BioCryst Pharmaceuticals, Inc. (BCRX) Earnings Call Transcript & Summary

Good afternoon, and welcome to the BioCryst Discovery Center of Excellence in Birmingham, Alabama. I'm John Bluth, the Chief Communications Officer at BioCryst, and we're so happy that some of you joined us here today, and a lot of you have joined us on the webcast to discuss our R&D Day portfolio. We will be making some forward-looking statements today. So please review those. Those statements contain risks and you can find the details in our securities filings and on our website. As you may have seen in the press releases we issued earlier today, we are going to be introducing you to 5 new programs today. And each and every one of them has the potential to be a first-in-class or best-in-class molecule, and we're going to take you through each of them in detail. We also announced today an exciting partnership with Clearside Biomedical that enables us to combine our plasma kallikrein inhibitor, avoralstat with Clearside's SCS Microinjector and device for patients with DME, and you're going to hear more about that today also. Now I'd like to introduce you to the BioCryst team you're going to be hearing from today. Joined here by Dr. Helen Thackray, who is our Chief Research and Development Officer; Charlie Gayer, our Chief Commercial Officer; Dr. Bill Sheridan, our Chief Development Officer; Dr. Ryan Arnold is our Chief Medical Officer; and Anthony Doyle is our Chief Financial Officer. Now I'd like to introduce Jon Stonehouse, our CEO, to get us started.

Good afternoon. Welcome to Birmingham, Alabama, Roll Tide. I'm sure I just offended a bunch of investors that are SEC fans from other teams. So I'll take that up for now. But let me add my welcome to you. I'm particularly grateful to those of you that made the treck here to Birmingham, Alabama, I know it's earnings week, it's a crazy time for you to be here, but we really appreciate it and trust me, it's worth your while. I also want to thank those of you who joined via the webcast. So today is a focus on the pipeline. But in addition to that, we're also going to show you how we build and discover first-in-class and best-in-class molecules. But before we dive in, I want to spend a little bit of time talking to you about ORLADEYO and make sure that you understand the impact that this therapy has had on patients and we'll continue to have on patients. In my over 35 years of being in the industry, I've seen some first-in-class and best-in-class molecules, I've been associated with them. I was involved with the first statin Mevacor when it was introduced back in the '80s. I was involved with Prilosec, I was the Product Director for Prilosec, the first proton-pump inhibitor. And I was involved with the EGFR monoclonal antibody Erbitux. So I've seen what first-in-class and best-in-class molecules can do, and they create massive value, massive value. But I've never seen the impact a drug has on patients than what I've seen with ORLADEYO. And it's all about rare. These patients need us and the impact that we have on them is amazing. And so what we're going to do and what we're going to show you today is that we can repeat this. We're able to continue to make first-in-class and best-in-class molecules over and over and over again and the value that we're going to create for patients is going to be huge and the value for our company is going to be huge as well. So to give you a sense of this impact, let me paint a picture for you. So imagine a little more than a decade ago, you were living with HAE. You had a few therapies available to you like androgens, but honestly, they had a lot of really horrible side effects. You spent years having your swelling attacks misdiagnosed. That led to countless trips to the emergency room and possibly even some unnecessary surgeries that led to stays in the hospital. You spent days cooped up in your house, waiting for the swelling to subside, coupled over because of abdominal attacks that were just unbearably painful. Couldn't recognize yourself in the mirror because of facial swelling. And all of this led to days miss from school or from your job that increased your stress level, added triggers that then gave you more swelling attacks. Horrible cycle. But worst of all, you lived in constant fear that the next attack, could be a laryngeal attack, and it could close up your airway and you could die. Thankfully, those days are over for many with HAE. In the last decade, there have been a number of really important therapies that have come forward that really control the disease. So the lives of patients with HAEs has gotten a heck of a lot better but all of these therapies are injectable. And you can imagine patients are saying why isn't there a pill for this disease. Simple question, reasonable to ask, but the science and the challenge is anything but simple. Many companies have tried, but only one company so far has succeeded. And today, HAE patients have the first and only once daily plasma kallikrein inhibitor -- oral plasma kallikrein inhibitor for the prevention of HAE attacks, ORLADEYO. And I can tell you, having recently been at a patient summit in Orlando, Florida this summer that -- it was the first time that ORLADEYO had been on the market for one of these patient summits, 1,000 patients and their caregivers, and people actually came to our booth to seek me out to say thank you. That's never happened to me in my career ever and they were so grateful they wanted the company to know the impact that -- and how it has changed their lives. Some of them even told me, occasionally, they forget they have HAE, that's the impact that we have with ORLADEYO, that's the impact we're going to have with some of these other molecules you're going to hear about today. And that impact is going to create huge, huge value. So we've been around for a while. A company that's been around for almost 40 years. Those who went on the tour today met people that have been in the company for 38 years and people that have been in the company for 30 years. That doesn't happen in biotech. But longevity is not the marker here, and this is a very different company today, a very different BioCryst. So how are we different? We're different in that we're expanding our pipeline and have more promising molecules than we've ever had before. And it's not just about more, more is important, but it's not just about more. It's also about bringing forward for those patients that have nothing, a therapy that finally gives them hope or for those patients that have something, bringing them something better that makes their life more like yours and mine, right? First-in-class, best-in-class. That's what we mean. And we believe we have the opportunity to help many, many patients and that's going to create continuous value for the company and for patients. We've also diversified our pipeline. So we've gone beyond small molecules and oral drugs and move to protein therapeutics and you're going to hear about that today. We use the same techniques, the same tools, the same skills we've developed over decades. But now you're going to see that we can build potent binding biologics. And so what does that mean? It opens the universe of rare diseases and targets massively for BioCryst to help more and more patients. Remember, 90% of patients with rare disease have no therapy at all, 90%. And so this just gives us an opportunity to help many, many more patients. You're also going to hear that we've expanded beyond with our small molecule oral drug program beyond enzyme targets. So our team has cracked the code on protein-protein binding with C5. Let me say it again. Our team has cracked the code on protein-protein binding with C5. And what that does is it gives us the potential to have an oral Soliris or Ultomiris. We know the value that we've created with an oral drug for HAE, imagine the value we can create for patients with myasthenia gravis. And today is not just about new discoveries, you're also going to hear about a drug that you've probably heard about before, and that's Avoralstat. This is a drug that we studied extensively in HAE. And our team and Clearside, as you heard from our announcement today have come up with what I think is a beautiful combination of drug properties and an injector device that gets it to the right spot that could help us create a best-in-class molecule for patients suffering from DME. The final important difference is our financial strength. Thank God in this market right now, having steady growing revenue, a strong balance sheet, enables us to be disciplined around only advancing and investing capital in the things that meet the bar best-in-class and first-in-class. And we have a track record of doing that, and we plan to continue. If we find ourselves in the fortunate position that many of these programs advance into advanced development and we don't have enough money to fund, we could always look to partners. They'll be beating down our door to help us with these programs. So we have never had this kind of optionality in terms of funding ever in the company's history. What does all this add up to? A biotech company that's poised to make a big difference in patients' lives. And we believe that's going to lead to sustainable growth for years to come. That's a very different company and a very different BioCryst. So before I turn it over to Helen, who is going to take you on a very interesting journey, I want to recognize the team here at BioCryst. No way, could you -- could we have what we have without these folks. The creativity, the brilliance, the perseverance, the commitment to deliver for patients is nothing like I've ever seen before. And you are in for a crazy good treat today because we're going to take you inside protein targets. And we're going to show you what we see, what our scientists see and you're actually going to see how we built atom by atom, amino acid by amino acid, best-in-class and first-in-class molecules. And this is why BioCryst has been able to do it when others haven't. So with that, I'll turn it over to Helen to take us on the journey.

Thanks, Jon. Good afternoon -- excuse me good afternoon, everyone. Very pleased to be able to share with you today our expanded pipeline and our specialized expertise in drug design. Our goal for our drug discovery of BioCryst is very clear. We are focused on delivering first-in-class and/or best-in-class medicines to patients with rare diseases. You'll see this today as we take you into our expanding pipeline and share how we are delivering more molecules faster and with greater potential to meet that goal. But before we get started, I want to share with you my view of what makes BioCryst special. As you may know, I joined BioCryst Board of Directors a little more than 4 years ago. And what I saw from that perspective impressed me. So much so that when the opportunity arose 1.5 years later, it was a privilege to jump in and join this great leadership team and be part of the high-quality science. So what was it that was so compelling? As you'll see today, the company is built on great science, starting with excellence and medicinal chemistry and structural biology right here in Birmingham. Second, our focus on developing and delivering medicines for patients with rare diseases is especially meaningful to me as a pediatrician. I've cared for patients with similar conditions and I've seen firsthand how devastating a serious rare disease can be for patients and their families and how huge an impact to successful therapy can have. And lastly, from my front row seat as a director, I watched this team demonstrate a level of perseverance and dedication that I found inspiring. What they did, as a result, obtain regulatory approval in 3 regions, and achieve the company's first rare disease launch in the midst of a global pandemic was unparalleled. And as a result, they discovered, developed and delivered a first-in-class medicine, ORLADEYO, the only oral plasma kallikrein inhibitor to be available to patients. This is why I made the unusual move from Director to become a member of the leadership team here at BioCryst. And this is the team you see now delivering on a robust extended pipeline that is bringing more options forward for differentiated medicines for patients. It's an honor to be here with my colleagues today and to be representing the excellent R&D team at BioCryst to share our progress and our plans for the future with you. So let's turn to what you can expect today. We will delve into our specialized approach that we use in our discovery engine to solve the challenges and drug design. First, you'll see why it's so hard to design a best-in-class drug and how we overcome this with our expertise in structure-guided drug design, including why and how we use crystal structures to inform building a high potency molecule to achieve that. Second, the common theme you'll hear today is that our goal for each of our molecules is to design a best-in-class or first-in-class medicine. And by that, we mean one that will alleviate the burden of disease or reduce the burden of therapy. How? We start with validated target, one known to impact the disease. We set a high bar for what we want from the molecules we build. And we look for excellent potency and specificity of our medicines to beat this bar. And then we test our molecules rigorously along the way to assure that we are advancing only those that could be differentiated, safe and effective medicines. This is how we developed ORLADEYO and delivered an oral drug that is a potent and specific kallikrein inhibitor when others have tried and only BioCryst has succeeded. Third, you'll also hear how we are expanding our platform technology by applying that same structure-guided expertise to protein therapeutics to increase and diversify our options in our pipeline and to bring select molecules to patients with more speed. And then you'll see why we are confident we can repeat the success we achieved with ORLADEYO. We'll show you the robust pipeline that results with more molecules that we believe can be differentiated drugs moving forward into the clinic than we've ever had before. We are advancing a broadened pipeline with plans to deliver proof-of-concept data for 6 molecules in the next 5 years. What I'm about to share with you is how we at BioCryst were able to build this robust pipeline filled with molecules designed to meet our high expectations for a differentiated medicine. You'll see how we create and deliver therapies with potential to be first-in-class and/or best-in-class medicines for the treatment of rare diseases. You'll also hear from Bill, how we're applying sophisticated preclinical testing to rigorously assess the molecules in our pipeline for their potential to meet this bar. As scientists, we remain disciplined. We make our decisions based on the data and the requirements we set, so we'll always allocate our resources to those programs, most likely to deliver a best-in-class molecule. And you'll understand when you've heard all this, why we are so excited about what this pipeline and this company can deliver for patients. As a first step, let's understand what we need to achieve to build a medicine meeting our high bar to advance into the clinic. When designing a drug, we're creating a molecule that binds to and blocks the active site of the protein. That's our goal. And we want to do that with high potency, affinity for the active site with target specificity, binding to the active site for only this protein and bioavailability, especially for an oral medicine to deliver the right amount of drug to the active site. To get there, we need a tight fit between the drug and the active site of the protein. And today, you'll see how we achieve this. You'll hear where we start the design process by working to understand the shape and characteristics of the target protein active site in the center of the larger protein molecule where binding will occur. Next, we grow crystals made of the pure protein using our specialized techniques and experience in crystallography, to see inside that protein active site and confirm the detailed atomic level structure and shape. Then we design a drug to fit that shape atom by atom. So it fills the active site completely, sticks to it closely and binds to it tightly. And this tight complete binding is what leads to higher potency. A key characteristic of a best-in-class drug, and it's very difficult to achieve. So let's look at why designing a potent specific drug is so hard and how we overcome this. What we'll do now is go deep inside the structure-guided design process of BioCryst. First, you'll see the protein sequence and how we gain detailed information about the larger protein structure and the active site where binding occurs inside that structure. We'll start with a 2-dimensional view of the protein, how the amino acids are arranged in the string, with each amino acid containing its own distinct assortment of atoms, represented here by the different shapes of the beads on the string. And you'll see in a minute how that string interacts and forms chemical relationships across the string and how this leads to create the bonds and links that define the 3-dimensional structure of the protein. I want you to notice, as we're watching this next video is the complexity of the 3-dimensional structure created and then focus on where the active site sits within the protein. So let's look at this. In Birmingham, I'm going to draw your attention to the screen on the left. There's the string forming 3-dimensional structure with twists and helices and the electron map showing the greater electron density around these amino acids. We're going to see that again. Here's that string, the 2-dimensional sequence, forming its 3-dimensional structure. It's very complicated. You can see and then the electron map, which shows the density around amino acids. Design a protein -- to design a drug for the best fit and best properties we need to see the exact way the string of amino acids fits and precisely how these amino acids and the atoms that form them are arranged together. What you don't see using this sequence of amino acid is the external forces that also influence the shape and 3-dimensional structure of the protein. In live physiology, the protein doesn't exist alone. It's surrounded by many other proteins, by molecules, by blood, by tissues, and it's constantly interacting with this environment. The protein's true shape is influenced by that environment including water molecules and hydrogen bonds that surround and interact with the structure and metal ions and minerals in the blood and tissues. These are not part of the protein sequence, but they are critical to how it folds. To design a best fit drug, we need to know this ultimate shape -- the true shape of the protein. The final structure as formed in its environment surrounded and filled with these other small ions and water molecules. And with what you just saw, we don't have all the information we need to build our drug. We're asked regularly whether we use AI or predictive models in our work. These are excellent tools that give us a much more advanced starting point that was possible before. They can predict using the 2-dimensional sequence of the amino acid string, what shape the folded string will take. And we, like many others, use these as a tool to provide a starting point in drug design. They provide us with the first set of the data we need, the 3-dimensional structure of the protein as formed from the sequence of amino acids and this solves the first challenge in drug design, understanding the basic protein structure. I want to be very clear on what these models can't do. They can account for how those external forces like the water molecules and metal ions in the plasma surrounding the protein, influence the detailed atomic level structure and interactions in that final structure which means the simple 3D prediction may be wrong, imprecise, inaccurate about the shape, charge and size of the most important part of the protein, the active site where binding of the intended drug occurs. And as a result, additional challenges remain when we start the drug design process. The second challenge we face is that we don't get high resolution for that final true structure. And by that, I mean being able to see through the atom, the exact and true positioning of specific atoms in their electron fields in the protein and around the active site for binding. Without the external factors like water molecules accounted for, the predictive protein stronger -- structure can be imprecise and even inaccurate. And so overcoming this and getting to a high resolution by knowing the impact of these external forces is important to design the best drug. Now we're looking at a representation of that general protein shape and 3D structure and deep in the middle in the dark spot in the middle, here's the pocket, the crevice that contains the active site within the protein. And the protein structure there is largely defined with the form, the shape, large bumps, some pockets defined, and we have a basic understanding of the protein structure, and we can start building our drug to interact with this. But what you'll recognize also is that it's not yet in high focus. It's fuzzy and that represents uncertainty around the precise arrangement of the atoms and the possible variations of that arrangement that haven't yet been confirmed or ruled out. We don't know enough yet to get to high certainty of the location of the atoms in the structure. And yet we need that high certainty to know exactly how to build our drug to achieve selection and placement of atoms to match the fit and to pair the electric charge of the atoms so that our drug not only fits, but it also sticks. We want to build a molecule that has a great fit, which includes both the right shape to fit the pocket closely and strong binding that -- affinity or sticking to achieve better potency and better specificity and best-in-class drug. So next, let's look at where we want to get to, which is a specific understanding of where the atoms are -- where their electron fields are. In the video I'm about to play, you'll see what we're looking for. There's positive charge, negative charge, positive is blue, negative will be red in the molecule and where external factors like water molecules, influence and change the exact positioning of the atoms and the strength of the positive and negative charge areas in the protein. We need to see the distance between electron fields at critical points of connection and see the placement of associated water molecules so we can get to that true high-resolution shape of the active site for binding so we can design our drug to fit that active site very, very closely. Here, you see the basic protein structure. And in a minute, you'll see the high resolution structure we need to get to with specific detail around the active site, you can see the bumps, you can see the folds, you can see the valleys. And here are the charge, blue is positive, red is negative and those external factors, water molecules and ions that influence the charge and shape. And you can see the contrast, the basic structure and the high resolution structure around the active site that we need to get to. This is much more detailed information. And it shows the key structural elements that influence how the protein is formed in a live physiologic environment. We need this to design a molecule that fits snugly with tight binding and pairing of electric charge at critical points of contact. And we needed to design our drug to interact with the protein active site to achieve excellent potency and specificity. You could think of it like this. If you imagine a satellite image of a neighborhood and you can see the buildings in the streets, park in the neighborhood. That's low resolution. High resolution, you zoom in, you can see the cars in the street. You can see some details in the building. And then zoom in further, and this is what we do, so that you can see the license plate on the car. That's the level of resolution down to the atomic structure or the license plate on the car that we need to get to. So now let's look at the next challenge. The last challenge we face is that the already complex shape of the protein changes the molecule binds to it. And it can do that in ways that the amino acid sequence does not describe. So we need to know what the structure will look like at all stages of the interaction so that when it interacts with their medicine, we design with those changes in mind. So here's the protein again, showing the high resolution structure, and let's focus on the shape. You see the active site in the middle as a detailed structure showing crevice in the middle with its deep pocket in the bumps and valleys around that pocket. And on the right, in purple is the smaller molecule with a shape. That's our drug, and it's built to fit perfectly into the active site, like a key in a lock. That's what we're building. And in this instance, we've used 3-dimensional structure information and also the high-resolution atomic level structure information to design that molecule for a great fit. And then everything changes. As the molecule binds to the protein as the drug binds the protein, you can see the protein changes shape around it. You can see, as it fits into the active site, the protein changes. So you see how it shifts, it changes shape in response to that binding. That's the way biology works. The protein interacts with its environment, the result is a change in protein structure. And how it changes, which atoms move, where the positive and negative electric charge areas shift is just as important to know for how we design our drug for the best fit. So in some ways, designing a drug to fit the protein active site is like working in [ Jell-O ] It's dynamic, it keeps moving. And that change in shape will have a direct impact on the potency and specificity of medicine that we're building. So let's recap. To deliver our first-in-class and/or best-in-class drug, we are designing to achieve high potency, specificity and bioavailability. You just saw the 3 challenges we have to solve, defining the 3-dimensional structure, defining the high resolution structure and seeing how this change -- how the structure changes as our molecule binds to it. We can get a head start by solving the first challenge using predictive models and the 3D protein structure they provide, and these are the first step. And as you just saw, we need to solve for high resolution, and see the final changes that will occur when the drug binds to achieve our goal of designing a differentiated drug, we need more. Which brings us to what makes our discovery capabilities so specialized at BioCryst. Our knowledge, our expertise, our ability to deliver a truly differentiated medicine starts with our distinctive capability that we use to augment our knowledge of the structure. We use protein crystals to determine the exact arrangement of atoms, not the predicted structure, but the real detailed structure. And this is just as much an art as it is a science. What's unusual is we do this here in-house at BioCryst. This is an art that involves crystal formation for examining by x-ray crystallography. We use this as in an iterative fashion to resolve our remaining challenges for drug design. We develop pure crystals that the target protein with a highly ordered grid-like structure built for multiple copies of the protein as you see on the left, and we evaluate that pure well-made crystal to determine the exact atomic level structure of the protein. If it's not a pure crystal, the information that comes back is imprecise. You can't get the exact structure. So there's an art to growing the crystal and it takes practice and patience to master it. And the reward is a map of the structure down to the Angstrom level that's one ten-billionth of a meter, the approximate diameter of an atom. And I'm going to repeat that, so it sinks in. We get down to the Angstrom level, about the diameter of an atom. What that means is we can see in stunning detail, individual carbon, oxygen and nitrogen atoms at this level of resolution. We can see the associated water molecules and metal ions, and we can build exceptionally well from that knowledge. And on top of that, and this is really critical to understand, to address the third challenge of how a protein changes shape when it binds, we co-crystallize our drugs with the proteins. And by that, I mean we form a crystal of the drug and protein bound together. I'm talking about more than adding the drug to an existing crystal of protein. That's one way that you can see how they bind together. What we do is more than that and it's much harder to do. We take the solution of the protein and the drug after they bind and then we make a crystal of the combination to see what changed. This is what I want you to remember. We can get to the same grid-like structure of multiple copies of the protein-drug pair after binding. And as you see on the right, where the purple drug is now folded into the middle of the protein. We can see the change in the active site when the drug is in place. On the bottom right, where the change shape of protein segments is shown in yellow, it's subtle, but it's there and we capture that change in a crystal for the most precise and accurate termination of the atomic level structure. When we then adjust the drug using this information to build and to better fit the changes into the active site, we do it again. We make a solution of the protein and the new adjusted drug bound together, we recrystalize, reanalyze and reassess our direct design. And if necessary, we repeat again. This is where the science becomes an art. This is what's really difficult and highly specialized. And this is where we bring our finely tuned and distinctive capabilities to ensure we learn every structural aspect of the active site in the highest atomic detail. Here at BioCryst, we are experts at this. The result is what makes our capabilities so special. And it gives our medicinal chemists and biologists the ability to see inside the protein and into the enzyme active site with a very high resolution to build our medicine for a glove-tight fit. Potency increases with tighter, better match fit, specificity increases too. And seeing the atomic level structure and building that fit is how we overcome the challenges of designing a truly differentiated drug. This approach is how we achieve success with ORLADEYO, delivering a first-in-class oral drug and this is really hard to do, and we're the only ones who have achieved it with an oral plasma kallikrein inhibitor. In a minute, we'll take you inside the proteins and molecules and show you how we built ORLADEYO and we'll show you another BioCryst molecule that I'm going to tell you about. But first, I want to introduce a really important advance that expands our opportunities to reach more patients with rare diseases. And I'm really pleased to talk today about how we extended our discovery capability to add biologics and specifically protein therapeutics to our platform. As we'll show you, the structure-guided drug design platform technology we apply to create small molecules like ORLADEYO, can be used for both small molecules and the large ones, protein therapeutics. The concept is the same. The difference is that when we're working with a protein, we have different building blocks, and we can rearrange amino acid residues instead of individual atoms. We're building a new protein by changing those beads on the string. And it's a logical and exciting way to broaden our opportunities. So let's answer the question, what does the addition of protein therapeutics bring to our pipeline? It adds to the way we can build new medicines and it diversifies the risks, benefits and options for our pipeline in several important ways. First, with protein therapeutics, we can achieve far greater potency and it can be 1 million fold greater potency. And that's a powerful difference. Second, for some targets, designing a protein therapeutic allows us to advance lead towards the clinic faster because we can get to a molecule that reaches our standards for differentiation more quickly this way. And we can expand the number of targets we can get to, including ones where a small molecule approach can't be applied. Some proteins have very flat binding surfaces, which means there isn't a pocket or crevice for small molecule to fit but a protein therapeutic can get there. And additionally, we diversify and balance risk with protein therapeutics, which is a different class of molecule, bring a different safety profile typically with a low risk of off-target toxicity and the great result of expanding our platform technology is what you see today. We've added protein therapeutics to our pipeline, along with small molecules bringing more potential medicines forward, increasing options, as you see from the number and type of programs and diversifying risk across our pipeline in a more balanced way. And in fact, we've created our first protein therapeutic to solve for the missing protein function in Netherton syndrome. We made a choice to pursue KLK5 inhibition knowing this was a validated target for Netherton syndrome, and this could be truly meaningful to patients. KLK5 is a serine protease, which is unregulated in Netherton syndrome, causing an ultra-rare and serious disease that manifests early in life. Lack of KLK5 regulation results in disruption of the skin structure with fragility and pluffing of the skin. We know that serious skin diseases in early childhood can be devastating for children and I'm motivated by my own observations of how difficult and disruptive conditions like this can be, keeping children from participating in typical childhood activities like play and going to school. You'll hear more about the disease and our approach later from Brian, Bill and Charlie. But for now, I want to focus on the structure of the protein that causes the problem. And why this makes so much sense for us to choose this validated target as our first target for our protein therapeutics platform. What we discovered early in our efforts to create an oral KLK5 inhibitor was that we could more quickly and with much better potency, design a better protein to replace the missing function. And so we made the choice to do just that. So let's look at how we did this with our structure-guided approach. This will explain the similarity to what we do with small molecules. The KLK5 protein has several natural ligands other proteins that in normal skin regulate its function. One is called SPINK9, which is shown here, and it's a natural inhibitor KLK5 and crucial to normal skin function. We started by evaluating this natural interaction. And when we applied our structure-guided approach, we identified that we can use its structure that of SPINK9 to design a better ligand. And by this I mean a protein therapeutic with a better fit than the native protein, matching the shape and charge in the active site to achieve better binding and higher potency and thereby replace the missing function of regulating, inhibiting KLK5. We can do this by substituting the amino acids of the SPINK9 protein instead of the atoms as we would for small molecule to achieve that better fit. Here on the left, you can see the histidine residue, with SPINK9, that's residue B and how it leaves space in the active site pocket. It has a neutral charge, that's the color purple, then doesn't share -- doesn't pair with a negatively charged pocket, which is in the color red. And the result is a weak interaction and poor binding affinity. It's the same way we look at designing a small molecule. We've identified a pocket at the active site and the points we can approve to get to better binding and a closer fit. And in this case, we can design not a small molecule, but a better ligand and a potential medicine to correct the underlying mechanism of disease. So we'll look at the mechanism and the medicine we're building. This is BCX17725, the medicine we're building. And we determined that instead of histidine amino acid and arginine, another amino acid would reach in and fill the active site pocket. And also pair positive charge in blue, this is amino acid Y, positive charge in blue and it pairs with the negatively charge pocket in red. And as you've just heard, a better fit gets us to higher potency with better specificity. And in fact, by engineering the protein and substituting several amino acid residues to fit the active site more exactly, we achieved greater than a million-fold increased potency. That's 1 million times more potent than the natural ligand. And we need dramatically less drug as a result to have the effect we want. So we designed a protein therapeutic and the data for this molecule, we see today tells us that we have a potential best-in-class therapy. It also tells us that we can repeat this approach with protein therapeutics for other targets. We can do this again. So now let's take a look inside the proteins. We'll look at how we designed ORLADEYO, and we'll look at our KLK5 inhibitor, the protein therapeutic you just saw. We're going to dive deep for close-up look, so you can see what we see at the atomic level, how we applied structure-guided design, to build and expand our pipeline. We're thrilled to be able to bring you inside the protein with us so you can experience how our medicinal chemists build our molecules, what they see, how they design for it, how we produce the pipeline you're seeing today. We'll take a break to do this. For those of you here in Birmingham, we'll go and flip on the virtual reality goggles. It's the same technology that our chemists use so you'll see what they see. And for those of you on the webcast, you'll also see this on your screens. And following the demonstration of how we build our molecules, you'll hear directly from patients about the great need for better treatment and why this work is so important. This activity will take about 30 minutes. So we'll continue the presentation after the break. [Presentation]

Welcome back. We're so pleased to be able to use the virtual reality experience to show you inside the molecules and inside how we build down to the atomic level. So now you've had a chance to see what our scientists see and understand why it's so important for us to be able to see down to the level of the atom. And as you just saw, we apply structure-guided drug design, using our expertise to co-crystallize the protein and the drug, to see the final protein structure after binding and design a better drug. With a closer fit and deliver a medicine that's more potent, with better specificity. And you've seen how we've expanded our pipeline, expanded our platform technology to add protein therapeutics and to increase the ways we can deliver better outcomes for patients. And this contributes to accelerating what our discovery engine can produce. So now let's turn to our pipeline to preview the exciting program you'll hear about today, each built with the same specialized approach, each with the potential to be a first-in-class and/or best-in-class drug. So here, you see the updated BioCryst pipeline with 7 different programs at different stages across the spectrum of development. We look forward to advancing these and we are confident this pipeline will deliver our next successful medicine. I want to highlight a few points for you here for you to keep in mind as we turned Charlie, Bill and Ryan to hear about the diseases we're pursuing and the data that shows we are on our way there. Today, we believe we are poised to become the leader in delivering medicines for the treatment of complement-mediated diseases. To do this, we're aggressively pursuing oral inhibitors for all the pathways of complement and a bifunctional inhibitor to treat multiple pathways at once. You'll see why we are excited about a new addition here, an oral C5 inhibitor. This is a remarkable achievement. And an example of what our distinctive drug design capabilities can produce. We're also really excited with the opportunity to evaluate avoralstat for the treatment of diabetic macular edema. This is a huge clinical need. And we believe avoralstat is a great drug and now paired with Clearside device to deliver to the suprachoroidal space in the eye, it has the potential to be a best-in-class therapy for patients with diabetic macular edema inadequately treated by other therapies. So what can you expect to see from this expanding pipeline? The answer in two words, a lot. Here's what that looks like. In the next year, we expect to have 17725 in the clinic and two new molecules, the C5 inhibitor and the bifunctional complement inhibitor in IND-enabling studies. And by the end of 2025, we expect to have a total of 5 molecules in the clinic, and we plan to file the sNDA for ORLADEYO for the pediatric population down to age 2 years. From there, you can see the continuing advancement across the pipeline so that within 5 years, we expect to have proof-of-concept data for all 6 of these pipeline molecules. And our prolific discovery engine will be producing as it accelerates a continuous supply of potential best-in-class medicine to follow these. I'm so proud of our research teams who have applied our specialized capabilities to produce this broad selection of molecules. The data you'll see today will show you, these are high potency, high specificity molecules with the potential to meet our high bar. And what you see here today is the result of their knowledge, experience and dedication to delivering differentiated medicines. We see tremendous potential here to improve the outcomes for patients with this full and diversified pipeline, and we're so excited to bring it to you here today. So now we'll turn to Charlie to describe more about the opportunities we see with these programs. Charlie?

Thank you, Helen. I love talking about ORLADEYO. And I'm fortunate I get to do it a lot, and I'm privileged to -- because I get to lead a really amazing global commercial team that gets to do it every single day. So like Jon did, I'm going to start by talking a little bit about ORLADEYO because I think it really sets the context for what we can do with this incredible portfolio of molecules coming behind. I need the clicker. So when we launched ORLADEYO, the campaign focused on the capsule as the hero and with a little play on words that this is big, of course, it's not big. It's very small, but really big for patients. And since the launch in late 2020 in the United States, over 1,000 patients now are benefiting from ORLADEYO therapy on a daily basis and hundreds more globally. And the reason it was so big for patients and for physicians, is that while they were grateful for how far HAE therapy had come over the previous decade or so, what they really told us they wanted was a low burden oral therapy. And so as more and more patients are switching to ORLADEYO, that's why the product is on pace for $1 billion in peak global sales. And so far, in the United States, 50% of patients who have come over to ORLADEYO are switching from an injectable or infused therapy. And patients told us that they're grateful for these therapies, and they should be. They're wonderful therapies. But each of them comes with a burden. And it's not just about the needle. It's about the fact that you have to go through the scheduling, the preparation, the time and the mind share that, that takes up for patients, for caregivers to get ready for each of those injections. It's about the inconvenience with travel. Some of these drugs require refrigeration. And so you have to plan and travel with cold blocks and that adds burden to their lives. And of course, it's about the discomfort of injection. Patients get used to this, they tolerate it, but most people, if they could, they would avoid doing that. So an oral drug -- the injectable drugs remind patients on a regular basis that they have a disease. And as Jon said, what a lot of patients tell us is that when they can take a daily oral therapy, they completely forget that they have a disease. So that's what we want to be able to bring to other patients in other disease space. And in the complement space, we have a lot of opportunity to do that. So let's look at the complement system. It's a complicated system, but it breaks down in some ways pretty simply. We have four opportunities here, at least four opportunities to help patients. We've got for the -- to inhibit the classical pathway and the lectin pathway, a potential oral C2 program. For the alternative pathway, of course, we've got BCX10013 already in the clinic. For the membrane attack complex, it's the oral C5 program. And then amazingly, this bifunctional inhibitor that can inhibit all 3 of the major pathways of the complement system. So at least four opportunities to bring value to patients. But if you think about it, it's really much more than four opportunities because each of these pathways is implicated in a growing list of diseases. And as we get into this as we study more, this list really is growing constantly. And so there are many, many chances to help patients with complement-mediated diseases. I'm going to start first with the oral C5 program, and I'm going to do this because I think, number one, the first indication, the probable first indication is very clear. As you heard from Jon and from Helen, generalized myasthenia gravis really makes sense. It's already been validated that C5 inhibitors work for GMG. And so that makes sense. And then the other reason is that there are a lot of parallels between HAE and how that condition has evolved and the treatment options for HAE have evolved and we see the same thing in myasthenia gravis. So I want to point you to the quote from a neurologist in some of our recent market research down in the lower right. And I think this really sums up exactly what we're trying to do. So the key unmet need is to have a high-efficacy drug like Ultomiris or Vyvgart in an oral form because that would reduce -- it would make it much more easy -- much easier to take that medicine over the long term. So that is exactly what we're trying to do with our C5 program. So MG is about 10x the size of HAE, but as I said, there's some real analogs to the conditions. So myasthenia gravis patients have chronic -- and chronic muscle weakness that can kind of wax or wane. And that's kind of like attacks that for HAE that come and go unpredictably. Myasthenia patients are also at risk of myasthenic crisis that can lead to respiratory failure. And that's a bit like the risk of a laryngeal attack for HAE, that can land you in the hospital and even cause a life-threatening situation. So for both conditions, the ideal situation is to prevent these attacks, to prevent these situations from happening in the first place. First-line therapies for myasthenia gravis are also nonspecific medications that often have a risk of side effects. So oral corticosteroids and immunosuppressive agents. And that's kind of like an HAE where before there were targeted therapies, the standard of care was oral androgen steroids. And finally, like HAE, the market has really evolved. So 6 years ago, eculizumab was approved as the first targeted therapy, a C5 inhibitor for myasthenia gravis. And now there are other C5 inhibitors and FcRn inhibitors. And that's really changed the landscape. So our goal then is to bring an oral therapy that is as effective as those injectable therapies and can reduce the burden for patients. And from a commercial perspective, to do this in a market that is expected to grow to about $6 billion by 2028, this alone is a commercial organization's dream. But of course, we have a lot more to talk about. So let's move up the complement system to the C2 inhibitor. And this one is different. This is a much wide -- a much wider open space than the C5 opportunity. There are very few, in fact, there's only one targeted therapy in this space for -- in the autoimmune hemolytic anemias for cold agglutinin disease or CAD. Another disease in this space is warm autoimmune hemolytic anemia or wAIHA. you have to abbreviate all these to make them pronounceable. And there's no targeted therapy for wAIHA yet. For both of these conditions, the standard of care, like we see in a lot of rare diseases and like we saw in myasthenia gravis is nonspecific therapy. So it starts with corticosteroids and then many patients move on to rituximab, and rituximab often has to be augmented with chemotherapeutic agents, which can come with risk of severe side effects. So the goal there is very much rooted in cancer therapy, ablate the B cells to prevent the problem. And that works for some patients, it works partially for other patients, but these are infused therapies and therapies with a high risk of side effects. So what if we have an oral convenient therapy for these patients that can control the ongoing hemolysis. That would make a huge difference for patients with diseases like CAD and wAIHA. And then, of course, BCX10013. The goal here is to develop a safe and effective once-a-day therapy. And as you've heard, we've recently started a proof-of-concept study in PNH that will tell us by the end of 2024, if we can achieve our objectives. And if we do, we believe that we will have the best-in-class alternative pathway inhibitor. And where we plan to start, there are a lot of places that we could go, but where we plan to start is in renal diseases like IgA nephropathy and C3G and in the case of IgA nephropathy, this is a really complicated disease, very heterogeneous in the patient population. And there's a lot of progress and a lot of evolution in terms of how the disease is managed. Multiple therapies are needed to control the disease, but there's increasing evidence that alternative pathway inhibition is validated and is going to be an important part of therapy. So our goal is to have the best-in-class an oral AP inhibitor for IgAN. For C3G, AP inhibition is exactly the problem that needs to be solved. And for C3G, which is a smaller ultra-orphan population, having a once-a-day therapy is exactly what patients need. So it's unlikely that 10013 will be the first oral AP inhibitor. But if it's the best-in-class, it is never too late to have a best-in-class therapy. So we think it has the opportunity for IgAN and for C3G to become the standard of care when an AP inhibitor is needed. So that's three opportunities for an oral therapy that can really reduce the burden of treatment for patients and help them control their disease. But then we have the opportunity for a bifunctional inhibitor. We're not moving away from our strategy of having low burden therapies for patients. What we're trying to develop here is not only inhibit all 3 parts of the complement system, but also to have a low-volume subcutaneous injection. And likely targets for the bifunctional inhibitor are patients in diseases where multiple pathway inhibition is required to take care of complicated disease. And so that could apply to patients in IgA nephropathy as well as patients in lupus nephritis. Both of these diseases are of a similar size in terms of the target opportunity. And there are a few other companies who are developing bifunctional inhibitors but we believe nobody yet is developing an inhibitor of all 3 pathways of the complement system. So putting this all together, we have many different ways to achieve market leadership in the complement space. First we can develop a best-in-class inhibitor for an ultra-rare disease like C3G or CAD. Next, we can have a first-in-class oral in an injectable marketplace like the C5 inhibitor for myasthenia gravis. Third, we can have a best -- a first or best-in-class treatment for patients who need multiple complement pathway inhibition. So that would be our bifunctional antibody, For example, and maybe someday, actually combining some of our oral therapies into a combination package. We also have opportunity to help patients at different stages of disease. So imagine, for example, 10013 helping a broader portion of the IgAN marketplace and then the bifunctional inhibitor helping more severe refractory patients both within the same disease state. And then finally, we know from the statistics of drug development that some of these molecules may not make it to the market. But we have so many different opportunities here, so many molecules, so many diseases where we can help patients that the path to market leadership is wide open and something that BioCryst can achieve. I'm going to turn it over to Bill who is going to go into more detail about each of these really promising molecules.

Thanks, Charlie. Well, it's a pleasure to be here today to speak to our complement portfolio. And I'll say that again, we have a complement portfolio. So let's get into some details about these programs. What I'll do is step through each of four programs in turn, share new information and a status update for each, starting with our oral small molecule programs against C5, C2 and Factor D and closing with a bifunctional biologic program that targets all 3 pathways. Before we get into that I would like to summarize what this all means? What it means for people living with these diseases that are caused by abnormalities of complement and also for our company. Three of these programs target different single complement pathways and one targets multiple pathways. We're aiming for first-in-class or best-in-class for each of these programs. It's a broad portfolio. It's unique, it could provide pathology driven choices for treatment of many complement-mediated diseases across many medical disciplines as Charlie already has explained. We aim to progress each of these as fast as we can and as much as it's feasible to do so, and we're focused on doing that. We're looking to file 3 INDs for new molecular entities deliver proof-of-concept results for 3 programs and start on pivotal trial across these programs in the next 4 years. For C5, our goal is to bring forward a really unique first-in-class orally administered complement C5 inhibitor. As Helen explained earlier, our research team has cracked the code on how to design inhibitors that block protein-protein interactions for the way C5 works. That's an amazing achievement and guided by the sort of structural biology insights and expertise that Helen described. That's being applied to a molecule that is not an enzyme. So that is quite a feat. Right now, we're in late stages of selection of candidates for IND enabling studies. So we've made rapid progress here. So what part of complement are we talking about? C5 is critical for the common terminal effective functions of all 3 pathways. It's a fascinating system and C5 is activated by C5 convertases that cleave the protein into the larger fragment stuff to build the membrane attack complex, that's called C5B, the smaller fragmented attracts and inflammatory cells and tox the rest of the immune system. We know a lot about targeting C5 because of the success of approved drugs that are monoclonal antibodies, eculizumab and ravulizumab. They're approved for several indications including generalized myasthenia gravis. That makes a big difference in thinking about the validation risk if you like. We don't have any. So C5 is a 100% validated target. As Charlie described, an oral C5 inhibitor could be a big step forward for patients with MAC mediated diseases who are currently dependent on injectable treatments and we could massively reduce the burden of therapy with an oral C5 inhibitor. C5 is not an enzyme but the strategy and the goals are pretty much the same as if it was an enzyme. Designing a small molecule candidate. We have a set of criteria that we have to satisfy. And here they are listed on the left-hand side of the slide, potency, specificity, oral bioavailability, sustained exposure with a pharmacodynamic effect that last through the dosing interval and we're always shooting for once a day. The better the potency, the lower the dose. Better selectivity drives lower risk of off-target toxicities. Good drug levels after oral dosing are a must for an oral compound and to see that in non-clinical studies gives us the support we need to move into the clinic. We're looking for a once-a-day schedule. So seeing a high ratio drug level to inhibitory constants a day after dosing is what we're looking for there. And we want oral medicines to pass all of these tests and the smaller than about 500 daltons in molecular weight. For the RLC5 program, there's been tremendous progress already. The number of molecules here illustrated is 11, representing a diverse array of structures already, and when we dose these orally in nonclinical species, we're seeing very good PK profiles. I'm very excited to share this. It's unpublished data. We're sharing it for the first time on the right-hand chart. The assay that we're using to look at potency is directly relevant to the function of C5 because it measures the membrane attack complex formation. Drug levels here, just to orient the chart shown on the Y-axis and the X-axis shows hours after a single oral dose. Each chart represents a different drug candidate. We see rapid absorption, concentration is over 1,000 nanograms per mil and drug levels sustained through 24 hours. So having nanomolar potency inhibitors with this type of PK profile is great to have several candidates to choose from at this stage. We're on the way to completing the other required studies to select an IND candidate as a potential first-in-class RLC5 inhibitor next year. Start Phase I studies in '25 proof-of-concept studies in generalized myasthenia gravis in '26 and delivering proof-of-concept data in '27. Next, let's turn to the C2 inhibitor program that targets a more proximal part of the complement pathways, an essential enzyme near the top for classical and lectin pathway activation. This is a very unique program with potential for a first-in-class therapeutic. Like the C5 inhibitor project, this is also at the stage of lead optimization, but not yet as advanced. Like some other enzymes in the complement cascade, C2 is a serine protease. In fact, Factor D is a serine protease, also plasma kallikrein where we've succeeded with all the data is a serine protease. So for this project, we can apply our accumulated expertise and knowledge and art in structured based drug design of serine protease inhibitors. The serine protease domain of C2 is illustrated in the structural diagram of activated C2 on the right. You can see the left-hand of [indiscernible] the protein there is a serine protease domain. This is really just a structural diagram. Of course, our scientists have atomic level resolution structures to work on in the C2 inhibitor discovery work. The range of applications of an oral C2 inhibitor is pretty broad because you can think of any antibody-mediated autoimmune disease falling into this category. So what are immune conditions that fix complement autoimmune conditions that drive abnormally glycosylated IgA or IgG, for example, and activate the lectin pathway. They're all good examples and a couple of bullous pemphigoid and autoimmune hemolytic anemias. So the general goals for favorable characteristics of an oral first-in-class C2 inhibitor, just the same as for the C5 inhibitor project. At this stage, we've made a number of different compounds that individually satisfy one or other of these criteria. The next step is to work through the iterations with crystallography and medicinal chemistry supported by bioassays that Helen described in our process of structure-based drug design to optimize and balance all these features in a lead candidate. Serine protease is a very challenging and very few companies have succeeded in bringing forward all the way to the marketplace to help patients any serine protease inhibitors, and we're in that fortunate category of succeeding with all the data. Nevertheless, they're still very challenging. We anticipate that this project will take approximately a year longer than the C5 inhibitor project. So that means we're aiming for an IND in '26, proof-of-concept starting in '27, and delivering proof-of-concept data in '28. And we look forward to sharing more information about this project as it matures. Now I'd like to move to our most advanced complement inhibitor program, BCX10013. I'm sure you've seen our recent press release, we've now commenced dosing in a proof-of-concept study with this agent in people suffering from paroxysmal nocturnal hemoglobinuria, starting that study is a major milestone. We look forward to reporting proof-of-concept data in '24. Today, I'd like to share some previously unpublished data from our Phase I pharmacokinetic -- pharmacodynamic and safety study in healthy volunteers and describe what we're looking for as success criteria in our PNH study. Here's another serine protease. It plays an essential role in the first step of the alternative pathway of complement. And over the years, we've grown to understand that the alternative pathway can be disregulated or pathologically activated in a number of different diseases and can play a major role in that pathology. And a few examples here are IgA nephropathy, C3 glomerulopathy, PNH and atypical hemolytic uremic syndrome. The list is growing. The depth of understanding of alternative pathway-driven diseases has made rapid advances, and we can now be very confident that inhibiting this pathway will lead to therapeutic benefit. Like for the other complement pathways, we can measure the function of this complement activation pathway in healthy individuals and the way to do that is in ex vivo stimulation assays before and after dosing with your oral agent. He was showing the data from a commercially available alternative pathway assay called the Wieslab AP assay. This specifically activates the alternative pathway and measures a major end product of the complement cascade, namely C5b-9 otherwise known as membrane attack complex. So the cohort sizes up to 10 with active in each cohort at each dose level with once-daily oral 10013, and we measure the activity of the pathway before dosing and at multiple time points after each dose. The values are normalized to each volunteers pre-dose activity, shown as a percent on the Y-axis. And the left-hand chart shows the PD profile in 2 ways, left-hand side of that shows the profile after the first dose. And the right-hand chart shows that after the last dose on day 14 of daily dosing. So what do we see? After dosing with 160 milligrams, in every single volunteer. This pathway is essentially completely and immediately suppressed right away, and it stays flat through 24 hours. You can't see 11 -- 10 lines on the chart because they will overlap. So the variability here is very small. It's quite a tight result. These are very encouraging results. The right-hand panel summarizes the dose response across all of the cohorts we've studied and it's a typical dose response curve that you want to see for any agent in an early Phase I study with crystal clear dose response. So what does this all tell us? We've maximized what we can measure actually in healthy volunteers in this trial. We've reached the maximum inhibition of the alternative pathway that the assay can validly measure. And we saw no safety signals at all with daily dosing for 14 days. So that sets up the testing that we're now doing in individuals with PNH, looking at clinically relevant outcomes and we're now doing that in the PNH trial. So now that this molecule has entered a clinical trial in patients, and we're looking forward to having data revolve through next year. And we've constructed it in a very simple way. We're able to do dose ranging and see what doses or what dose level can optimally impact the disease. And this is a straightforward thing to do. In terms of measuring outcomes, we can look at hemoglobin, LDH, transfusions and the like. We can look at the symptoms. We can look at fatigue. And of course, we're looking at the safety of chronic dosing. Our goals haven't changed. We're looking for a first-in-class or best-in-class in every program. And here, we're looking for a best-in-class once a day oral alternative pathway inhibitor. And our standard for that is to have LDH levels less than 1.5x upper limit of normal. In other words, to have efficacy that's similar to iptacopan and a satisfactory safety profile. So pending that data, our intent is to confirm pivotal study designs where we do that is to work with patient advocates, the world's best key opinion leaders in the field and regulators and settle on the study design and initiate pivotal program in 2025. Our fourth program in complement therapeutics is our bifunctional complement inhibitor aimed at very serious diseases where multiple pathways of complement are involved. The speed at which the discovery team at BioCryst has brought this along is astounding. We've made very rapid progress and we're now in advanced stages of selecting a candidate for progression to IND-enabling preclinical studies. This holds tremendous promise for many patients who are suffering from very serious illnesses where the complement cascade is activated in multiple ways and also where the disease processes induce overwhelming multi-pathway complement activation. There's another aspect to this, which is the alternative pathway amplification loop that gets recruited every time any of the pathways gets activated. So combining an AP inhibition module, with inhibition of the classical and lectin complement pathways is a really cool idea. It's very attractive. That's what our team has achieved, and it could lead to superior potency and better therapeutic benefits when either the classical or lectin pathways are involved. So that's the challenge here, and we want to provide strong clinical inhibition across multiple pathways. So we can test that with in vitro assays. This challenge has been tackled here by engineering and biologic therapy that can target at the same time, more than one bad actor in the pathology. It's a very cutting-edge approach to do that in a single bioengineered monoclonal antibody targeting C2 and the alternative pathway. So let's look at a couple of examples where we might be able to apply this type of therapy where multiple complement pathways are involved. Lupus is a very complicated disease, has a lot of subsets, but there's a group of patients where when you look down the microscope, you can see evidence of involvement of multiple types of immunoglobulins and multiple aspects of the complement cascade. So in some patients with lupus nephritis these biopsies show deposition of initiators or products of activation of all 3 complement pathways. And that's illustrated in the left-hand group of 4 panels on this slide. This is pathologic deposition of complement. You shouldn't be seeing stuff in normal kidneys. MBL is a marker of lectin pathway activation, IgG initiates the classical pathway. C1q is the first enzyme in the classical pathway. Bb is a critical enzyme in the alternative pathway and a marker of AP activation. C5b-9 is the membrane attack complex. Patients with this type of full house of immunological and complement-mediated pathologic picture in lupus, are typically very difficult to treat with standard of care approaches and they're at risk of progression to kidney failure and need for dialysis or transplantation. Similarly, we're learning more about diseases like IgA nephropathy, which is not a monomorphic disease. Like Charlie mentioned, this is very heterogeneous. Generally, the illness progresses rather slowly over decades, but there's a group of patients who can progress quite quickly. And they're facing sooner rather than later the prospect of end-stage renal disease. These patients typically have evidence of involvement of both the alternative and lectin pathways. This is illustrated here in the right-hand panels showing immunohistochemistry of kidney biopsies with prominent signals for both the lectin pathway marker C4D and the alternative pathway marker, Factor H related protein 5. So we've now developed a set of bifunctional complement inhibitors using the structure approach Helen described earlier that can tackle these types of very serious illnesses. And we're supporting that with a series of comprehensive assays that inform us about the ability of these candidate molecules to inhibit all 3 pathways, classical, lectin and alternative. They do that by looking at major effective functions of the complement pathway, optimization, formation of the multi-molecular membrane attack complex and cell lysis. I'm going to step through the next few slides that have a lot of data from these assays one step at a time. In each slide, the bar charts that you'll see on the right-hand side showed potency results for a representative bifunctional complement inhibitor in the green bars, with results for 4 different positive controls, monoclonal antibodies that are depicted in different shades of orange. What are they? The eculizumab, that's an ATC 5, of course, sutimlimab and anti-C1S, also a bifunctional anti-C5 combined with the alternative pathway Factor H regulator and anti-C2. On the axis that you can see on the horizontal line, that gives you molar 50% inhibitory values, that's a log scale that covers 5 orders of magnitude from picomolar to a tenth of a micromolar. So what have we got for the classical pathway, 5 different assays, including 2 commercially available assays. We had sub-nanomolar or nanomolar level potency in every single assay. Compared to the controls, our bifunctional candidate is superior in every single assay. For assays, it specifically measure optimization, which is a major feature of the way complement works, our candidate has 100x more than 1,000-fold better potency than the controls, including the approved C1s antibody and an investigational C2 inhibitor. The alternative pathway, we've got 2 assays, including a commercially available assay with sub-nanomolar potency in both and candidate is at least as good or superior to all the controls with more than 100-fold better potency than the anti-C5 factor H bifunctional inhibitor. So that's an important result here. The lectin pathway, we used the commercially available assay that specifically initiates the lectin pathway cascade and measures C5b-9. In this type of assay format, you could expect to see 2 inhibitor to work. You could also expect anti-C5 antibody to show activity by blocking the terminal step. In this lectin pathway-specific assay, we've got sub-nanomolar potency and our bifunctional candidate is at least as good or superior to all the controls and more than 100-fold more potent than the anti-C2 monoclonal antibody. I think very importantly, we've also had the opportunity to test a sample from a patient with a relevant disease, cold agglutinin disease. In this hemolytic illness, which destroys red cells, that's triggered by deposition of complement on the surface of red cells by formation of immune complexes with IgM antibodies and a red cell antigen. So those immune complexes trigger complement. The C1s inhibitor, sutimlimab is approved to treat this disease. So in the assay shown, we're measuring complement deposition on red cells. That's exactly how this disease works. And that's caused, in this case by the patient's IgM antibodies. We have picomolar range potency in this assay. We don't need much drug here to inhibit this process. Our bifunctional candidates superior to all the controls and is more than 1,000-fold more potent than sutimlimab, which is approved for this illness. So what can we say in summary, that's a lot of data with a lot of assays. So across 9 assays, the bifunctional complement inhibitor candidate is more potent than any of the controls, including an approved anti-C5 and an approved anti-C1s. This is great data. It's also better than an investigational bifunctional complement inhibitor targeting C5 in the alternative pathway. This is really encouraging for the potential utility of this type of bifunctional complement inhibitor with best-in-class and first-in-class activity across a range of difficult-to-treat diseases. Like all of our programs, it's go as fast as possible. Patients are waiting. So given these excellent results, we intend to finalize selection of an IND candidate in '24, start Phase I studies in '25, proof-of-concept in '26 and deliver proof-of-concept data in '27. So that completes the review of what is, I think, just an amazing complement inhibitor portfolio, and I'll turn it over to Ryan, who will introduce our KLK inhibitor program.

Thanks, Bill. I'm thrilled to crawl down from those very uncomfortable chairs and introduce myself. My name is -- for those who I haven't met, my name is Ryan Arnold. I'm the Chief Medical Officer of BioCryst. I joined BioCryst about 2 years ago. And the reason I joined is -- and hopefully, you're getting inclusive of why today. But I saw a company that has the capabilities and people to potentially be the next great biotech and also, at the same time, continuing to be committed to patients with rare diseases. I'm pleased to introduce you to BCX17725, which is an example of that ongoing commitment. Charlie and Bill just walked you through all the programs that highlight our opportunity to become a world leader in the treatment of complement-mediated diseases. Our aspirations, however, extend beyond complement. BCX17725 is our most advanced biologic protein therapeutic designed to inhibit KLK5, designed by our team with initial focus on Netherton syndrome. I'd like to have introduce you to Betty Ann, and she will share more about her daughter and their journey with Netherton syndrome. [Presentation]

Try not to miss the little things while you're caring for the big things. That has two meanings for me as a parent. I think first of all, I'm always trying to live by Betty Ann's advice and try not to miss on the important little milestones that our kids have. But also it speaks to, I think, the need for our industry to continue to think about the people living with rare diseases. And hopefully from that video, you can start to appreciate how horrible this disease is and how devastating a diagnosis of Netherton syndrome can be for a family. Now that it is a rare severe genetic disease that predominantly targets skin and also attacks the hair and has other systemic manifestations. In a healthy individual, your skin will normally turn over every 2 to 4 weeks on average. In a Netherton patient, their skin is continuously peeling off, babies present with red, scaly inflamed skin. It puts them at risk for infection and dehydration. If children survive these initial years, they battle lifetimes of developmental delays, recurring flares of immune reactions and mental health burdens. This is caused by a loss of function mutation of the SPINK5 gene that normally encodes for the protein that naturally inhibits KLK5. And you can probably guess what KLK5 is. It's part of a family of serine proteases that maintained healthy immune function in the body and in this case, help us to maintain a healthy skin layer. So excess or uninhibited KLK5 activity leads to the constant breakdown of skin. There are no approved treatments for Netherton syndrome. Right now, a family that's facing this disease is consumed by daily activities of bathing, applying lotions repeatedly throughout the day. You may have heard what Betty Ann said around the trauma of this. She kind of glazed over it, but I want to highlight this. As a parent, giving a back to my child or our children was a wonderful event. For parents dealing with this condition, it is traumatic. The first years of life -- sometimes they need to medicate their children to get them through these baths , but it's critical for them to do this because they need to maintain the hydration of the skin as well as peel off the dead skin. So these patients -- and again, you could probably gather this from the video, these patients and families are resilient. They're gritty. They deserve better options. As Helen referenced earlier, BCX17725 has been engineered to provide a million-fold increase in binding affinity compared to the natural wild-type ligand and could be a disease-modifying option for these patients and help restore a normal skin turnover. I'll turn it over to Bill, who'll share more about BCX17725 and the data we have thus far.

Thanks, Ryan. What a horrible disease. So our goals in the clinic include subcutaneous administration of BCX17725, a schedule of administration of every 2 weeks or better, no clinically significant immune reactions and a low volume of injection for the subcutaneous shot. I'm really happy today to be able to share our nonclinical results as these all support the potential for 17725 to achieve these goals in the clinic. So Helen already mentioned that we have very high potency with this drug. And what I'm sharing today is evidence for a very good bioavailability after subcutaneous dosing in a nonclinical study. So this is the first time we've shared this, it's the information on the right-hand side of the chart and represents drug levels in the plasma after subcutaneous dose in nonclinical species. Just to orient you, the X-axis shows time in days. The Y-axis shows plasma concentrations in micrograms per mil. And what are we seeing here after a single subcutaneous dose, we get high plasma levels achieved very quickly and they last a long time. So that's great news. We can get the drug circulating in the blood. What else have we discovered? About -- well, one of the few worries with biologic therapies, the risk of immune reactions. So a key safety parameter for any protein therapeutic is assessing the potential for immune reactions. Very interesting development in the field in the last decades with the accumulated knowledge about biologics therapies has enabled now in silico assessment of the potential for immunogenicity. Basically, you can run any peptide sequence and calculate a score that tells you what's the risk. The score for our Fc fusion protein 17725 is very favorable. In fact, it's lower than the natural peptide sequence for the Fc of IgG. That's very important. It's a great result and build more confidence in our program. So if we put all that together, we can expect a relatively low dose because we have high potency. We can expect infrequent subcutaneous injections because we have good nonclinical PK profile and we can expect a very low risk of immunogenic reactions in the clinic because we have such a low predictive score. This is a skin disease. The target is in the epidermis. So getting the drug into the blood is all very well and good, but it's not enough. We have to get it into the skin. So how do we evaluate that? This is critically important. The enzyme that we're trying to block is in the skin. One way to do it non-clinically is to inject into an organism like a mouse and just take a look down the microscope. So we have now directly shown that 17725 penetrates into and binds in the epidermis. That's where KLK5 acts. The images shown here are before and after injection of 17725, the top 3 panels are before injection, the bottom 3 panels are 4 hours after injection. This is a standard immunohistochemistry method of checking the drug and it lights up brown and the stronger the signal, that means there's more drug there. So the more intense signal, that's a lot of drug. We can clearly see the epidermis lighting up with a high-intensity signal. This is an encouraging result. So we intend to try to help individuals living with this really nasty disease as soon as we possibly can. We're making rapid progress. We've already produced a master cell bank, and we have very high titers of pure protein from a standard sterile disposable culture bag process at our contract manufacturer, so it's full speed ahead. We're looking to file an IND in the second half of '24, start proof-of-concept studies in '25 and deliver data in '26. Now I'd like to turn it to Charlie, who will provide a perspective on the target product profile that we're looking for here.

Thanks, Bill. So Netherton syndrome is a classic ultrarare disease. And I'm always amazed by the stories to hear about caregivers like Betty Ann, patients like Carlie. If you saw the video we shared earlier, another young woman living with Netherton syndrome, Caroline and their resilience is amazing. They -- when they have no therapies, they learn how to manage. It's hard, but they live their lives. And what you heard from Caroline in her story is she's living a full life. She's managing. She works the routine of the daily ointments and all of that into her daily routine. But what happens in ultrarare diseases like that is and we hear this from patients in Netherton syndrome is they actually kind of give up on seeking help a little bit. They go to dermatologists, they go to other physicians, but nobody has anything new to offer them. And so they just -- they manage their lives. And so what -- that keeps an ultrarare disease really ultrarare. But when therapies are developed, ultrarare patients come out. They -- patients like Caroline and Carlie find their way because physicians finally have something to offer them. So we've done some initial work on Netherton syndrome. There's no diagnosis code for Netherton syndrome, but we've done some deep claims analysis, and we have high confidence that there are at least 1,600 patients in the U.S. who have been diagnosed with this disease and are under the care of healthcare professionals. Once therapies are available, we see this growing to about 5,000 patients in the U.S. As you've heard from Helen, from Bill, from Ryan, with the potency of 17725 with the characteristics of this molecule, we really can develop the best-in-class therapy here. And what that means is a low-volume, infrequent injection. So we're shooting for low volume every 2 weeks or better. And what you can see is there are some other therapies under development for Netherton syndrome, and that's great for patients. Any options are great. The one that's most advanced is a topical -- a topical therapy, which if it reaches the market, will be very helpful for patients, but they already spend so much time dealing with their skin conditions. So this is unlikely to be truly disease-modify. That's what we're shooting for is something that modifies the course of that disease. There is another KLK5 inhibitor monoclonal antibody in the clinic right now. But as you can see, it looks like it's a much higher volume, more frequent injection or infusion. So with 17725, we really think we have a best-in-class therapy. There are other therapies that have been investigated. There's an IL36 in development right now. But that's nonspecific. So it's likely to be more symptomatic treatment and not disease modifying. If 17725 reaches the profile that we hope and expect, it will be a transformative therapy for Netherton and then we think there are other indications that we could explore after that. And so we look forward to that opportunity. I'll turn it back over to Ryan to wrap up this section.

Thanks, Charlie. So hopefully, we've given you a good understanding of what we see in BCX17725 and the opportunity in Netherton syndrome. As you probably saw, again, Netherton syndromes a horrible disease caused by loss of function mutation, a natural KLK5 inhibitor. There are no approved treatments. And again, patients deserve a better option than what they have right now. Our molecule with BCX17725 is bioengineered to have some significant advantages over the natural wild-type ligand, and we're very excited to advance it. It has a favorable nonclinical profile. Bill walked through some of the data, which shows you it gets to the place where it needs to be to have the effect. And we aim to deliver proof-of-concept results in 2026. And then finally, again, to study -- to steal from Betty Ann, you don't miss out on the little things when you're caring for the big things. So those are the important takeaways. I'm equally excited about our next program. And again, that's a theme of excitement today. As we're going to go through avoralstat, our program for diabetic macular edema. As Jon mentioned, avoralstat is a plasma kallikrein inhibitor previously studied as an oral formulation in patients with HAE. So we have a good sense of the safety and tolerability of this molecule when it's administered systemically. Before Bill spent some time talking through the preclinical data on avoralstat, I will walk through the current unmet needs and important factors for treatment of diabetic macular edema or DME with a potent plasma kallikrein inhibitor delivered via suprachoroidal microinjection. In contrast in Netherton syndrome, diabetic macular edema is a much more insidious disease. It slowly steals away your vision as well as abilities to do things that you love for diabetes patients such as driving and reading. It continues to be the most common cause of vision loss in patients with diabetes despite the advances in care with use of anti-VEGF treatments. Up to a 1/3 to 2/3 of patients continue to have persistent progressive diabetic macular edema and vision loss despite receiving ongoing injections of anti-VEGF treatments. I know this from a place of personal experience because my father has diabetic macular edema. He was diagnosed several years ago, and he's continued to lose his vision despite the use of different anti-VEGF injections. He gets them repeatedly over months. One of the hardest realities of diabetic macular edema and for our family, we're seeing the disease steal away his vision ultimately his right to drive this year. He is among the many patients that need another option beyond anti-VEGF therapies. So what would be happening to cause this. There have been multiple studies that have shown the presence of elevated plasma kallikrein levels in diabetic macular edema patients as well as preclinical models. The barograph at the right depicts results from a study from Kita et al. They looked at immunoassays of vitreous samples of patients with DME. The blue bars represent increases in plasma kallikrein and you can see those represented across while the green bars represent the levels of VEGF. What I want to highlight here. Again, with the blue bars, you see consistent elevations of plasma kallikrein in all these samples of patients with DME. Whereas this VEGF is detectable only in some patients. This mechanism may start to explain why up to 2/3 of DME patients may be less responsive to these therapies with anti-VEGF therapies. But there may be other important factors that ultimately determine if and how plasma kallikrein can deliver meaningful outcomes for patients. So what are those factors? This may seem obvious but getting the drug with the right mechanism to the right place in the eye or the right compartment of the eye is extremely important if you want to treat diabetic macular edema. Let's walk through the anatomy of the eye to better understand other important factors to consider here when you're -- when you want to effectively treat these patients. The upper left picture represents a normal eye and architecture of the retina, whereas the lower left picture shows how fluid leakage from damage vessels begins to cause swelling and the pressure to build up in the eye. This leads the disorganization of the retinal layers and ultimately results in vision loss. Let's now zoom in on the retina and choroid blood vessels shown in the picture on the right. The chronic hyperglycemia diabetes leads to the small vessel or microangiopathic damage in the eye weakening these vessels, triggering inflammatory process, including the contact activation system. This cascade of events include the increase of plasma kallikrein levels we just noted, and up regulation in bradykinin receptor expression on the endothelial cells of the blood vessels and a breakdown of the blood vessel wall causing fluid leakage into the retina. Finally, the location or compartment of the eye where all this is occurring is also really important. To consider to best deliver this treatment. So let me highlight the potential space in the posterior eye called the suprachoroidal space. And as you can see here, it's highlighted in blue. You can see the blue line at verticals right of this picture. Again, this is important to highlight as we think about reaching the target tissue in treating DME. The suprachoroidal space sits inside the sclera and right next to the choroid and retinal epithelial in an optimal location to deliver drug, to inhibit this overactive contact activation system. It's a potential space and some retinal experts refer to it as the natural depot of the posterior compartment of the eye, which brings us the opportunity with suprachoroidal injection. Let's look at what that means in terms of comparison to current intravitreal injections. The combination of avoralstat with suprachoroidal delivery creates a very intriguing opportunity. I think what's obvious and if you can't see it on the screen, you can pare them live, and I do have some examples of this here. When you compare a suprachoroidal injector microinjector is less than 1 millimeter in length versus almost half inch of length of an intravitreal needle. So you can imagine there's obvious advantages to this in terms of administration to a patient and what they think of. So there's additional advantages. We can get it again, right to a compartment in the eye that allows delivery of drug into a natural reservoir. It also can establish a gradient for the drug to slowly release into the retina, the retinal pigment epithelium and the choroid. Again, this is right where the swelling is occurring in fluid leakage. And this less invasive approach can also minimize potential adverse events such as vitreous hemorrhage which are often reported in patients with DME. And again, this is something my father has had several times. So in summary, the combination of a potent and durable plasma kallikrein inhibitor such as avoralstat, delivered with a suprachoroidal microinjection directly to the affected tissues of diabetic macular edema provides some significant advantages for patients. So I'm going to see the floor to Bill, who will talk through more on the details of avoralstat, our plans moving forward.

Thanks, Ryan. As Ryan explained, people who have diabetes who develop diabetic macular edema who aren't doing well on standard of care therapy needs some alternatives with different mechanism of action. So a suprachoroidal depot of avoralstat represents an opportunity to dose a slowly dissolving drug to the right place, delivering treatment to prevent contact activation of kallikrein in the retinal and choroidal blood vessels. That's where contact activation happens in blood vessels. We know a lot about avoralstat, it's like meeting an old friend again. So it was safe and well tolerated in our clinical studies, and that included over 250 individuals and dosed orally and the adverse event profile in those studies were similar to placebo, including in a controlled Phase III clinical trial. Avoralstat had low solubility, which made that program a challenge but it makes this program an opportunity. It makes it ideal to formulate in a suspension depot without the need for foreign carriers like gels or methylcellulose or the like. And we have nonclinical evidence that we can get it to the right place using a suprachoroidal injection and get it at high concentrations. So the unpublished data on the right-hand side show the nonclinical ocular PK profile of suprachoroidal avoralstat suspension. And just another orientation, X-axis this time again is days after injection of 2 milligrams of drug. The Y-axis shows drug concentration in micrograms per milligram of tissue. There are 2 lines here. The upper line is drug concentration in the compartment that includes the retinal pigment epithelium, the choroid and the sclera and these drug levels are very, very high. That's what you would expect because that's where the depot is in between the sclera and the choroid layers. The lower line shows that these very high concentrations drive the drug into the retina. Two things are important here. The concentrations in the retina are well above the IC 99 for plasma kallikrein inhibition. And this is true for at least 3 months. So that's very important to emphasize. We have such a long period of drug exposure in the right place. These data support the potential for very infrequent dosing, ophthalmic dosing of avoralstat in the clinic for example, every 3 months or longer. And because the depot delivers high concentrations of avoralstat to the right place, the retina and the choroid. So on avoralstat suspension delivered in this way has the potential to be a best-in-class plasma kallikrein inhibitor for DME. We're now working our way forward through 2024 to complete all steps required to enable DME trials to begin such as required nonclinical studies and a formulated sterile drug product manufacturing supply for the clinic. Pending satisfactory progress, we plan to begin proof-of-concept studies in DME in '25 and deliver results in '26. I'd like to turn it to Charlie who will provide his perspective on all of this.

Thanks again, Bill. So Ryan and Bill have described a lot of what we're looking for here with avoralstat for DME. We're looking for is to deliver what we think is the right drug to the right place, no more frequently than every 3 months for patients with suboptimal response to a VEGF inhibitor, such that for these patients, we can actually help restore some of their vision. That's what the patients are looking for, that's what their physicians are looking for. And the current standard of care, as Ryan alluded to, with the story about his father is if one VEGF doesn't -- inhibitor doesn't work, try another one, then try a third one, sometimes even more. And so you're throwing the same -- essentially the same solution after the problem and it's just not working. And you can see from the quotes here from some retinal -- some DME KOLs that when they looked at the target profile for avoralstat in this case, they were really intrigued because what they said is what we don't need is another version of a VEGF inhibitor. What we do need is other mechanisms of action. So the opportunity here is to maybe have avoralstat come in after that first VEGF inhibitor or maybe the second VEGF inhibitor to help improve vision for these patients. Now clearly, DME is not a rare disease. There are approximately 1.5 million patients in the U.S. alone with DME. Many of them haven't been properly diagnosed or not receiving proper therapy, but there's still hundreds of thousands who are under treatment for their DME. That said, the number of specialists, retinal specialists who actually care for these patients and who deliver those injections is actually quite small, between 2,000 and 3,000 physicians in the U.S. And to put that in context, year-to-date, our ORLADEYO team has already reached about 4,000 physicians for ORLADEYO. And so what we think is, while this is not a rare disease, if ORLADEYO meets the profile that we're shooting for here, it is absolutely an opportunity that BioCryst could manage to bring this therapy to DME patients based on the size of the treater population. And from a positioning standard here, what we really are looking at is avoralstat as the best-in-class second-line therapy after VEGF inhibitors. This is not competing with VEGF inhibitors. But what we would plan to do is a study, a head-to-head comparison of continuing with a VEGF inhibitor or go into avoralstat and looking for superiority for avoralstat in those patients who are not responding adequately to VEGF inhibitor. There are other therapies -- later-line therapies available, specifically corticosteroid, glucocorticoid implants. And what we hear from DME experts is they will use these sometimes but they're really hesitant to do so because of the concerns around side effects. So these implants can cause cataracts, they can cause an increase in intraocular pressure. And so that really gets to they're looking for a new mechanism of action for these patients. There are 2 other therapies in development right now. Two other kallikrein inhibitors. But you can see that one is an intravitreal injection on a monthly basis. And so when we talk about best-in-class, every 3 months for avoralstat, we think would be superior to that. And then there's an oral therapy which if it worked would be great for patients, but we think that delivery to the suprachoroidal space is the optimal place to deliver a kallikrein inhibitor. So really exciting opportunity, even though it's not rare disease, a great opportunity to help patients who are in great need. So the key takeaways for overall set in DME. We've got a very promising old friends that we're repurposing here for a high need in DME. The characteristics of avoralstat that made it not optimal for HAE, we think, make it perfect for DME and with the Clearside partnership and the ability to use that incredibly small needle, to deliver it to the right place, there's a chance to be the best-in-class second line therapy for patients with DME. So last, in our pipeline here, definitely not least. We started with ORLADEYO, we'll finish with ORLADEYO here, is the ORLADEYO pediatric indication. And the pediatric population for HAE is actually probably the smallest rare disease population or subpopulation that we've discussed today but a really, really high need. This -- our APEX-P study is in a pivotal trial -- it's a pivotal trial right now to bring that to patients very soon. So the -- there's an incredible high -- incredibly high need for kids with HAE. And some of this is similar to what I talked about earlier with adults. Fortunately, kids now have access to targeted therapies with Takhzyro, Haegarda and Cinryze. But these are injectable therapies. And so all the burdens of injectables that are applied to adults, also apply to the pediatric population, but in some ways, even more because parents or caregivers really share in this burden. And it's maybe a little similar to Betty Ann's story about treating -- giving her daughter Carlie, the baths. We hear from parents and caregivers with HAE that sometimes giving them the injections can almost be worse than HAE attacks themselves. And so that's a burden that we're trying to reduce here for kids and for families. And we have a really innovative formulation here. Our team here in Birmingham has developed these tiny granules. And you could see an example there on the slide. These are granules that don't dissolve until they get into the stomach, and you can take them with a glass of milk, a glass of water, or for younger kids, with a soft food, mashed potatoes, mashed bananas, peas. I'd like to think of it as maybe mashed potatoes most days, and then chocolate pudding for a special treat once a week, depends on your family. But what we're hearing back in the APEX-P study is that this is -- the delivery of this new formulation is going really well for kids with HAE. The APEX-P trial, as Helen described earlier, is designed to get an indication age 2 to under 12. It's well underway. It's -- the goal is to enroll 30 patients across 15 different sites, and we're on track to submit an sNDA in the U.S. in 2025. And then right after that, we'll start filing in other regions because there are kids all over the world who are waiting for this therapy. So again, this is a really -- it's a small population. We think in the U.S., about 500 patients may need -- kids may need prophylaxis therapy. But to have an oral to do it is something that they're waiting for. The granules make it easy to take, the APEX-P is the open-label pivotal study right now that we hope will get the indication for ORLADEYO in pediatrics, and we're on track to submit an sNDA in 2025. So putting this all together, you can kind of imagine a future, and there are a lot of different potential futures here for this expanding portfolio. But you can start to see how BioCryst can go beyond just allergy, immunology to have drugs in multiple therapeutic areas. So in allergy and immunology, we've got our first-in-class oral Kallikrein inhibitor with ORLADEYO. In the future, we'll expand, we hope to ORLADEYO pediatrics. Dermatology is -- start with 17725, and there might be an interesting connection there because some Netherton syndrome patients actually show up in allergists' offices. And then in the future, we can expand the dermatology portfolio with our other complement inhibitors for conditions such as Bullous Pemphigoid. Nephrology, neurology, hematology, there are any number of paths to therapeutic areas here. We're starting with generalized myasthenia gravis in neurology, maybe going to neuromyelitis optica, or multifocal motor neuropathy. And then ophthalmology, even in ophthalmology, starting with Avoralstat, and then there could be potential in the future for complement inhibitors for macular degeneration or geographic atrophy. So really from a commercial perspective, lots of opportunities to help patients in a really exciting future. I'm going to turn it over to Anthony to tell us how we're going to allocate our capital.

Thanks, Charlie. So as CFO, I couldn't be more pleased to share with everybody today that BioCryst is in the best financial position that it has ever been in its near 40-year history. John talked about some of the drivers earlier, with growing ORLADEYO revenue, a disciplined approach to capital allocation. The strong balance sheet that we have in addition to optionality on a go-forward basis. All of those things combined give us a high confidence that we will remain in a strong position as we move forward and advance this exciting and new pipeline. So Helen talked about earlier the [ rigor ] that we use when we're talking about our pipeline, and when we're talking about the investment strategy in our pipeline, specifically around molecules that need to be first-in-class and best-in-class. That's a high bar. Where does that start? That starts with our strategic discovery process. This is a process that involves multiple teams across the organization, predominantly the R&D team and the commercial team, but also stretching into teams like supply chain, regulatory, Jinky's data team, legal, finance and others. What we need to do here from the get-go is to make sure that we have alignment. So the team is looking at a bunch of individual factors when we're determining what we need to do and what we need to see in order to move forward with molecules. Factors include areas like high unmet need, the scientific validation of the indication. The discovery team's capabilities and its ability to move these molecules forward, factors like regulatory and supply considerations, and then also existing and investigational options that exist for patients. We also, at the same time, run complex financial models, we run business cases, and we do early research to make sure that our information is validated. We try to come up with timelines, reasonable credible timelines. For the development strategy, we look at stage gates and we agree to what those stage gates will be, both for data collection and for investment stage gates. And we look at the investment requirements for each molecule as it were to move forward. We use a consistent approach for all of these molecules when we're looking at our pipeline. What we want to make sure is that, we're looking at this from a consistent perspective such that when we get to the point of prioritization, we have a consistent bar to use so that we can develop the pipeline. In terms of our disciplined approach and how we use stage gates in order to manage further investments, while each stage gate is important along the way in the development cycle, the proof-of-concept area is one that has a significant short-term focus for us. The level of investment to get there is relatively modest. As you get to that point and thereafter, you're looking at, as Bill said earlier, getting into pivotal trials. Pivotal trials are larger, more global, larger patient populations. They're longer in duration, and usually, they require additional investments in key areas like CMC in preparation for our potential commercial launch. What do we need to know at the point of proof-of-concept? The team talked about it earlier. We need to know that we have a safe, effective and differentiated drug. We also need to make sure that we have sufficient investment to move these programs forward. As I said earlier, we're in the best financial strength, our best financial position that we have been in our company's history. We have cash on hand of almost $400 million. We're looking at no less than $320 million this year in global ORLADEYO revenue. And yesterday, we revised our guidance down for OpEx to between $365 million and $375 million. So the elimination of doubt that does include the milestone payment to Clearside based on the partnership on the Avoralstat molecule. Looking forward to 2024, and looking specifically at R&D as it relates to the pipeline, this new exciting pipeline that we announced today. Here, I'll give OpEx numbers or R&D OpEx numbers that do include non-cash stock compensation. We usually eliminate them, but I'll include it for ease of [ burying ] it back to the K and the Q. What we're looking at next year is spend, investment that will be in and around $230 million to $240 million. Compared to this year, that's about a $25 million to $35 million increase. When I look at it versus 2022, it's about $13 million to $23 million lower than that period. So what do we get for that modest increase on a year-over-year basis, given the depth of the pipeline that the team has shared today. We get completion of the proof-of-concept trial for 10013 in PNH. We'll advance, as Charlie said, the ORLADEYO pediatrics trial as we prepare for an sNDA submission and then commercial preparation from there. And as Helen said, at least 1 new program being in clinical trials and the preparation for the additional pipeline programs to be getting ready to go into the clinic. For 2025 and beyond, we're looking at a pipeline that will evolve. And as that happens, we will continue to evaluate our financial options. And again, from a proof-of-concept perspective, we're only looking at assets that are safe, effective, differentiated and fundable. The fundable one, I'll go into a bit more detail because it's important. At that point in time, we will look at the financial position of the company. We'll look at our balance sheet, we'll look at the balance -- the strength of the balance sheet as we see ORLADEYO revenues grow, and as we continue to be disciplined in our investment from a capital allocation perspective. We'll also look at instruments like debt and royalty, specifically royalty as it would relate to any new molecules that would be -- we would be developing through the pipeline. And as John said earlier, we'd also look at partnering out molecules. There might be partners at that point that will be able to add value, and ultimately fund and advance some of these novel molecules. To conclude, we will continue to grow ORLADEYO revenues. We will strategically invest in our pipeline. We will bring new therapeutic opportunities to patients that have high unmet needs. We'll continue to build on the strength of our balance sheet, and we'll continue to support this new era of growth for BioCryst. And now I'll hand it back to Jon.

I'm feeling really short right now. All right. Wrap up. We're just about to get to your questions, but there are some takeaways. Number one, the bar we've set for our programs is first-in-class and best-in-class. We believe the molecules you've seen today fit that profile, and that's how we're going to allocate capital going forward. Number two, we've already shown you that we can make a first-in-class molecule with ORLADEYO. Today, we showed you actually how we built it, down to the angstrom. That's the size of an atom. We showed you how we built this. It wasn't by luck, it wasn't by accident, it was by design, by design. Number three, we've -- you've seen today how we've expanded our discovery capability. So we not only expanded the pipeline, but we've expanded our ability to go after more targets. Protein therapeutics, we have an inhibitor protein therapeutic that is 1 million fold more potent than the natural ligand, 1 million fold more potent than nature, is what our scientists have built. We've got an oral drug that disrupts protein-protein binding with our Oral C5 inhibitor. And we've come up with creative approaches to take a drug that we studied in HAE, take the great characteristics, potency, rate target, solubility that keeps it where it needs to go, and then combine it with a device that delivers it where it needs to be for DME. All best-in-class or first-in-class. Number four, you've heard that we'll continue to be disciplined around capital allocation, and that we will stick to the bar that we've set of best-in-class and first-in-class. And the options to fund right now have never been better. We are no longer, thank God, dependent on the capital markets for funding, we have choices. Number five, and this is the most important one, you've heard the huge difference we can make in patients' lives. And as I told you at the beginning, when you do that, you create massive value. And we believe this is going to create sustainable value for years to come. So thank you.

So question-and-answer time. Here's the rules. In the room, and you're all welcome in the room to ask questions, but we'd like you to come up to the microphone, in the middle of the aisle here, and give us your name and your affiliation. And then those of you on the webcast, we will also take your questions and John will repeat them on the microphone, and we'll spread those out periodically. So who's bold to go for the first question? Yes, just walk up. You don't have to raise your hand.

I'm [ Catherine Okoukoni ]. I come from JMP. My question is about the 10013 program, and just how you see the translatability of the PNH population to the IG -- the other nephrology indications, and also how you're prioritizing the next indication, whether you're planning on doing them in parallel, or whether IgAN is coming first? That's my questions.

So I'll pass this to Helen, I think talking about the alternative pathway, I think, is the key.

So 10013, what we're looking for with the PNH trial is a dose. And it's -- we're looking for a dose that is safe, effective, and that will be effective in terms of complemented inhibition as well as clinical outcomes. Once we reach that dose, it should translate to other diseases. So what you'll see us do is get to proof-of-concept. And if we can achieve that once daily, that will be the dose that we take forward. In terms of prioritizing, amongst the other programs, there's a great need. We know the alternative pathway is relevant for treating multiple other diseases. And we've just spoken about IgAN and C3G. We're moving those both forward at a similar speed.

I'm Mauri Raycroft from Jefferies. Great to be here. I was going to ask a couple of questions about the C5 inhibitor. You mentioned the nanomolar potency. Can you talk more about the assay you're using to measure inhibition of MAC formation? And what else can you say about how the molecule interfaces with C5? And what evidence gives you confidence this will be selective enough?

Bill?

Sure. Can we bring up the slide that has the assay results for the C5 inhibitor? Maybe that's a good place to start. So there, you can construct multiple assays that look at the terminal part of the complement cascade. A lot of the commercially available assays, no matter which pathway you stimulate, end up measuring C5b-9, you can block all of those with a C5 inhibitor. You can also set up assays that measure cell lysis. So that's the -- so you have to have a cell to do that, a typical one is a red cell. So hemolytic assays do that. So they're the types of assays we've used. And if we have a look at the chart here. Actually go to the assay one, with the little orange -- and orange things. Keep going, keep going, keep going. Okay, we don't have that. That's right. So it might be -- so it's exactly the same suite event, actually showed the bifunctional summary because that has all of the assays. So all of those are the same type of assays you would apply. It's just a matter of picking the ones that have C5b-9 or cell lysis as the readout. So that takes care of the -- which assays. Selectivity here is a bit different compared to enzyme inhibitors because if you had a kinase inhibitor, you would go to a vendor and do a kinome screen, you can't do that here. If it was a serine protease, we have a bunch of in-house assays of various serine proteases that we could look at off-target effects. Here, we're more reliant on 2 things, one of the broad spectrum off-target platforms like G-coupled protein receptor, assays of more than 100 of those, and the non-clinical safety profile in 2 species would be the key elements. That takes care of selectivity, and sorry, I've forgotten the third part.

If you could talk more about how it interfaces...

At this stage, we're not disclosing that for proprietary reasons. But it's pretty cool.

Maybe one other question. Just how do you think about biologics that potentially have more intermittent inhibition of C5 versus continuous inhibition? I guess, what are some of the trade-offs of that?

When you think -- I think it's very dependent on whether you have a continuous disease process that you're trying to block, or whether you have a waxing and waning disease process. So I'm struggling to think of a waxing and waning disease process that involves cell lysis. The hemolytic anemias aren't like that. But for any chronic disease where there's continuous activation of complement and continuous cell lysis destruction, I think it would be disadvantageous to back off on the drug because then the disease process will come back.

Hey, Bill, Maurice's questions remind me of something else that I think is really important that I'd like you to answer it. And that is, with C5 antibodies being on the market and all we've learned from them, what does that do in terms of choosing dose and exposure or things like that with a small molecule?

This is a very interesting position to be in for a novel oral C5 inhibitor. There's a ton of published literature now on the relationship of the monoclonal antibody C5 concentration to the effect it has in assays and the effect it has in patients. So the specific example is in PNH. We know what the free C5 level needs to be below in order to get control of hemolysis in that disease. So PNH sets a very high bar for the amount of complement inhibition you need in order to control the disease process. So what can we do there? We can take eculizumab, like we did for the bifunctional inhibitor, put it in an assay, dose response and see where do we get C5 levels below the clinically validated target C5 level. And how much inhibition in that assay does that correspond to. That's easy to do it, right? Then side-by-side, we can put our target C5 inhibitors in a similar assay, in exactly the same assay, and understand what concentration of the C5 inhibitor or what concentration range gets you to the same functional outcome as having achieved the targets, free C5 that you would have with a monoclonal antibody. So it's a direct comparison. And that's going to give us in advance, any dosing of any human being is going to give us in advance the plasma levels we need to achieve in order to match the efficacy of a monoclonal antibody. So that's a big advantage.

Stacy Ku from TD Cowen. So first, just a quick question on 10013, can you narrow the timing to when we might get some results? Would you release anything interim? Are you going to just help set expectations there? And then I have another question on the pipeline.

So Helen, maybe just talk about what numbers of patients that we need and how long we need to study them. That will give them some idea of recruitment and then the length of the study.

Yes. So with 10013, we don't need very many patients in PNH to understand what's happening with the disease, to understand if we're getting the level of complement inhibition that we need, and if we're getting there with a sustainable degree. So it won't take very many patients. We follow for a few weeks. We're dose escalating within the patients, we'll follow up to the level at which we see the effect. I still -- I'm going to point you to mid next year for results and for an answer on that.

And then another question on your oral C5 inhibitor. So can you just talk about your plan in myasthenia gravis? Are you going to look into the broader population for proof-of-concept? I know it's some ways away, but just trying to understand how you're thinking about things. For instance, some other companies looked in mild to moderate severe patients first as proof-of-concept. Just curious on your thoughts there.

Charlie, that's a good question for you to tackle, and the parallels you pointed out with HAE are probably the best way to look at it.

Yes. I think with an oral drug, the great thing is we have options. If we can figure out the right way to study it, myasthenia gravis is, they're up to 70,000 patients. So that's a wide range. We know that the existing therapies have typically been restricted more to the later stages, more refractory of those patients. What I would want to do from a commercial perspective is think about both because I think there's a lot of opportunity and a lot of need. And as I was explaining in my comments, for patients to take nonspecific therapies that have other side effects, steroids and other things, it's having a -- if you can have a safe and effective targeted therapy, that's just much better for patients, and an oral drug is a perfect way to do that.

Yes. And unlike HAE, there's more indications that we could go after, more complement-mediated diseases we could go at.

Opportunity.

Next?

Ananda Ghosh from H.C. Wainwright. A couple of questions, mostly on the C5 inhibitory landscape. So if you look at the landscape, the initial lot of focus was development of antibody-specific therapeutics, right? So what's changed? I mean, what were the -- what was the real barrier to develop small molecule drugs? And where exactly -- so what was that barrier, which the small molecule drugs are overcoming?

I'll start. And I'm not the guy qualified to answer, but I'll take a shot. So I think the key -- and this is -- I think Helen said it, Bill said it, I'll say it again. The ability to put a small molecule to break a protein-protein binding is really challenging. Very few people have done it, and our scientists figured it out. So that's what's prevented other people from doing it, is they weren't successful. And again, I think it goes down to what we see through our structure-based drug design that allowed us to build what we built. But Helen?

That's exactly right. And I don't know that we're saying that others can do this. We're saying we figured it out.

Got it. And the next question is pertaining to the DME. And here again, if the anti-VEGF therapies have not been working for so long. Why haven't kallikrein was the choice of target for so long? And like what makes kallikrein, -- like what is the scientific rationale in thinking that kallikrein is the right target for DME?

Ryan, I'll give that one to you.

Yes. Again, I'll point back to the slide I presented on -- there's multiple things. You need to have the right mechanism, you need to have the right drug, and you need to deliver it to the right place. So as far as the mechanism, the evidence has been consistent around suggesting that plasma kallikrein plays a prominent role in this disease. You have multiple studies that point it's elevation in this disease from samples and patients, as well as preclinical. So the mechanism, we feel really comfortable and confident in, in terms of what the evidence suggests. And there's other analogs, other diseases where things haven't worked before, and you have to then crack the code of having the right drug in the right place. So getting to the second point, Avoralstat is a very potent plasma kallikrein inhibitor, with the right solubility properties, perhaps to deliver it to the right compartment. Which brings me to the third part, and that's the suprachoroidal delivery gets it right to that area where the choroidal vessels are, as well as the retinal vessels, to really have a -- see if we have an effect on that contact activation system. So those 3 things together give us a lot of confidence that this is a different approach than what's been done before.

Got it.

And Bill, you gave me a lesson on diabetes and eye vessels. And so maybe you want to just make a few comments on that front around validity of the target.

Sure. So the evidence are involved -- it's not that VEGF isn't involved. Obviously, it is because there are approved VEGF inhibitors that help patients with Diabetic Macular Edema. The evidence is both nonclinical and clinical, and nonclinical evidence comes from, for example, looking at diabetes in a rat model of Streptozotocin-Induced diabetes. And interestingly, macular edema can happen within weeks of inducing diabetes in this rat model. So you can study it in the lab. What we see there is the type of vessel damage, which is the diabetic microangiopathy that Ryan mentioned, happening. And you see upregulation of Bradykinin B1 receptors, for example, you see activation of plasma kallikrein. And in the clinic, we see the same thing in terms of increased plasma kallikrein levels in vitreous humor, which is the only compartment you can access an assay in a living human being. And additional literature has evidence from [ cadaver ] studies, which is the only other way you can do it that sort of replicates the mRNA expression levels, the protein expression levels on the receptors and the involvement of kallikrein. So the real test here is to get on with the experiment that we have described and make sure we're getting kallikrein into the right place in the eye.

And Helen, you might want to talk quickly about -- just like the speed at which we could move once we get into the clinic because you can't study this in healthy volunteers, making injections in the eye. So you might want to just briefly talk about numbers of patients that give us an idea of, is this drug working, and how quickly we can do that?

Yes. One of the great things with this program is we're not starting from scratch. We're starting at a point where we already know a lot about the drug. We have a randomized safety database for systemic safety, and we have the preclinical data now, and our own evidence about the drug and its potential PK in getting to the eye. So it's -- our next move is into patients, rather than healthy volunteers. So it's sort of step forward into the development process. And our move from there is to understand probably with 1 dose, a single dose in patients, what we see in the timeframe after. So it's a sort of jump start into being able to assess if this is going to help a patient.

So just to follow up. Are there biomarkers for these kind of studies? Or like how do you progress -- how do you test the efficacy?

So do you want to add to that?

Yes. I mean, in addition to looking at visual acuity, OCT is a very reliable measure to see if you're affecting the disease process in the eye.

Serge?

Serge Belanger from Needham. It's great to meet the extended team. First question on profitability. How much of a priority is it for you, the Board and your shareholders to get there? And do you have a timeline for that?

I'll take the first part. Anthony, you can take the second part. So of course, you want to have profitability, but you don't want to just have it for a quarter, and then not have it for the next quarter. And I think the key is to be very profitable, ultimately. And with the assets that -- the therapies that you saw today, and the difference that they can make in patients' lives, we think we can be a very profitable company. And what we've told you repeatedly, I've said it, Anthony said it, is we're going to be really disciplined about how we use the capital, and how we invest to meet that bar so that we get there as quickly as we can.

Yes. ORLADEYO is already there, right? ORLADEYO on a direct basis is already a profitable program for us. To Jon's point, there's an opportunity that we have given the depth and breadth of the pipeline at the moment. But from a valuation creation perspective, I think is better invested in this pipeline than getting too soon or too quick to the point of profitability. I'm confident we will get there. We're talking about ORLADEYO at peak sales of -- or peak revenue of $1 billion. So I am confident that we will get there. But in the interim, these assets, these molecules are too important, too valuable not to invest in. So I'd rather slow that part of the process down, build up to it. And then to Jon's point, the value it being potentially magnitude or orders of magnitude, as opposed to kind of eating it out and put some of these on the backburner, I think is the right approach for the company.

And then on the DME program. It's nice to see you have a real step back. I think another company has tried with the PKal inhibitor for DME and had mixed results. I'm sure you've seen the study. But just curious if you can give us -- the wrong molecule, the wrong delivery or maybe the wrong study?

Might have been all of the above, but I'll let Ryan take that one.

Yes. I mean, we are following what the field is doing. And again, we feel as though the combination of the 3 factors, especially now with the partnership with Clearside gives us -- it's a distinct advantage combining with our molecule, which is very potent, and has the right solubility property. So we -- the evidence very clearly points to plasma kallikrein having a significant role in this disease. And we feel now we have a really plausible way forward to take a shot at this process.

I think the other part is the creativity to take a drug that was, I think Avoralstat was more potent than ORLADEYO. So the potency of this molecule is fantastic, but the challenge was the solubility and that to take that characteristic that was a problem in oral, but perfect in the eye because you wanted to stay there because you don't want to keep giving more and more injections. And then combine it with delivery, the Clearside microinjector to get it to the right spot. We're very excited about this. Seema?

This is [ Seema ] from Evercore ISI. I have a question on 10013. You have some dose-related observations in your nonclinical studies, and you wanted to figure out efficacy and safety around the dose. So if you can provide any update on that, that would be great.

Helen?

Sure. So we -- the most important thing here is that we're in the clinic and in patients. And the data that you saw today, the healthy volunteer data is evidence that we are in healthy volunteers and have the suppression that we need with this drug. The evidence from patients will tell us if we have a safe and effective drug at the doses that we need to dose. The other studies that you mentioned are still ongoing, so we have nothing new from there. But regardless, what we need to know is what we will discover from this study with PNH.

Okay. And you're expected to finish those studies end of next year, like -- when are you supposed to finish those nonclinical studies?

Mid next year, mid-2024. So nonclinical studies will continue through this year. But I also want to say that the most important information will be coming from the patient studies mid-next year.

Others in the room? All right. It looks like John's got some from the webcast.

So we do have a question from the web. With so many opportunities here, what are the key things you're going to look for to decide which molecules to take to the finish line yourself, and which ones you want to partner?

I'll start, Charlie, and then maybe you can chime in. Commercial attractiveness is obviously one that's really important. Can we manage it ourselves? Actually, all of the things that you saw today, including DME, from a commercial perspective are attractive because the number of centers that actually do the injections is smaller than the number of HAE doctors that we call on for with ORLADEYO. So the size of the commercial infrastructure, I think, is something that we could manage. I think the biggest reason for that, John, is do we have so many things that are successful, that we have the capital needs when we get to advanced development are so high that it makes more sense to partner one of the programs. So that will be a hard decision, but one I'm pretty confident that we can make. Charlie, I don't know if there's anything else?

I think I very much agree with what you said in that last part, which is if certain things are going really well, and we'll look at our capital, we'll look at how the competitive environment is shaping up. We'll look at all of this. And so what Anthony was describing about milestones and the broad, the cross-functional team that looks at this, as we look at our portfolio, we look at these choices constantly, and we'll continue to do so over the next several years as our portfolio evolves. So it's hard to say now. And -- but I'm confident that any one of these, if we can afford to do it, and the drugs work out, any one of these we can commercialize as BioCryst.

Yes. And listen, partners add a lot of value. The capital is one of them, the skill set and the people and the numbers of people and resources that they have access to is important. But we've also seen that the company that discovers it treats the molecule a little bit differently than the one that you hand it to, and just cares a little bit more, and we've all had those -- I see heads nodding in the audience. We've all seen those experiences where the company licensed to didn't move it as fast, didn't invest in at the right way. And so these are things that we discovered that we believe are going to create crazy value because they're first-in-class and best-in-class.

But we will continue to have the right amount of discipline, right? To Charlie's point, to Jon's point, we want to make sure that they work. We want to make sure that they're going to help patients with high unmet need. But we talked about the fundability. And so if we were to get to the point with this very dense pipeline, that from a capital allocation perspective, we needed to make some decisions, given the opportunity that each of these molecules have to be differentiated. I don't think we'd be short of suitors. And I think in that regard, that would be something that we'd be absolutely open to if it freed us up to do other things.

Yes. I think our Factor D inhibitor, if it's once a day, it's a best-in-class molecule, even that could be attractive to suitors. So other questions? John's got another.

So we've got this from a couple of folks on the web. What dose range will you be studying in the 10013 PNH trial?

Helen or Bill, who wants to take that one? Bill?

So just as a reminder, we studied for once daily dosing in the healthy volunteer trial of 20 to 160 milligrams. Our experience is that, we may need to study a range of doses in PNH, and we're starting off at about 150 and going up to about 250 milligrams. That's the plan. I beg your pardon, starting off at about 100, going up to about 250.

Another one, do interest rates or the IRA impact your capital allocation decisions?

Anthony, take the interest rate piece. And Charlie, yes. I mean, Anthony, could take both, but...

Yes, On the interest side of the house, we're -- finger on the pulse as to what it means in terms of the capital that we have specifically as it relates to the debt side of the house. It doesn't help in other areas around discount rates. It doesn't help in general from a macro environment perspective. Funding, I'm glad we funded when we did. I'm glad we refied the debt that we did when we did. The market out there is not very receptive to, whether it's equity financing, whether it's any other's type of financing at the moment. So it's definitely something we're acutely aware of. We take it into consideration when we look at the overall cost of capital. It's not impacting us right now in terms of our capital allocation, other than those macroeconomic environment factors and continuing to be disciplined in our allocation of capital for preservation of cash. For the IRA, I can start, and you can chime. Some things we know and some things we don't, right? As much as there are plans out there, I think we'll have to wait and see a little bit what happens once it is enacted. I think it's a great opportunity for patients who have high co-pays to max some of those co-pays so that they can make a lot of these drugs more affordable. What happens downstream, I think, is yet to be seen. What happens with PBMs, what happens with insurers, what happens with premiums, what happens with government funding, I think, will come into play far more next year. But the interplay, the risk opportunity side of the house between the max or the co-pay being tapped. And then the opportunity then for patients to be able to source funding in order to have these life-changing drugs and have them being reimbursed, I think, is a really good opportunity.

And Charlie, you may want to just talk about impact of the IRA in general to us. We don't see it being a big capital allocation issue because we don't see a big impact.

It's possible that the part of the question is referring to what some other companies have done in terms of choosing where, what disease states, how to invest in their pipeline based on the long-term implications of the IRA. And if you get a drug that ultimately is subject to negotiation from CMS, that does not factor into our decisions. We -- I think it's clear today, what we focus on is scientifically where can we develop a drug to help patients and then it's all about the patient need. We're not trying to be overly clever about this. It is about the patient need and where we think we can be commercially successful.

Other, web?

So this a question and a sort of related question on IgA nephropathy. IgA nephropathy is more prominent in Asian populations. Do we plan to commercialize our molecules in that region to treat IgA nephropathy? And then alongside that, would BCX10013 or the bifunctional molecule be a better fit for the IgAN, nephropathy population?

Ryan, do you want to?

I mean as far as the patient populations go, there is -- IgA nephropathy is very heterogeneous. And so you -- when you see a patient in an Asian population has a different disease process than those in the U.S. or Europe. So that, I think, speaks to the opportunity in targeting multiple parts of the pathway, and that can -- why we feel still confident in targeting the alternative pathway. So as far as commercialization plans, I don't want to speak for Charlie, but absolutely, I think we'd want to get a Factor D inhibitor to all patients that could benefit if we prove that it's safe and effective in that population.

Bill, do you want to add anything or Charlie?

That's our plan for ORLADEYO, is to bring ORLADEYO to patients around the world, and that would be our plan for other programs where patients -- there's global need, we will bring it to patients globally.

And Charlie and I were in Tokyo 2 weeks ago, and met with one of the top treaters in all of Japan of IgAN and he was really enthusiastic about our program, so. Other questions, no? In the room? Going, going, gone. Got it. All right. Well, listen, first off, again, to those of you that made the track, just super, super grateful. I hope I see a lot of smiles. So I hope it was worth your time and energy, especially on a week when it was so busy. We believe we're doing something special here, and I'm glad you got to see it firsthand. And for the rest of you, we hope to share more with you. If you're interested in coming to Birmingham, we're happy to host you at some point in the future. And we look forward to sharing more with you as our programs progress. So thank you, and have a great weekend.