Welcome back, everyone, to H.C. Wainwright's second annual Autoimmune and Inflammatory Disease Virtual Conference. My name is Matthew Caulfield. I'm a senior biotechnology analyst here at H.C. Wainwright. We're grateful to be joined today by BioCryst Pharmaceuticals, and specifically Dr. Helen Thackray, Chief Research and Development Officer at BioCryst. Thank you, Helen, for joining us today. Thanks, Matt. Pleased to be here. Absolutely. So most of us know BioCryst as a commercial-stage company focusing on complement-mediated and rare diseases, particularly with approved oral Hereditary Angioedema prophylactic therapy, ORLADEYO. Today, we're going to turn our attention to the advancing pipeline of small molecule and protein therapies, and specifically, your work being done in Netherton Syndrome. So maybe to start things off, we wanted to discuss the broader pipeline and specifically, the, as I mentioned, the KLK5 or kallikrein five inhibitor for the treatment of Netherton, that's Candidate 17725. Can you give us an overview of Netherton Syndrome overall and what the current treatment landscape looks like for patients? Sure. First, I will be making some forward-looking statements, and these statements have risks, and the associated risk factors can be found on our website. So, we have a broad and developing pipeline. Mm-hmm. We are experts in structure-guided drug design, and we've expanded our platform to be able to apply that to both small molecules and now protein therapeutics as well. Mm-hmm. The goal, as we do that, is to develop a drug that delivers a first-in-class or best-in-class differentiated molecule for rare disease, improving the burden of disease or the burden of therapy, and we've done this with ORLADEYO. Our goal now is to do this with a second molecule, and a third, and Netherton Syndrome is one of the areas that we're focusing. Netherton Syndrome is a genodermatosis. It's an ultra-rare disease, and it is a genetic or inherited disease of the skin, hence the name genodermatosis. It's lifelong and manifests with three main areas of clinical hallmarks. One is the skin. It manifests with very poor skin barrier. We'll say more about that in a minute. Mm-hmm. Second is atopic manifestations or allergy-like manifestations, and the third is fragile and abnormal hair. So, to say a little bit more about how it manifests then, it's lifelong, as I said. Manifests first then in infancy. It tends to be most severe in infants, and it is a severe- Mm-hmm ... disease. So infants are identifiable immediately upon birth by their red and very scaly skin with very poor skin quality. And as they age to children and then to adults, the disease tends to become less severe. However, it remains severe over the course of life. There's an associated high morbidity rate, so complications from the disease that are worse in infancy. There's also a fatality rate, about a 20%, up to 20% fatality rate in- Mm ... infants and young children. It's less likely to be fatal as patients age. So back to the hallmarks that I mentioned, skin and poor skin barrier is a major hallmark in infancy. The atopic manifestations come later in life. The skin performs a really important function. It protects and maintains moisture within the body. It also protects against outside sources of injury, such as infections. And in infancy, the lack of a good skin barrier is really important. It means that infants may require intensive care to maintain- Mm-hmm ... the moisture, so hydration, maybe an intensive care therapy in the hospital. They also require care to maintain protection against infection and then to treat infections. And over life, that poor skin barrier function means that there is a chronic redness, scaliness, thickness to the skin. It's poor in terms of its quality, it tends to get infected, and it requires lifelong care that is entirely over the entire surface of the body. Finally, the atopic manifestations that tend to show up in childhood and later in life, that's an inflammatory component of the disease that leads to allergic-mediated or allergic-like symptoms. Patients have high levels of IgE and manifest symptoms that you see in other allergic diseases like asthma, hay fever- Mm-hmm ... food allergies, very itchy skin, red skin that can get infected easily. And these things plague patients throughout their lives. Third, the last piece that I mentioned is not as serious from a medical perspective, but the fragile and abnormal hair can be incredibly disturbing to patients. Hair is produced by the skin. In Netherton Syndrome, there's abnormal hair that's produced, and it's brittle. It breaks off, so that includes hair on head, eyebrows, eyelashes. Mm-hmm. Patients live with the disfiguring manifestations then of having abnormal hair. You also asked about treatment landscape? Yeah. So there is no targeted treatment. So right now, there is a high unmet need for targeted treatment that gets at the source of the disease. Treatment is supportive, treatment is symptomatic- Mm-hmm ... topical treatments to maintain as much the skin barrier as possible, treatments for infection, treatments for those atopic manifestations as well, and that is a lifelong daily need for patients. Mm-hmm. That was very informative and, you know, very helpful to kind of hear about the manifestation and also the current limitations in therapy. So the team had mentioned at your R&D day in November that you could use your structure-guided design platform tech used to create ORLADEYO, which is a small molecule, to also develop large molecules, such as protein therapeutics. Can you discuss the process of creating a protein therapeutic, and how that differs from the development of a small molecule, as an example? Sure. So our structure-guided design is applied both to small and large molecules. It's the same platform- Mm-hmm. It's the same approach. It allows us now to choose the best tool for treatment of a disease, if it's a small molecule or if it's a protein therapeutic. Our goal is to develop a drug that is, as I said, first-in-class or best-in-class- Mm-hmm ... and to do that in a way that allows for optimal treatment of the disease. That needs to be a drug that is potent, that is specific, and that has appropriate bioavailability to deliver the drug to give exposure at the target at the right amount to have an effect. That has to be done, to get to that degree that it could be best-in-class. Mm-hmm. It's a difficult task, and it's one that we use our structure-guided approach and an iterative approach to design for small molecules or large molecules. The difference between the two is just the size of tool that you're using. Mm-hmm. With a small molecule, we're building a discovery drug atom by atom. With a large molecule, we're building it amino acid by amino acid. Mm-hmm. But it's the same underlying approach to defining the structure and building a drug that fits well to deliver that potency and specificity. Okay, very helpful. Thank you for that. And then maybe more specifically then, could you speak to why you particularly chose the KLK5 as your first target for this program in looking at Netherton Syndrome? Yeah. So we always look for validated targets, and- Mm-hmm ... KLK5 is a biologically validated target for Netherton Syndrome. It is dysregulation of KLK5 that is the source of disease. Mm-hmm. We also are always looking for areas of high unmet need in rare disease, and clearly, if there's no targeted treatment for Netherton Syndrome, this is an area of high unmet need. Mm-hmm. It's also a very severe disease, and so the ability to deliver a targeted treatment would have a meaningful benefit for patients. And finally, KLK5 itself is a serine protease, and that's a particular type of enzyme. It's a difficult one to design a molecule to fit. It's the type of enzyme we've been working with for decades, and we know that type of structure very well. So for us, it's attractive as a target for all of those reasons, validated biologically- Mm-hmm ... and could have a big impact on patients, and it's a type of enzyme that we know very well. Mm-hmm. Okay. And then regarding the approach to creating 17725 and the choice to pursue KLK5 inhibition, can you speak to how this compares to considering anti-inflammatory therapies, such as IL-17 or IL-23 therapy, as examples? Yeah. So I might take that in two parts. Yeah ... one, the design of the molecule, and then two, that over an anti-inflammatory. Mm-hmm. So first, the design of the molecule is structure-guided, as we've been talking about. KLK5 is a serine protease, one, as I said, that we know the type of structure. Mm-hmm. We understand the structure to a great degree to start building a molecule, and we do it through protein crystallography and X-ray crystallography, then getting to a deep understanding of the structure, but also, as we build the molecule, co-crystallizing and getting to a deep understanding of the structure and the drug together, and any changes in the protein as it then binds with the drug. In this case, we designed atom by atom and amino acid by amino acid- Mm-hmm ... to achieve that end. The way we need to do it is to design a molecule that fits very specifically, close, tight fit into the binding space. Mm-hmm. The active site in the enzyme is an area of great inspection at this point. We started with a natural ligand for KLK5. SPINK9 is a protein that's a natural ligand, and we built or changed the amino acids that fit in the binding site to develop a molecule that fills the gaps in the binding site better, matches- Mm-hmm ... charge, positive to negative, better, and by doing so, gets to higher potency and tight affinity, great affinity. And as a result, we designed a molecule, our 17725 molecule, that is a million-fold more potent for KLK5 than that natural ligand. Hmm. So we have a highly potent medication, that's also highly specific, that we believe has the potential to be a best-in-class drug. The second part of your question was the choosing KLK5 over anti-inflammatories, and I'll go to- Mm-hmm ... the pathway of disease for to answer this one. The source of Netherton Syndrome is a mutation in SPINK5 that regulates KLK5. If you no longer regulate KLK5, it can be overactive, and it activates downstream kallikrein, kallikreins. It also activates downstream inflammatory molecules and cytokines. We want to treat at the source of the disease, KLK5. An inflammatory therapy might treat one part of that downstream cascade, the inflammatory cytokine part of the downstream cascade, but it's not gonna treat- Mm-hmm ... the other elements of the cascade, the other kallikreins. So for us- Mm-hmm ... we went to the source, that KLK5, which then will down- inhibit downstream the overactivity of both the inflammatory molecules and the other kallikreins. ... Very interesting, and I think this kind of plays into the next question, but I wanted to ask you, so LifeMax is currently in the process of developing a candidate, LM030. That's a topical KLK7 treatment for Netherton. That's going into their pivotal phase. I was just curious to ask you if you could discuss the difference between the KLK5 and the KLK7. That's essentially different stages in the pathway, or what, what more can you- Yeah kind of speak to that distinction? I can give you a little more on that. So yes, they're different- Yeah -stage pathway. KLK5 is at the top, it's the initiating piece of the pathway. KLK7 is the next step. So KLK5- Mm-hmm ... activates KLK7. If you have too much activity of KLK5, you have then too much activation of KLK7. Both are involved in regulation of skin function. Mm-hmm ... and skin formation, as well as, degradation of skin in a normal manner. You want to have some activity, in order to have normal degradation and turnover of skin, but you don't want to have- Mm-hmm ... too much activity, or you will have degradation of the skin beyond what's needed, and you get to a fragile skin barrier. Right. Very helpful. And then in thinking about the understanding of the SPINK9, I believe you also mentioned SPINK5 possibly, and poor binding affinity. How is this considered in designing a better ligand for improved binding affinity, which could lead to a potential treatment that could correct the underlying mechanism of disease? So SPINK5 is the mutation and- Okay ... non-functional in Netherton Syndrome. Mm-hmm. We use SPINK9 as the framework, the scaffold, to build our fusion protein 17725. Mm, mm-hmm. It is a natural ligand. It does have activity on KLK5. It has gaps and opportunities in the structure to improve. Mm-hmm. That's what we did, what we used, changing amino acids and building the binding site portion of the protein, sort of rebuilding it over the natural SPINK9 structure to fill those gaps, to get to a matching of charge, and matching of size, and better potency, and that's how we ended up with the million-fold potency improvement of 17725. Mm-hmm. Very interesting. Thank you for that. And then just kind of thinking overall, what does the future of this structure-guided platform look like? Is the plan to focus on developing protein therapeutics, or to branch out to other large molecule therapies, or kind of what's the thought process currently? So our future, we think, is exciting. It's Mm ... what you're seeing today with the number of molecules in our pipeline is an expansion of our ability to deliver on targets now with the two different ways of using our platform, both small molecules and protein therapeutics. Mm-hmm. For us, that means we have more targets that we can deliver molecules for. We're not limited to those, for which we can design a small molecule. We are agnostic to which type of molecule we choose. We'll pick a char- Mm ... target first, and now- Mm-hmm ... we have the opportunity to deliver a small molecule, or if that's not achievable, or might take longer, we can deliver with a protein therapeutic first. In terms of branching out to other types of large molecules, that's not currently in our plan. But- Mm-hmm ... I I can't speak for what we do in the future. All right, great, thank you. Very, very helpful. And then kind of turning gears to regulatory considerations and timelines, what are some of the regulatory considerations that you'll have to take into account when developing and producing a protein therapy? And maybe you can speak to the experience and process for developing and commercializing protein therapeutics. So the regulatory considerations are going to be the same, where the disease is the involved, so the clinical side. Mm-hmm. The disease is what drives the regulatory considerations, and that will be very similar between a small molecule and a protein therapy. Mm-hmm. On the manufacturing side, of course, there are different rules and guidelines that apply. Those rules and guidelines are actually very clear. It's really standard to make- Mm ... protein therapeutics. It's standard in terms of what's needed for manufacturing, what's called good manufacturing practice. It's standard procedures- Sure ... the guidances are clear, and this area is pretty well-known. So, while it's different, it's also very well-known. Very helpful. Then when it comes to the processing, storage, and delivery of protein-based drugs, are you concerned about degradation or denaturation? What is the plan to overcome any such challenges? So bottom line, we're not concerned. Mm-hmm ... if we have a molecule that, as with any of our pipeline programs, if we have a molecule that's not meeting our standards, we would not continue with it. Sure. But the class of molecules, again, so it's fusion proteins and protein therapeutics, the class is well-known. The handling and storage approaches to address some of what you're mentioning, it's also fairly standard and well-established, and so we're not concerned in terms of these being challenges. Mm-hmm. Okay, very helpful. And, you know, we had alluded to a little bit of the mechanism, but have you received any feedback from physicians or KOLs regarding the decision to target KLK5 rather than targeting the immune response or other proteases? We obviously touched on KLK7 as well. Bottom line, patients, physicians are excited, because there isn't a targeted therapy for this disease. Mm-hmm. So those that we've spoken with have indicated that they... They're very interested in what we can potentially deliver, and they're interested also in collaborating with us. In terms of the target for KLK5, I think the experts who understand the disease recognize very clearly that KLK5 is the top of that cascade. Mm-hmm ... and the number one target, so there's general excitement in the approach that we're taking. ... Okay, very, very helpful. Then just kind of a broad overall question: How easy is it to, you know, I mean, I guess these patients, as you said, they're identified at birth. Can you speak to a little bit of the size of the population? Has that evolved over time or- So, this is- I guess within the U.S., maybe to start there. Yeah. Yeah. So it's ultra-rare. Yeah In the initial work that we've done looking at claims-based data, we've identified that there are probably somewhere around 1,600 patients in the U.S. Mm-hmm. The challenge is that this is categorized by clinical diagnosis, most commonly, and that falls under ichthyosis, which is thick, scaly, abnormal skin. Mm-hmm. That means that there are probably patients who have Netherton Syndrome who've not yet been identified as having Netherton- Hmm ... Syndrome. They are just put in the larger category of having ichthyosis. So the population may actually be larger than what's recognized in the claims database. But regardless- Hmm ... it's going to be an ultra-rare population. Gotcha. Understood. So an educational component would probably be part of the commercial story- Yeah ... then as well, it sounds like. Yeah. Okay. Very helpful. And then the previously mentioned plan was to initiate the phase I for 7725 this year, and then start the proof of concept work in 2025, with data expected in 2026. Does this timeline still hold, and can you add any color as to what you're hoping to see from the proof of concept data kind of down the line here? Yeah. So the timeline still holds. We're on target. Mm-hmm. Um Okay. In terms of what we expect to see in proof of concept, we always involve assessing patients for disease as early in program as possible. In proof of concept, we would be looking for not only the safety that you would usually look for early in a program and information about dosing, but we'd also be looking for clinical activity. So we'd be assessing- Mm-hmm ... whether we're, whether we have indications that there is effect in the skin once we deliver the drug. So that would be part, built into part of our, proof of concept, along with any symptoms that patients are experiencing. Mm-hmm. Understood. And then just kind of off the top of my head, like, do you feel that there'd be any sort of uphill recruitment issues for those preliminary clinical investigations as far as identifying patients and getting enough patients to be able to start the proof of concept work? So there are positive elements and negative elements to this. Yeah ... it is an ultra-rare disease. That means that there are very few patients, and they can be difficult to find. That's the case with any rare disease. Mm-hmm. On the other hand, it's a disease that once diagnosed, it tends to be treated by specialists, and so working with a specialist allows us to identify within the pool of patients they treat, those who might be interested in participating in a clinical trial. So it will take special attention to be able to recruit a trial like this, but that's- Mm-hmm ... what we do. We are experts- Sure ... for disease, and we know how to partner early with the specialist- Mm-hmm ... to treat for the disease, how to collaborate with them, to design our trials, make sure we're designing trials that make sense for what patients and the providers need, and so, and that then makes a trial that's compelling to patients. And, it makes it more likely that they'll enroll. Okay. Well, definitely very exciting, you know, for Netherton families or people that have been affected. It's encouraging to see sort of the real progress that you guys are making. Just in our last couple minutes, I wanted to make sure we did touch on Hereditary Angioedema and HAE, sort of a main focus from the commercial side of the platform. ORLADEYO is currently the only approved oral therapy in HAE, and there are several therapies currently in development, outside of your own platform. Can you speak to the new clinical developments for the treatment of HAE? Some of them, you know, Pharvaris' immediate-release capsule, currently in phase III. Intellia has a gene therapy that they're working on, publication in the New England Journal. Overall, how does ORLADEYO fit into sort of this growing, HAE landscape from your perspective? Treatment for HAE has really evolved. It's really great to see, and that means- Mm-hmm ... there are more options for patients, which is also great to see. Mm-hmm ...... ORLADEYO is a differentiated option for patient because it is the only targeted oral prophylaxis therapy on the market- Mm-hmm ... and that's the reality today. Versus injectables? Versus injectables. Right. Right. Mm-hmm. Right. So there are injectable therapies. ORLADEYO, as an oral, reduces the burden of therapy for patients with HAE. Absolutely. that you're talking about programs that, so the programs that you mentioned, there's one that's an acute treatment in clinical- Mm-hmm ... trials, and so that would be relevant for breakthrough attacks. Sure ... there's also the gene therapy, which physicians tell us that they would reserve for their most serious patients. Mm-hmm. Mm-hmm. Mm-hmm. What we understood is that more options are good, and as patients have experienced ORLADEYO, they have been able to experience that continuing control of attack- Mm-hmm ... with an oral therapy. So the question for a future therapy is going to be: What's new? What additional benefit does it bring beyond what patients are using, you know, now? Mm-hmm. And if a patient's controlled, and their attack rate is controlled on their current therapy, they're going to then look for anything that might improve their burden of therapy, but otherwise, be quite satisfied with the level of control. So with ORLADEYO, patients get both the level of control of the attack rate and the reduced burden of therapy. Mm-hmm. I think it's gonna be hard to offer meaningful benefit to patients who are already doing well on oral or once-daily oral- Mm-hmm ... therapy. But as I said, more options are always beneficial to patients. Yeah, absolutely. I mean, we followed the ORLADEYO story for some time here on our side. So one question maybe just to clarify for our listeners, in regard to your discussions with physicians, what still remains some of the biggest pushbacks or concerns about switching a patient for seemingly burdensome injectable therapy to switch over to a prophylactic oral, such as ORLADEYO? Like, what holds patients out from, you know, at least giving it a try? So, there's no pushback. Mm-hmm. ... but there's inertia. If a patient's doing well, it's not an immediate thought to go and try something else. Mm-hmm ... and so, what we found is that as patients get to know that there's an oral therapy available, as they go in to see their physicians and have their regular checkup, and, and, have a chance to talk about the therapy, that's when they start to look at whether they want to do something to reduce the burden of therapy. So switching from an injectable to an oral therapy is something that patients are doing at a fairly steady rate at this point. Sure. We've also been able to demonstrate in our real-world evidence that patients who switch are maintaining excellent control of their attack rates from their prior therapy to when they're on ORLADEYO, that control is maintained. And so it's. I think it's just a matter of time to have patients come in through for their routine visits and have a chance to talk through with their physicians what's the best choice for them, to be able to see whether the factor of inertia is something that Mm-hmm ... each patient, as they make their decision, they want to change course and move from an injectable to an oral. Understood. Yeah, it's been very interesting to see the innovation in the space, and obviously from BioCryst standpoint, it's been exciting to see the commercial progress quarter by quarter complement, you know, what, what's happening on the, the preclinical and the pipeline side. So very exciting to, to interact today and, and hear the updates. So with that, based on timing, I mean, that went pretty quickly, but I definitely want to thank BioCryst Pharmaceuticals and Dr. Helen Thackray. It's been a great conversation to learn more about Netherton disease or Netherton Syndrome, and also some of the differentiating considerations in that platform. And I'd also like to thank everyone for attending. This has been H.C. Wainwright's second annual Autoimmune and Inflammatory Disease Virtual Conference. So thank you again, everyone. Have a great-