All right, well welcome back everyone to H.C. Wainwright's BioConnect Investor Conference here at NASDAQ. My name is Matthew Caulfield. I'm a Senior Biotech Analyst at H.C. Wainwright and we're very grateful to be joined by Cerrozen. It's our next participating company and we welcome Craig Parker, CEO at Cerrozen, as well as Andrew Malecki, CFO. Thank you both very much for being here. Thank you. Good to be here. Excellent guys. So maybe to start off, could you provide a kind of a high-level view of Cerrozen's platform focusing on the WEND pathway and how that could have important therapeutic implications for vascular renewal and repair as we look at retinal vascular disease.

Of course, yeah, we're really excited about the opportunities that this biology presents, particularly in the eye. So the company started off as a specialist in focusing on Wnt biology as a way to regenerate tissue. Really decades of elucidation of this pathway as a really critical pathway in biology. pointed to this being a really great opportunity for therapeutic intervention to be able to activate the pathway for therapeutic benefit. There are several human diseases that pointed the way towards one particular receptor in this pathway being critical for retinal vascular diseases. So I won't go into those diseases in detail, but they did highlight that frizzled four in particular, which is one of the receptors in this pathway, is critical for normal retinal vessel development and normal retinal vessel function. So when we started the company, we worked on developing a very drug-like antibody-based format for targeting the receptors in the pathway. There's a receptor and a co-receptor called LRP, and making these very developable molecules, so very well-behaved pharmacologically, very well-behaved for being able to formulate into even intravitreal administration type of formulations and then pointed that towards some of these areas like retinal vascular disease where we knew that one particular receptor was critical so um i think we've got the company was the discovery of the formats the specific antibodies that we're developing um what's really interesting about this biology in the eye is these rare childhood diseases suggest it's really important for retinal vessel development and for normal retinal vessel function so some of these kids will have a mild phenotype when they're born and then as they grow into adolescence they'll start to lose their retinal vessel function and even vision so that looks like what happens in diabetics you know when they're 40s and 50s, and then age-related macular degeneration, you know, in your 60s or 70s. So that, I think, really pointed to the opportunity to intervene in this pathway for therapeutic benefit in these other diseases.

That's very helpful. I mean, there has been buzz around the WEN pathway, obviously, for example, the Merck acquisition of iBio back in 2024, over a billion-dollar deal, as well as milestones as well.

Are there other ways you see WEN biology potentially addressing unmet needs as we think kind of broadly about retinal diseases yeah so i mean as most people probably know the vegf molecules that are on the market today treat these diseases quite well you know until the very first vegf molecule was launched it's now going on 20 years ago um you know prior therapies had barely been able to slow the disease and it's really great for patients that the VEGF molecules actually improve visual acuity. They actually dry the retina. So that's been, you know, really fantastic benefit for patients. But there are still some patients who have what would be called residual fluid in their retina. And then there are patients who have areas where they don't have adequate vessels. And so one of the hallmarks of this disease or both these diseases are that the retina becomes hypoxic. So not enough oxygen. That's what stimulates VEGF production and this really unwanted excess vessel development. But what also happens is you lose vessels and you have these areas where there are no vessels. And one of the very unique aspects of Wnt biology that you alluded to was the ability to regrow vessels in those areas. And we think that's an opportunity to really differentiate the pathway and our molecule in human disease is to not only provide very good drying, which is really critical. It's what drives the treatment choice for retinal specialists is how well the retina dries after you give the drug, but also be able to address these areas of what is called retinal non-perfusion. And these sometimes are areas that affect vision. Sometimes they're more peripheral, but they're still believed to be and are correlated with more aggressive disease and more rapidly progressing disease. So I think it could be really important, even if there's not an immediate visual acuity benefit or visual function benefit to address these areas of non-perfusion. And that's what's really unique about Wnt biology. So we've taken that, best of Wnt biology, coupled it in our molecule with BGF inhibition. And we think that's really going to be, hopefully, have added to benefit on both those endpoints.

Very, very encouraging. So one distinction along those lines in Wnt development is that Merck's phase 1-2 asset Restored is a tri-specific Wnt agonist and fcd4 binder while lead asset scn8141 uses both the fcd4 targeted antagonism and vegef inhibition how do you view sort of overall the most important differences between those assets is that kind of the core differentiation yeah so you know it gets very confusing when you start to talk about specificity and valency of these really complex molecules so So the Wnt end of our molecule, and so the principal difference, maybe the most easily identifiable difference between our molecules, is they do not have a VEGF inhibition compound.

So if they wanted to achieve that, you would have to co-inject a VEGF inhibitor, and that has its own challenges to be able to get reimbursed and have the patient agree to basically twice as many injectors. the wind end of the molecule is doing the same thing now there are very different characteristics we think our molecule is more potent than restaurant it is in vitro we'll see if that translates in vivo but you know the most really easily identifiable difference is not the valency or the specificity because they're binding two different lrp epitopes that may or may not be important but it's really this difference of adding the veg f on and then the wind portion being more potent okay and it's really it's not because of the specificity of their molecule for lrp different epitopes of lrp5 that probably makes the difference there are probably some other aspects to the format where you put the binders um and the affinity of the binders that might make a difference we'll see um one point i wanted to make was rosin has its strategic partnership with Boehringer-Ingelheim for retinal asset SCN413, which had positive outcomes from its IND-enabling GLP talk study.

How has that collaborative partnership and 413 progress provided further validation for the internal Wendt platform?

Yeah, so we actually worked on Frizzled 4 quite early in the company's history and invented what became the molecule to be licensed to BI. you know we had a really productive collaborative research phase of the agreement at this point it's an out license you know we're excited for them to get in the clinic we don't know a whole lot more about their own you know plans or timing we just know because they had to pay us a milestone that they completed ind enabling talks but you know excited that there'll be another molecule that we're going to get some economics on. So, you know, this partnership has kind of typical additional milestones and royalties associated with it. So, of course, we're excited for them to move forward but don't really know anything about the timing yet.

I mean, as we think about kind of read-through from that development to the current internal development, so 413 had prior success in the preclinical models of retinopathy with lens signaling, retinal vessel regrowth, pathological vessel suppression, reduced vascular leakage, Should investors separately look to the internal molecule 8141 that's in development, either match or possibly better that profile? Like, are there kind of new distinctions for the internal pipeline?

Yeah, I mean, the reason we put the VEGF on is we think that certainly in the human retinal vascular diseases, there could still be a contribution of VEGF, even if you're getting all the benefits that you see in preclinical models of the Wnt activation of all that you just listed. So obviously, we've added VEGF on because we believe there could still be a contribution of VEGF to the pathology in human disease, and they don't have that component to their molecule. So we would hope to have all the benefits of the Wnt signaling along with the VEGF inhibition. And then we also have a next molecule that adds IL-6 inhibition onto that.

And the foundational story is the same you know take individual pathways that have been shown on their own to be individual contributors to the disease where the monotherapy has an effect you know put those into one molecule and there's um growing data on the role of il-6 and multiple retinal vascular diseases yeah absolutely um very helpful so in terms of thinking about differentiation with standard anti-VEGF in wet AMD, for example, for those treatments with those treatment durabilities lasting roughly two months, two months in terms of their intervals, maybe three to four month durability with ILEA-HD or Biasmo, novel TKIs, possibly expanding that to maybe six or nine months or beyond. How do you believe a therapy like 8141 could be most kind of uniquely positioned within the landscape?

Yeah, I mean, I think durability is important. It's certainly important to patients to have the least number of injections. But I think what's really paramount is retinal drying. And I think if you ask retinal specialists, and you see this in some of the surveys, you know, as new mechanisms have emerged, I think you've heard retinal specialists talk a little bit less about the unmet need being durability and more about the unmet need being retinal drying. Because three years ago, four years ago, there wasn't really an opportunity for better retinal drying. And now with multifunctional antibodies, with Wnt, with IL-6 emerging, I think we're seeing opportunities to achieve better retinal drying. So I'm not saying patient convenience and durability are unimportant. I think you probably should hope to get to no more frequent than every eight week injections. But if you don't have better retinal drying, I don't think less frequent injections are going to position you ideally in the market. And I think if you look at the actual use of Vavismo, and this has been presented at conferences by multiple investigators and clinicians, the average number of injections of Vavismo is seven a year. In their phase three trial, 80% of patients got to every 12 to 16 weeks, but that's not how the drug's being used because you want to make sure to never have fluid accumulation because that's what leads to vision loss. So I think if you had better drying and every eight week, and we could have much less frequent than that, but if you had better drying in every eight week, I think that's the ideal profile. Every 12 week might be ideal, But I think if you have better drying, the durability of getting past every eight weeks becomes secondary to the retinal anatomy effects.

I think that's very helpful. Kind of along those lines with maybe the benefits of targeting the retinal drying, are there certain types of patients in wet AMD or DME, for instance, that could be optimal candidates? Like maybe more advanced patients, maybe earlier patients? Maybe a little too soon to know.

No, I mean, I think, you know, we have our head of clinical development is a retinal specialist. And, you know, he's asked this all the time. Are there baseline characteristics where you can have someone who predicted to have a better treatment effect? And I know he would say, you know, it's one of the challenging aspects of being a retinal specialist is so far, no one's identified any baseline characteristics that tell you whether someone's a good VEGF responder or a durable VEGF responder. Now, what he would also say is, if someone has a rapid response, that's predictive of a durable response. But prior to treatment, there aren't baseline characteristics that would help you identify responders versus non-responders, or durable responders versus shorter-term responders. so um the i know what he would also say is the psychology of retinal treaters is if something shows a drying benefit in one patient segment you will use it everywhere and i think you see that in vabiasmo's commercial success and you know that it was adopted very quickly and became i don't know if it's exactly the market leader in every uh in every segment of the market uh you know it went from being launched and within a couple years to being a five billion dollar drug because of that better drying and that better drying translating to utilization across you know treatment naive incomplete responders dme wet amd understood that's very helpful and encouraging it shows there's still ample demand there's there's clearly still unmet need right as as as beneficial as these drugs have been to improving visual acuity and and and um and clinical benefit compared to what we had you know 25 years ago there's still an opportunity for better drawing Not 100% of patients are achieving a completely dry retina or absence of macular edema, in DME anyway.

So also for SCN 8141 development, the IND is targeted for second half of this year. Even at a high level, what can the team share with us now in terms of hypothetical or actual relevant indications? kind of what your thoughts are around highlighting the novelty and the benefits of the WEN agonism in these initial indications.

Yeah, so I don't, you know, I don't know that we're going to break new ground on trial design or indication selection. You know, retinal vascular disease would all be relevant for this pathway. So that would be DME, wet AMD, retinal vein occlusion for IL-6 containing molecule uveatic macular edema because that's a more inflammatory driven disease um you know whether you go after incomplete responders or not and try to show some benefit i think is valuable but it's challenging because their expected response is not very well characterized there's no accepted definition of who an incomplete responder is and So that's why you see many studies enroll treatment-naive diabetic macular edema because it's the way it's well-characterized what their response to VEGF would be. A retinal specialist, I think, would describe it as sort of the cleanest population with respect to the disease progression. And so, again, we're not going to probably break new ground. But it would be some combination of DME, probably treatment-naive DME, wet AMD, possibly retinal vein occlusion. That's very helpful. In terms of, you know, one of the nice things as a drug developer in this field, compared to a lot of other therapeutic areas, is there's a very rapid response to these class of drugs, to the VEGFs, at least, and in Merck's data, to Wnt agonism. So you see a treatment effect in weeks, not days. It's clearly measurable at four weeks, eight weeks, and 12 weeks. it could be really valuable and important to follow patients for a couple more months to see what the durability is but you see a treatment effect very quickly both retinal drying and visual acuity treatment effect really quickly so we would hope to see that better drying you asked what would differentiate the drug yeah and there are well-established modality imaging modalities for measuring this reperfusion effect. So there's OCT angiography and something called ultra-wide field angiography where you can identify these lesions that are ischemic or not perfused and see whether you've been able to increase the perfusion.

Very interesting. So that could be something that could be looked at in addition to visual acuity, the drying, sort of the initial sort of biomarker. Yes, exactly. Very helpful. um one important pipeline distinction is that there is the additional preclinical progress for scn 8143 which you alluded to um that targets the the fizzled for anti-vegf and the il-6 kind of the tri-specific approach can you speak more to the il-6 blockade and its relevance to targeting inflammatory signaling sort of retinal edema and how that plays into that target yeah i mean the il-6 story is really interesting i mean this is not uncommon in medicine where you know case reports from drugs being used in a particular patient population where the patient has another disease comorbidity leads to drug development of that mechanism in a different disease so in this

case there were people who had autoimmune diseases like lupus or you know they're they're a large set of autoimmune diseases that are associated with uveetic macular edema and these patients were getting systemic IL-6. And when they went to their ophthalmologist, because they had UME, they could see that there was some improvement from getting IL-6 inhibition, probably at very low doses because it was being given systemically. That led people to look for IL-6 in the eye, and then observations were made that indeed IL-6 was elevated in some of these diseases like DME and UME. So that's what led to development of intravitreal injections of anti-IL-6 antibodies. What's been really, I think, encouraging for our approach is that there's now data from companies like Kodiak, for example, where VEGF plus IL-6 inhibition can lead to really very impressive drawing outcomes in UME, where it is a more inflammatory-driven disease. many of these patients have that background, but also there's been recent data showing an additive benefit of IL-6 to VEGF inhibition in DME. So clearly it's a contributor to the pathology of DME. You know, the magnitude of that benefit, I think, you know, we'll just have to see with our molecule in the clinic, but there's, there's, I think, emerging evidence that IL-6 inhibition can add on to VEGF until our molecules in the clinic. We won't know if the triple combination provides additive benefit, but there's certainly a growing data set that IL-6 is important to you as well as you may.

Yeah, very encouraging. And then also, I know we're a little shorter on time, but I wanted to touch on the ARVO presentation as well. Team highlighted preclinical efficacy of 8141, can you maybe just go through some of the high-end, high-level takeaways from the OIR mouse model that you shared?

Yeah, so I alluded to this about what differential treatment effect we might see. So this is a mouse model where you damage the retina in the mouse. You can see that there are leaky vessels, like in the human disease. You can see these areas where there are no vessels, like these areas of non-perfusion that I alluded to. And in that model, what we've seen previously is that Wnt can address both the leaky vessels and the areas of non-perfusion, that a VEGF molecule can address the leaky areas but doesn't really do anything in these areas of non-perfusion, and that the combination in one molecule seems to have synergistic effects over each of those approaches individually. and so that's really exciting that something about combining those mechanisms into one molecule and by the way we had a control and a cohort in this experiment where we mixed the veg f and the wint and putting them in one molecule even had a better effect than just a co-mixing of the two separate antibodies so something about putting the the two mechanisms into one molecule seems to have an additional additional benefit so you know we'll see does that translate to better potency better durability the potential is both and the potential could be that you know that you're able to stay above a minimally effective concentration because you're so potent that you have a very durable effect very encouraging maybe just in our last minute or so um obviously second half of this year, the IND for 8141, that's kind of key to investors' radars.

Do you feel there's anything that's been underappreciated by investors about the platform? Is it just that they want to see that clinical validation?

Yeah, I mean, you know, I think there are few enough scientific contributors to this field that people know we're one of those leaders, if not the leader. You know, there's really only one other group that is what ultimately became the restaurant molecule um that had pursued this field and published on it so i don't think we've had a challenge convincing people you know that we're experts in the pathway experts and being able to agonize the pathway with antibodies experts and coming up with formats of these antibodies that you know look to be very um desirable from their pharmacology and obviously desirable to partners. You know, I think people are pretty well attuned to the Merck data being really important. A crucial concept for the target, I'd say maybe what we've tried to emphasize is that, you know, let's say Merck's, I don't know when they'll present this data, numerically isn't quite as good as VEGF. I think that's still very good for our foundational approach that's you know adding mechanisms you know they don't have to be exactly equal to veg f for our thesis i think to still um still be completely intact so i think you know they clearly show activity have clinical benefit be safe but i don't think they need to be exactly as good or a little bit better than the veg f arm that's their comparator arm right understood well very helpful i will with that thank you everyone for participating thank you very much to sir Rosen.

We're very excited to get into the clinic here.

Yeah.

Thanks for having us. Thank you. Thank you.