design. Now, I think where you're going with the question is also, you know, um, um, you've, you've, I'm sure heard from retinal specialists that, you know, there may be a large majority of patients who I wouldn't call them refractory, but still have fluid on the current drugs um and you know some people have called them incomplete responders is that a viable target population you know for us to pursue and i think the answer is there's unmet need in that population for sure um and sorry my lights just went off um and um and you I think one could envision a study that investigates those patients, and that could be quite important to show, for example, that if someone has incomplete resolution of fluid on ILEA or of a BISMO, and you were able to resolve fluid, switching them to 8141 could be clinically really meaningful. But again, there's no precedent for that resulting in a labeling for you in that indication. But I think in reader psychology, that could be quite important.

Okay, that's very helpful. Maybe taking a step back just to think about the landscape, where do you see the greatest unmet need when we think about what AMD, DME, UME, you know, in the context of standard of care therapies, is there a direction that you think the WENT platform could be best positioned strategically among those different indications?

You know, I think our preclinical data and the biology would suggest that, you know, those and other retinal vascular diseases are all really viable target populations for us. You know, another disease that has overlapping pathology is retinal vein occlusion. And so, you know, there are, I think, you know, a pretty broad array of opportunities for Wnt signaling and VEGF inhibition combined. You know, we've talked about this before. I think the biology in the retinal vessels in particular is like very straightforward and quite elegant. activating wind signaling up regulates tight junction proteins these are directly reducing vessel leakage um and um and so there may be maybe you could argue there's a a straighter line to dme for the wind agonism portion of the molecule you know on the other hand wet amd is very vegef sensitive and vegef driven disease so having the combined molecule could be very important in wet AMD. So, so I think they're all really tractable opportunities. And, you know, I think we would anticipate, you know, over time exploring, you know, many or if not all of those.

Okay. Excellent. So one other question I wanted to ask was considering the therapeutic development in the retina, including tyrosine kinase inhibitors, buy and try specifics, even biosimilars, for instance, how do you envision a candidate such as 8141 ideally positioned within the retina market?

Yeah, I mean, you know, ideally, I think you'd achieve those clinical benefits that I described, you'd be the best drying agent. And so just to give an example of what that might mean in DME, you know, in DME, if you had 80% of patients with no macular edema, no intraretinal fluid, I think that would be, you know, a really clinically meaningful and differentiating benefit. You know, the current agents get to about 40 to 55, 60%. If you add it on top of that, this reperfusion, you know, that would be, you know, I think, again, clinically highly differentiating. And then if you really wanted to say, what would it take to, aside from what those really important clinical benefits as you know, durability is important. Um, less frequent injections is important. If you could achieve those and have an every six to nine month injection, I mean, that's sort of your world beater profile, I think is to do all of those. Um, and, um, you know, we're, we're, I think enthusiastic and opportunity and optimistic about the potential for this to be, a less frequent injection than every other month, maybe. Maybe it's every three to six months. But the animal data, ultimately the human data will really dictate how durable the treatment response is.

Sure. Understood. And I know we only have a minute or so left here, but we've touched on this in the past with AD141. As that program moves towards the clinic, what biomarkers or imaging endpoints do you think could have the most important impact from a clinical proof concept standpoint? I just wanted to note that that IND is targeted for second half of this year, I believe. What kind of biomarkers or what kind of initial signals do you think could be most useful for folks?

Yep. So, you know, you know, in this field, people call changes in retinal anatomy a biomarker. So sometimes people are confused because we also do measure like an aqueous humor proteins to see if there's something, for example, that if you activate wind signaling, is there a protein that's upregulated that would be a biomarker for wind signal activation? We'll look at that and take aqueous taps in the study to see if there are any soluble biomarkers of treatment response or wind signal activation. On the imaging side, it's really everything that's very well-established modality like OCT for the identification well first of all something called ETDRS for the visual acuity right that's a well-established and validated visual acuity method OCT for the fluid measurements and then for this reperfusion there are actually some other methods that are you know typically used but again VEGFs have not shown a response in those. And these would be what's called OCT angiography and ultra wide fluorescence angiography. So the sites that we and others would use, you know, would typically have all of these instruments available. And, and, you know, so these are, these are, I don't think there's, there's, there aren't any unique endpoints. There would just be a unique treatment effect if we saw it.

Right. Okay. Understood. That'll be great to see that program in the clinic. Maybe just lastly here in our last minute, are there any aspects of the pipeline or when biology overall that you believe investors are not fully appreciating in terms of the WENT therapeutic opportunity, the unmet needs in the retina, kind of what folks may or may not be missing at this stage of development?

I mean, I think, you know, I think our program, you know, the Merck program, you know, general now rising interest and understanding of Wnt in the retinal specialty field. I think people have really begun to understand how this is a really critical pathway in the retina, you know, both for development and also function. You know, we don't have other programs that are funded that we've emphasized, but there are a lot of other targets in the eye for Wnt potentially. And so we've talked to you a little bit about the front of the eye. There are quite a few Wnt responsive tissues in the eye. So I think, you know, vision, long-term vision for the company, I think if we achieve some success with 8141, you know, that could lead us to pursue other cell types and targets in the eye. It really turns out to be a, quite a good, um, opportunity set of cells that, um, express not necessarily frizzled for, but other frizzled receptors where wind agonism could potentially have a therapeutic benefit.

That's very exciting. Um, well, with that, I'd really like to thank Sorosin and Craig, obviously for joining us, you know, a very engaging platform and approach as a novel, novel path in the retina. So really excited to see the progress and thank you again for joining us. It's been really helpful and really great.

Have a good rest of the day.

Appreciate it. Thank you, everyone, for tuning in. Appreciate it.