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 have 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 five new programs today, and each and every one of them has the potential to be a first-in-class or a best-in-class molecule. We're gonna 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 device for patients with DME, and you're gonna 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's our Chief Research and Development Officer. Charlie Gayer, our Chief Commercial Officer. Dr. Bill Sheridan is 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 off for now. But let me add my welcome to you. I'm particularly grateful to those of you that made the trek 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 gonna 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 will continue to have on patients. In my over 35 years of, 34 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 1980s. 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 gonna do and what we're gonna 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 gonna create for patients is gonna be huge, and the value for our company is gonna 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, doubled 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 missed 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, and so the lives of patients with HAE 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.
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 had 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 gonna have with some of these other molecules you're gonna hear about today, and that impact is gonna create huge, huge value. So we've been around for a while. A company that's been around for almost 40 years. Those that 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, 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. We believe we have the opportunity to help many, many patients, and that's gonna create continuous value for the company and for patients. We've also diversified our pipeline. We've gone beyond small molecules and oral drugs and moved to protein therapeutics, and you're gonna hear about that today. We use the same techniques, the same tools, the same skills we've developed over decades, but now you're gonna see that we can build potent binding biologics. 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 gonna hear that we've expanded beyond it 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 gonna 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 of best-in-class and first-in-class. 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 gonna 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 gonna take you on a very interesting journey, I wanna recognize the team here at BioCryst. No way 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 gonna take you inside protein targets, and we're gonna show you what we see, what our scientists see. And you're actually gonna 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. Oops. I gotta go back one. Sorry.
... Thanks, Jon. And 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 at 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 the BioCryst Board of Directors a little more than four years ago, and what I saw from that perspective impressed me.
So much so that when the opportunity arose a year and a half 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 in 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 a 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 three regions and achieve the company's first rare disease launch in the midst of a global pandemic, was unparalleled. 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. 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. 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 in 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 meet this bar.
Then we test our molecules rigorously along the way to ensure 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 six molecules in the next five 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 differentiated medicine. You'll see how we create and deliver therapies with the 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.
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 to 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. 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. 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 at 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 two-dimensional view of a protein, how the amino acids are arranged in a string, with each amino acid containing its own distinct assortment of atoms, represented here by the different shapes of the beads on the string. 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 three-dimensional structure of the protein. I want you to notice, as we're watching this next video, this, the complexity of the three-dimensional structure created, and then focus on where the active site sits within the protein. 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 a three-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 two-dimensional sequence, forming its three-dimensional structure. It's very complicated, you can see. And then the electron map, which shows the density around the amino acids. 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 acids is the external forces that also influence the shape and three-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 its 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, of 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. 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 two-dimensional sequence of the amino acid string, what shape the folded string will take. We, like many others, use these as a tool to provide a starting point in drug design. They provide us with the first of the data we need, the three-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't 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 to 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 predicted protein structure can be imprecise and even inaccurate. And so overcoming this and getting to 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 the 3-D 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. 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 a best-in-class drug. 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 charges. Blue is positive, red is negative.
Those external factors, water molecules and ions, that influence the charge and shape. 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 the electric charge at critical points of contact. We need this 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 and the streets and parks 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 as 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 our medicine, we can design with those changes in mind.
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 a crevice in the middle with its deep pocket and the bumps and valleys around that pocket. On the right, in purple, is a 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. In this instance, we've used three-dimensional structure information and also the high-resolution, atomic-level structure information to design that molecule for a great fit. Then everything changes. As the molecule binds to the protein, as the drug binds to the protein, you can see the protein changes shape around it. You can see as it fits into the active site, the protein changes.
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. 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. 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 the medicine that we're building. Let's recap. To deliver a first-in-class and/or best-in-class drug, we are designing to achieve high potency, specificity, and bioavailability.
You just saw the three challenges we have to solve, defining the three-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 3-D protein structure data they provide, and these are the first step. 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. 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 in an iterative fashion to resolve our remaining challenges for drug design. We develop pure crystals of the target protein with a highly ordered grid-like structure built from 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 to the exact structure.
There's an art to growing the crystal, and it takes practice and patience to master it. The reward is a map of the structure down to the Angstrom level. That's 1/10,000,000,000 of a meter and the approximate diameter of an atom. 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.
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 a 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.
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 changed 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 determination 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 recrystallize, reanalyze, and reassess our drug 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 matched 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. 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 million-fold greater potency, and that's a powerful difference. Second, for some targets, designing a protein therapeutic allows us to advance a lead towards the clinic faster, because we can get to a molecule that reaches our standards for differentiation more quickly this way.
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 a 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.
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 sloughing 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 Ryan, 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 SPINK5, which is shown here, and it's a natural inhibitor of 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 is SPINK5 , to design a better ligand. 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 or inhibiting KLK5. We can do this by substituting the amino acids of the SPINK5 protein instead of the atoms, as we would for a small molecule, to achieve that better fit. Here on the left, you can see the histidine residue of SPINK5 , that's residue B, and how it leaves space in the active site pocket.
It has a neutral charge, that's the color purple, that then doesn't pair with the 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, the active site, and the points we can improve 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, the amino acid, and arginine, another amino acid, would reach in and fill the active site pocket and also pair a positive charge in blue.
This is amino acid Y. It's a positive charge in blue, and it pairs with a negatively charged 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 a 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'll 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 gonna dive deep for a 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 slip 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.
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.
Today, we are going to walk through how we use structure-guided drug design to develop a small molecule, ORLADEYO, a potent selective oral inhibitor of plasma kallikrein for HAE, and then how we apply the same principles to develop BCX17725, a protein therapeutic for Netherton syndrome. Let's begin with the design of ORLADEYO. Uncontrolled plasma kallikrein activity is a key driver of HAE attacks, and our goal was to develop a potent, selective, oral, once-daily drug that could block plasma kallikrein to prevent HAE attacks. Here you can see the plasma kallikrein protein. These darkened regions below are one area of plasma kallikrein that interfaces with other proteins. The other is above. You can see it right here in pink. This is a serine protease region and is what we're actually going to be targeting with ORLADEYO.
Helen described the resolution we are able to generate to see inside the atomic structure, and you can see that here. Every drug discovery program at BioCryst begins with a high-resolution structure of the target protein like this one. This experimentally determined structure provides us with the necessary high-quality atomic structural framework of the active site we need for our structure-guided drug design. The added resolution we get from our process gives us visibility to important additional details, like where water molecules are binding on the protein. Lower-resolution models don't have these details, and they are critical to adequately and accurately characterize the binding site and direct the best drug design decisions.
Another important consideration for our scientists as they designed ORLADEYO, that based on the many nooks and crannies of a binding site, we need to assess which chemical structures will have the right shape and charge to bind most effectively. With the high level of resolution we have, we are able to build our molecules atom by atom and make adjustments as we go to optimize the result we are looking for. Now, I'm going to come to your side here, and we're going to take a look at exactly how this was achieved. First, we're going to take a look at the active site itself that we're targeting. And so here we have negative red regions, and we also have blue positive regions.
We're going to want to complement those charges, and so we'll have blue positive atoms for the negative red regions and red negative atoms for the blue positive regions. We also have gray regions that are uncharged, and we'll complement those with other gray atoms that are also uncharged. You can also see numerous sub-pockets, nooks and crannies, and clefts that we'll fill in with each of our fragments that will be able to fit the shape of them very nicely. We also have two important sub-pockets: the S1, which, if we take a look, we can see is very deep, and that's going to be important for us to fill. And then the S2 sub-pocket, that is a bit more shallow, but it's right next to this pink region here that we saw before, and it's actually key to the selectivity of ORLADEYO.
Let's take a look at our first fragment. So here we have a benzylamine. This has a positive blue atom into the back with a negative red region, which is a great complement. We have this six-membered ring here at the benzyl group that's going to fill this area very nicely. This is a really good anchor position and first fragment. From here, we'll build off with the pyrazole. We'll see how this is going to go in and fit. We'll add a trifluoro right here to fill into this side, and then we'll also have an AND that will go red to blue and blue to red and complement both the charge and the shape. We'll watch this snap into place. You can see how this is going to fit the contour of just this side cleft, as well as allowing us to build across.
Our next sub-pocket is the S3 sub-pocket below. This has a gray region right here, so I'm going to fill it in with a number of gray atoms. But of course, I have some reds and blues, so I'm going to complement that with a fluorine. And once again, we'll watch that snap into place and see how well we fill in the S3 sub-pocket. Moving right across, we have here the S4 sub-pocket. I'm going to need a little help getting to there, so I'm going to build a methylene linker, and then I'm going to bring a benzyl group to fill in this gray region. And finally, we have our negative red region that will complement a positive blue atom off of our nitro. Excellent. We'll now watch that snap into place. Very good. And our last sub-pocket is the S2 sub-pocket.
We'll build out with a nitrogen and build up with a carbon, and that's really just to get us close to it with our cyclopropyl. Now, it is a smaller pocket, so I can use a smaller ring. Still going to fill it in very nicely. You see that snap into place... We can see how each of our fragments is both complementing the shape as well as the charge of each of these different subpockets. However, let's take a look at this, the space-filling model. These atoms are a little bit larger than they appeared before, and this is how big they actually are. We can see how close and how well we're filling in all of these spots, especially highlighting the S2 subpocket that's completely filled by the cyclopropyl, the S1 subpocket that we can't even see into due to how well the benzamidine is fitting in.
We can see how all the way across each of our fragments fits the overall active site. Excellent. This is how we built the first and only oral once-daily medicine to prevent HAE attacks. We can apply the same structure-guided drug discovery approach that we use to develop oral medicines like ORLADEYO to protein therapeutics also. We can see the start of that here. Now, we'll show you how we designed BCX17725, a highly potent fusion protein inhibitor targeting the kallikrein-5 enzyme, also known as KLK5. As you saw with the small molecule in ORLADEYO, structural biology is critical to inform how we design our protein therapeutics. The same principles are applied here. We use atomic models of proteins to provide structural insight using the shape of the targeted protein pocket.
However, instead of using functional groups and fragments like we did to build a small molecule, protein therapeutics, we manipulate the amino acids or replace them to improve the binding affinity. To help you understand how all this was done for BCX17725, we'll start the demonstration with a structure of KLK5, then describe its binding to the natural inhibitor, SPINK5, and finally, to select a mutation of key amino acid residues leading to the discovery of BCX17725. This is KLK5. It's a serine protease that plays a key role in the disease pathology of Netherton syndrome. Netherton syndrome is caused by loss of function mutations in SPINK5. Now, here, we can see in magenta, SPINK5. We can see how it's able to block the activity as the natural inhibitor of KLK5 by where and how it sits on this white region, key to the activity of KLK5.
Loss of the natural inhibitor of KLK5 will lead to its hyperactivation of both KLK5 and related enzymes. Now, I'm going to come to your side here as we start taking a look at how this overall is going to affect KLK5, and how I'll be able to make a very strong inhibitor able to block this area in place of the natural inhibitor. All right. Well, let's get our surface up here, and let us take a look at the key binding residues. So I'm going to make this a little bit larger, make it easier for us to see. So here we have four key residues of SPINK5 that we're going to be replacing to be able to produce a million-fold increase in binding over the wild type.
To start off, let's remember that the red regions we see are negative regions, and we're going to complement those with positive blue atoms. We also have blue positive regions, such as down here, that we're going to complement with negative red atoms. White regions on this one are the neutral areas. All right, so let's take a look at our first residue. First residue will be this histidine up here. This histidine does have the right blue atoms for the red surface, but it's too shallow. If I get a little closer, I put my hand back here, we'll see there's a lot of space that we could fill in. We're going to want to bring in a different residue. We're going to replace the histidine with the longer arginine.
It's going to be able to go all the way back into that pocket and also has blue positive atoms to complement. Our next residue of interest is the methionine. This methionine doesn't have any red atoms that complement the blue surface, and it's not really fitting in as well as it could. So we're going to replace that with a glutamic acid that both fits better, but more importantly, has negative red atoms that complement the blue surface we see here below. Now, this histidine is a little too close to our glutamic acid, and it's just not really going to fit in well. So we'll replace that one with a threonine, gives plenty of space for our glutamic acid. And lastly, I'm going to bring over our phenylalanine that we can see right here, and we're going to replace it with actually a similar residue, tyrosine.
Now, this tyrosine has an additional atom, a red oxygen, and we'll see in just a moment why that's so important. All right. So these are our four mutations, and we're going to see how these all come together and how they're superior to the magenta wild-type SPINK residues. So here, we're going to start off with, once again, our arginine and histidine. So we see up here that once again, the arginine goes much farther back, and we can see a number of interactions that are now possible with the protein due to the depth of the arginine, the histidine was just too shallow for. Coming right across, we're gonna look at our glutamic acid now. You can see it picks up two interactions, these dashed lines, that it's able to pick up with this blue region, the thiamine didn't have the correct atoms for.
Also, it does fit a bit better. And lastly, we have our tyrosine and phenylalanine over here. We can see these hydrogen bonds that the tyrosine is able to pick up due to its additional atom here, allowing it to fit in much better. All of these different interactions that these four residues are able to take care of are what provide that million-fold increase in binding affinity over the wild type. Now, let's take a look at this when considering the entire protein. We can still see, though, that just with these residue changes alone, we're going to complement the contours of KLK5 better. But let's zoom out and take a look at the entire protein of BCX17725. Here, we can see that it's able to fit all the way around and really complement the surface and bind to it very, very well.
Overall, it's clear to see that it's much more than just each of the individual changes, but how they all come together to provide a million-fold improvement in the binding over the wild type, and what makes BCX17725 such a potent and promising inhibitor. Thank you for your time and your attention.
My name is William Webb. I'm 84 years old. I was diagnosed with HAE when I was 81 years old. Through the challenging moments with HAE, my wife has been my rock. We've been through it together. I had a swelling. They sent me to, the hospital. So my wife was interviewing doctors, asking questions, and she was writing notes. It's important that, those of us who have rare diseases, that we do become advocates, you know, that we do look for and support efforts, people are making. When you talk about it, you get emotional when you see other people dealing with, with HAE.
Then there is an elation, or you feel really hopeful when you meet the experts and they tell you what they're still doing, show you on a graph about the different therapies and where they are and what they do. My message to researchers and advocates: keep up the great work. I love you for it. You really have given me a better lease on my life. Life journey, you never know when it's gonna end, but you still got a plan for the tomorrow, and so you gave me tomorrows.
When you have a rare disease, it's really important to not accept less than you deserve. My name is Lindsay Fuller, and I'm living with C3 glomerulonephritis. I was diagnosed 10 years ago at 33. C3 glomerulonephritis happens when you have dysregulation of your complement system, which is part of your immune system. Damage happens to the kidneys, filters are damaged, and they stop working as well, and that just progressively gets worse over time. My son is also a patient, so that kind of complicates everything. A lot of things that we're dealing with, we're dealing with times two. A day in the life with C3G for me right now looks like pretty much a normal day, except that I do it a lot more tired, a lot more difficulty, a lot of brain fog that comes with the fatigue, a lot of cognitive dysfunction.
When I get home from work, a lot of times it's either taking a nap or struggling to stay awake so that I can do things with my family. With C3G, it's very hard to envision the future because there's so much that is unknown. I don't know if I will have a treatment that will work for me. I don't know if I will need to have a transplant. I don't know if that transplant will be successful. I don't know how long my son is going to be healthy without treatment.
An ideal treatment would be convenient. A once-daily oral therapy would allow C3G patients to have some normalcy in our lives. Have a pill you can take once a day, and it manages your condition. There's a lot of potential for treatments. That is kind of, kind of the dream scenario. I know we have researchers who are working very, very hard on this disease, and, you know, they're very dedicated. There are definitely a lot of reasons to be hopeful.
My name is Caroline, and I was diagnosed with Netherton syndrome at six months old. Basically, Netherton syndrome is a genetic skin condition. It affects my skin by making it dry and flaky. Netherton is a very rare form of ichthyosis. From what I understand, it's kind of a one in a million chance that somebody has Netherton.... I think one thing about Netherton syndrome specifically, just like in, like, the skin perspective, if nobody has seen it before, it's, it's different throughout your whole body. Like, my skin on my arms is different than the skin on my feet and is different than the skin on my scalp, so they all require something a little bit different. I would say that the ichthyosis community is really interested in new research and new treatments.
There are a lot of people that are really struggling right now with battling different aspects of ichthyosis because it's not a cookie-cutter condition. We need people to be receptive to us coming in with our, our needs and our ideas of solutions and being able to, I guess, brainstorm and come up with something together. I feel like right now in my life, I'm... A word that would describe where I'm at is confident. Confident in myself and confident in my routine that I have set up right now. That took a lot to get there, too, so don't take that lightly. Having ichthyosis and the way that it has kinda shaped my worldview has been really influential for becoming the person I am today, and I think I like the person I am today.
I'm Betty Anne Folks, and my daughter, Carly Folks, has Netherton syndrome, which is a type of ichthyosis, and she was officially diagnosed at about 13 months. We would start every morning with a bath, which she hated until probably at least five or six years old. I've kinda blocked some of that out, the trauma. I actually kind of went through a bit of a grieving process just because just all the unknowns. She has kind of grown up around pageantry, and she wanted to compete, when she turned 13. And at this point, Carly, no longer had very much hair at all.
So, for her to be bold enough and confident enough to wanna go up on a stage and compete and wear a dress and answer questions and go in an interview and do all of those things, of course, I was super excited about and very proud of and just excited to help her in any way I could. Go fast because children with these rare conditions need help as early in their life as possible, so that they can live a full and healthy life and receive the care that they need, and their parents can receive information to help them feel more at peace. To the parent, I would say, to try to not miss the little things in the midst of caring for all the big things.
My name is Serena Valentine. I'm 40 years old. I was diagnosed with type 2 diabetes at age 20, and I was diagnosed with diabetic retinopathy at 34. I am the executive director for Health and Wellness Education Nonprofit, and we do a lot with diabetes. So in 2017, I was diagnosed with diabetic retinopathy in both eyes. I saw floaters. It was blurriness. I just figured I was tired from working 12-hour shifts. The symptoms I was experiencing were precursors to a diagnosis for diabetes. I went blind, and it is... It was kind of like a, like a brick wall hit me, and I said, "Everybody needs to know about this." My family has been a key component in my support, especially when I was blind for nine months, totally blind. I needed them, and they were there for me.
My message to researchers would be, Go fast because patients are desperate to find a solution. There are so many patients who are living with diabetes and living with vision loss. If there were other treatment options, I believe that I would definitely have given them a shot before surgery. Not given the ability to choose can make someone feel powerless. I am hopeful about injections. I am very hopeful for the folks that I serve because they are really depending on these treatments. Hope is the perspective that I take. Hope. Always believe that something can get better.
She loves to go to the library, and she loves to read, and that's where the books come in real handy 'cause, you know, she can show them to others. My name is Lisa. I'm from Dothan, Alabama, and I have a granddaughter that is six years old, and she has been diagnosed with HAE. Lettie is a loving child. She's just full of joy. She loves bugs, and she'd rather hold the worms and the crickets. She gets so excited, and ladybugs, tree frogs! ... Just, she makes me smile. The needle part is the biggest thing for her. There's still that fear when it's time to do her medicine, you know, she'll kind of run and, you know, not want to do it. You know, it kind of upsets me because I know she's got to go through this.
It would be wonderful if we had an oral form for children Lettie's age. The children have a hard time with needles. If you won't have to go through the trauma, being held down, have that needle, waiting on that medication to be pushed slowly, an oral form would be so wonderful and so much easier on little ones. In turn, it makes the parents and grandparents feel much better. Thank you for all your research that you've done so far. We just keep continuing to support the HAE community, the researchers, and hopefully making this easier on the children.
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 tech, technology to add protein therapeutics and to increase the ways we can deliver better outcomes for patients. And it contributes to accelerating what our discovery engine can produce.
Now let's turn to our pipeline to preview the exciting programs 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. Here you see the updated BioCryst pipeline with seven 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 turn to 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 are 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 a 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 BCX17725 in the clinic and two new molecules, the C5 inhibitor and the bifunctional complement inhibitor in IND-enabling studies. By the end of 2025, we expect to have a total of five molecules in the clinic, and we plan to file the sNDA for ORLADEYO for the pediatric population down to age two years. From there, you can see the continuing advancement across the pipeline so that within five years, we expect to have proof-of-concept data for all six of these pipeline molecules. Our prolific discovery engine will be producing, as it accelerates, a continuous supply of potential best-in-class medicines 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. 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. 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 the—because I get to lead a really amazing global commercial team that gets to do it every single day. So like, 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, of, of molecules coming behind.... I need the clicker or-
That's right. It's right there.
Oh, thank you. 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 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 injections. Patients get used to this, they tolerate it, but most people, if they could, they would avoid, 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 states. 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 three 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.
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 gonna start first with the oral C5 program, and I'm gonna 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. 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 things in myasthenia gravis.
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. 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 easier to take that medicine over the long term. That is exactly what we're trying to do with our C5 program. MG is about 10x the size of HAE, but as I said, there's some real analogs to the condition.
So myasthenia gravis patients have 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 crises 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.
Finally, like HAE, the market has really evolved. Six 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. Let's move up the complement system to the C2 inhibitor, and this one is different.
This is a much wider open space than the C5 opportunity. There are very few, in fact, there's only one targeted therapy in this space in the autoimmune hemolytic anemias, for cold agglutinin disease or CAD. Another disease in this space is warm autoimmune hemolytic anemia or WAHA. You have to abbreviate all these to make them pronounceable. And there's no targeted therapy for WAHA 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 a risk of severe side effects. So the goal there is very much rooted in cancer therapy, ablate the B cells to prevent the problem. 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 had an oral convenient therapy for these patients that could control the ongoing hemolysis? That would make a huge difference for patients with diseases like CAD and WAHA. Then, of course, BCX10013. The goal here is to develop a safe and effective once-a-day therapy.
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. If we do, we believe that we will have the best-in-class alternative pathway inhibitor. 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. In the case of IgA nephropathy, this is a really complicated disease, very heterogeneous in the patient, in the patient population. 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 so for C3G, which is a smaller ultra orphan, orphan population, having a once-a-day therapy is exactly what patients need. So it's unlikely that BCX10013 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. And 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 three 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 three 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 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, BCX10013 helping a broader portion of the IgAN marketplace, and then the bifunctional inhibitor helping more severe refractory patients, both within the same disease state.
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, market leadership is wide open and something that BioCryst can achieve. I'm going to turn it over to Bill, who's going to go into more detail about each of these really promising molecules.
Thanks, Charlie. Well, it's a great pleasure to be here today to speak to our complement portfolio. I'll say that again, we have a complement portfolio. Let's get into some details about these programs. What I'll do is step through each of the 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 our bifunctional biologic program that targets all three pathways. Before we get into that, I'd 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 is feasible to do so, and we're focused on doing that. We're looking to file three INDs for new molecular entities, deliver proof of concept results for three programs, and start one pivotal trial across these programs in the next four 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 a 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 three pathways. It's a fascinating system, and C5 is activated by C5 convertases that cleave the protein in two. The larger fragment starts to build the membrane attack complex. That's called C5b. The smaller fragment attracts and inflammatory cells and talks to 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 bio, bioavailability, sustained exposure with a pharmacodynamic effect that lasts 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 of drug levels 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 be smaller than about 500 daltons in molecular weight. For the oral C5 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 a non-clinical 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. The drug levels here, just to orient the chart, are 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, concentrations of over 1,000 ng per mL, 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 oral C5 inhibitor next year.
Start phase I studies in 2025, proof of concept studies in generalized myasthenia gravis in 2026, and delivering proof of concept data in 2027. 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, the Factor D is a serine protease. Also, plasma kallikrein, where we've succeeded with ORLADEYO, is a serine protease. So for this project, we can apply our accumulated expertise and knowledge and art in structure-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 lobe of the protein. There is the serine protease domain. This is really just a structural diagram. Of course, our scientists have atomic-level resolution structures to work on in their 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 autoimmune 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 are bullous pemphigoid and autoimmune hemolytic anemias. So the general goals for favorable characteristics of an oral first-in-class C2 inhibitor are 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 proteases are 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 ORLADEYO. 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 2026, proof of concept start in 2027, and delivering proof of concept data in 2028.
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 from our recent press release, we've now commenced dosing in a proof of concept study with this agent in in people suffering from paroxysmal nocturnal hemoglobinuria. Starting that study is a major milestone. We look forward to reporting proof of concept data in 2024. 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...
Over the years, we've grown to understand that the alternative pathway can be dysregulated or pathologically activated in a number of different diseases and can play a major role in that pathology. 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 simulation assays before and after dosing with your oral agent. Here, we're showing the data from a commercially available alternative pathway assay called the Wieslab AP assay.
This specifically activates the alternative pathway and measures the major end product of the complement cascade, namely C5b-9, otherwise known as the membrane attack complex. So the cohort size is up to 10, with active in each cohort at each dose level, with once-daily oral BCX10013, and we measure the pathway activity of the pathway before dosing and at multiple time points after each dose. The values are normalized to each volunteer's pre-dose activity, shown as a % on the Y-axis, and the left-hand chart shows the PD profile in two ways. The left-hand side of that shows the profile after the first dose, and the right-hand chart shows it after the last dose on day 14 of daily dosing. So what do we see?
After dosing with 160 mg 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 all 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 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.
We saw no safety signals at all with daily dosing for 14 days. 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. Now that this molecule has entered a clinical trial in patients, we're looking forward to having data evolve 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, 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 the 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. We. The way we do that is to work with patient advocates, the world's best key opinion leaders in the field, and regulators, and settle on a study design, and initiate a 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 multipathway 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 complement inhibition across multiple pathways, so we can test that with in vitro assays. This challenge has been tackled here by engineering a 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 three complement pathways, and that's illustrated in the left-hand group of four panels on this slide. This is pathologic deposition of complement. You shouldn't be seeing this 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-based approach Helen described earlier, that can tackle these types of very serious illnesses.
We're supporting that with a series of comprehensive assays that inform us about the ability of these candidate molecules to inhibit all three pathways, classical, lectin, and alternative. They do that by looking at major effector functions of the complement pathway, opsonization, formation of the multimolecular membrane attack complex, and cell lysis. I'm gonna 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 show potency results for a representative bifunctional complement inhibitor in the green bars, which results for four different positive controls. Monoclonal antibodies that are depicted in different shades of orange. What are they? They're eculizumab. That's an anti-C5, of course.
Satalimab, an anti-C1s, also a bifunctional anti-C5, combined with the alternative pathway for Factor H regulator and an anti-C2. On the axis that you can see on the horizontal line, that gives you molar 50% inhibitory values. It's a log scale that covers five orders of magnitude from picomolar to 0.1 μmol. Okay, so what have we got for the classical pathway? Five different assays, including two commercially available assays. We have subnanomolar or nanomolar-level potency in every single assay. Compared to the controls, our bifunctional candidate is superior in every single assay. For assays that specifically measure opsonization, which is a major feature of the way complement works, our candidate has 100 times more than a 1,000-fold better potency than the controls, including the approved C1s antibody and an investigational C2 inhibitor.
The alternative pathway, we've got two assays, including a commercially available assay, with subnanomolar potency in both, and our candidate is at least as good or superior to all the controls, with more than a 100-fold better potency than the anti-C5 Factor H bifunctional inhibitor. So that's an important result here. For lectin pathway, we used a commercially available assay that specifically initiates the lectin pathway cascade and measures C5b-9. In this type of assay format, you could expect a C2 inhibitor to work. You could also expect an anti-C5 antibody to show activity by blocking the terminal step. In this lectin pathway-specific assay, we've got subnanomolar potency, and our bifunctional candidate is at least as good or superior to all the controls and more than a 100-fold more potent than the anti-C2 monoclonal antibody.
I think, you know, very importantly, we've also had the opportunity to test a sample from a patient with a relevant disease called the 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 a 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 candidate's superior to all the controls, and is more than 1,000-fold more potent than sutimlimab , which is approved for this illness. So what, what can we say in summary? That's a lot of data with a lot of assays. So across nine assays, the bifunctional complement inhibitor candidate's more potent than any of the controls, including an approved anti-C5, 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 2024, start phase I studies in 2025, proof of concept in 2026, and deliver proof of concept data in 2027. 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 at BioCryst. You know, I joined BioCryst about two years ago, and the reason I joined is, and hopefully, you're getting a glimpse of, 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 an initial focus on Netherton syndrome. I'd like to have, introduce you to Betty Ann, as she will share more about her daughter and their journey with Netherton syndrome.
I'm Betty Ann Folks, and my daughter, Carli Folks, has Netherton syndrome, which is a type of ichthyosis, and she was officially diagnosed at about 13 months. We would start every morning with a bath, which she hated until probably at least five or six years old. I've kind of blocked some of that out, the trauma. I actually kind of went through a bit of a grieving process just because... just all the unknowns. She had kind of grown up around pageantry, and she wanted to compete when she turned 13. And at this point, Carli no longer had very much hair at all.
So, for her to be bold enough and confident enough to want to go up on a stage and compete, and wear a dress, and answer questions, and go in an interview, and do all of those things, of course, I was super excited about and very proud of, and just excited to help her in any way I could. Go fast because children with these rare conditions need help as early in their life as possible, so that they can live a full and healthy life and receive the care that they need, and their parents can receive information to help them feel more at peace. To the parent, I would say, to try to not miss the little things in the midst of caring for all the big things.
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. Netherton is a rare, severe genetic disease that predominantly targets the skin. It also attacks the hair and has other systemic manifestations. In a healthy individual, your skin will normally turn over every two to four weeks on average.
And in a Netherton’s patient, their skin is continuously peeling off.... Babies present with red, scaly, inflamed skin that 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 maintain healthy immune function in the body, and in this case, help us maintain a healthy skin layer. So excessive 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 some of what Betty Ann said around the trauma of this. She kind of glazed over it, but I, I wanna highlight this. As a parent, giving a bath 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 normal skin turnover. I'll now turn it over to Bill, who's 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 two 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 non-clinical results, as these all support the potential for BCX17725 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 very good bioavailability after subcutaneous dosing in a non-clinical 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 a subcutaneous dose in a non-clinical species.
Just to orient you, the X-axis shows time in days, the Y-axis shows plasma concentrations in micrograms per mL. 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? You know, well, one of the few worries with biologic therapies are the risk of immune reactions. So a key safety parameter for any protein therapeutic is assessing the potential for immune reactions. A 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 your any peptide sequence and calculate a score that tells you what's the risk.
The score for our Fc fusion protein BCX17725 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 it builds 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 non-clinical 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, and 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 a microscope. So we have now directly shown that BCX17725 penetrates into and binds in the epidermis. That's where KLK5 acts. The images shown here are before and after injection of BCX17725. The top three panels are before injection, the bottom three panels are four hours after injection. This is a standard immunohistochemistry method of detecting 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. 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 2024, start proof of concept studies in 2025, and deliver data in 2026. 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 ultra-rare disease, and I'm always amazed by the stories, you know, to hear about caregivers like Betty Ann, patients like Carli. 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 ultra-rare 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 ultra-rare disease really ultra-rare. But when therapies are developed, ultra-rare, the patients come out. They... Patients like Caroline and Carli 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 BCX17,725, 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 two weeks or better.
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 therapy, which, if it reaches the market, will be very helpful for patients. But they already spend so much time dealing with their skin condition, so this is unlikely to be truly disease-modifying. That's what we're shooting for, 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 BCX17725, we really think we have a best-in-class therapy. There are other therapies that have been investigated.
There's an IL-36 in development right now, but it's nonspecific, so it's likely to be more symptomatic treatment and not disease modifying. If BCX17725 reaches the profile that we hope and expect, it'll 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 syndrome is a horrible disease caused by a loss-of-function mutation of the 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 non-clinical 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 steal from Betty Ann, "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 gonna go through avoralstat, our program for diabetic macular edema. As Jon mentioned, avoralstat is a plasma kallikrein inhibitor. It's previously studied as an oral formulation in patients with HAE, so we already have a good sense of the safety and tolerability of this molecule when it's administered systemically. Before Bill spends 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 to 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 third to two-thirds 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 differing anti-VEGF injections. He gets them repeatedly over months.
One of the hardest realities of diabetic macular edema and for our family was seeing this 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 bar graph at the right depicts results from a study from Kita et al., that 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 two-thirds 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 inhibition 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 right compartment in 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 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 damaged vessels begins to cause swelling and the pressure to build up in the eye. This leads to 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 of diabetes leads to the small vessel or microangiopathic damage in the eye, weakening these vessels, triggering an inflammatory process, including the contact activation system. This cascade of events includes the increase in plasma kallikrein levels we just noted, an upregulation 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 that's vertical towards the 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 epithelium 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 compare them live, and I do have some examples of this here. When you compare a suprachoroidal injector, Microinjector, it's less than 1 mm 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. But 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 in 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, 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 cede the floor to Bill, who will talk through more on the details of avoralstat and 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, need 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 when dosed orally, and the adverse event profile in those studies was 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. We have non-clinical evidence that we can get it to the right place using a suprachoroidal injection and get it at high concentrations. The unpublished data on the right-hand side show the non-clinical ocular PK profile of suprachoroidal avoralstat suspension. Just another orientation, X-axis this time, again, is days after injection of 2 mg of drug. The Y-axis shows drug concentration in micrograms to milligram of tissue. There are two 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 IC99 for plasma kallikrein inhibition, and this is true for at least three 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 three months or longer, and because the depot delivers high concentrations of avoralstat to the right place, the retina and the choroid. So an 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 the steps required to enable DME trials to begin, such as required non-clinical 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 2025 and deliver results in 2026. 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. What we're looking for is to deliver what we think is the right drug to the right place, no more frequently than every three 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 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 from 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 standpoint 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 going to avoralstat and looking for superiority for avoralstat in those patients who are not responding adequately to a 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, 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 two other therapies in development right now, two other kallikrein inhibitors, but you can see one is an intravitreal injection on a monthly basis. And so when we talk about best-in-class, every three 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 avoralstat in DME, we've got a very promising old friend 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 a 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, and 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 high need. 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 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 apply to adults also apply to the pediatric population, but in some ways even more, because parents or caregivers really share in this burden. You know, it's maybe a little similar to Betty Ann's story about treating, giving her daughter Carly 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. We have a really innovative formulation here. Our team here in Birmingham has developed these tiny granules, and you can 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 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 two to under 12. It's well underway. 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 small population. We think in the U.S., about 500 patients, 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 oral 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 allergist offices. And then in the future, we could 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, where 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 and a really exciting future. I'm going to turn it over to Anthony to tell us how we're going to allocate our capital.
Oh, let me make sure I have this. 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. Jon talked about some of the drivers earlier with growing ORLADEYO revenue, our 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 gives 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, Genki'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. 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 investment, 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 investment in key areas like CMC in preparation for commercial or 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 or 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. For the elimination of doubt, that does include the milestone payment for 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 marrying 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-$240 million. Compared to this year, that's about a $25 million-$35 million increase. When I look at it versus 2022, it's about $13 million-$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 BCX10013 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 one 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 we would be developing through the pipeline. As Jon said earlier, we'd also look at partnering out molecules.
There might be partners at that point that'll 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 seen. You've seen today how we've expanded our discovery capability. So we've 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 one million-fold more potent than the natural ligand. One 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, right 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 gonna 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. Who's bold to go for the first question? Just, yeah, just walk up. You don't have to raise your hand.
Hi, I'm Catherine Okoukoni . I'm coming from JMP. My question is about the BCX10013 program and just how you see the translatability of the PNH population to the IgAN, the other nephrology indications, and also how you're prioritizing the next indications, whether you're planning on doing them in parallel or whether IgAN is coming first. Those are my questions.
So I'll pass this to Helen. I think, you know, talking about the alternative pathway, I think, is the key.
Yes. Yeah. Yeah, so thanks for the question. So BCX10013, what we're looking for with the PNH trial is a dose, and we're looking for a dose that is safe, effective, and that will be effective in terms of complement 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 spoken about IgAN and C3. We're moving those both forward at a similar speed.
Thank you.
Yep. Maury.
Hi, Maury Raycroft from Jefferies. Thanks for hosting this event. Great to be here. I was gonna ask a couple questions about the C5 inhibitor. You mentioned a 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 are... 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 so you have to have a cell to do that. 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-
Next.
The orange things. No, next. Keep going. Keep going, keep going, keep going. Oh, no. Oh, okay, we don't have that. That's right. So my bad. So but the, it's exactly the same suite of actually, show, show the, 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, you know, 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 two things, one of the broad spectrum off-target platforms like G-protein-coupled receptor assays of more than 100 of those, and the non-clinical safety profile in two species would be the key elements. That takes care of selectivity, and I'm sorry, I've forgotten the third part.
If you could talk more about how it interfaces with C5?
At this stage, we're not disclosing that for proprietary reasons, but it's pretty cool.
Okay. 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?
You know, 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, 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. You know, 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.
Got it. Thanks for taking my questions.
Hey, Bill, Maury's questions remind me of something else that I think is really important that I'd like you to answer, 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, and exposure-
Sure.
and things like that with a small molecule?
Yeah. 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, in a 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, 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 target 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 of any dosing of any human being, it's gonna 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.
Thanks.
Stacy Ku from TD Cowen. So first, just a quick question on BCX10013. Can you narrow the timing to when we might get some results? Would you release anything interim, or are you gonna just help us set expectations there? And then I have another question on the pipeline.
So, Helen, maybe just talk about what, you know, numbers of patients that we need and how long we need to study them. That'll give them some idea of recruitment and then the length of the study.
Yeah, so with BCX10013, 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, you know, 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 gonna point you to mid-next year for results, and for an answer on that.
Okay. Thank you. And then, another question on your oral C5 inhibitor. So can you just talk about your plan in myasthenia gravis? Are you gonna 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 look in mild to moderate to severe patients first as proof of concept. Just curious your thoughts there.
Charlie, that's a good question for you to tackle, and you know, the parallels you pointed out with HAE are probably the best way to look at it.
Yeah, I think with an oral drug, the great thing is we have options. If we can figure out the right way to study it, you know, myasthenia gravis is, you know, they're up to 70,000 patients, so it'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 wanna 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, you know, 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.
Thank you.
Yeah, and unlike HAE, there's more indications that we could go after, more complement-mediated diseases we could go after.
Opportunity.
Yeah. Next.
Hi, Ananda Ghosh from H.C. Wainwright. A couple of questions, most, mostly on the C5 lens, you know, the C5 inhibitory landscape. So if you look at the landscape, you know, the initial lot of focus was, development of antibody-specific, therapeutics, right? So what changed? I mean, what was the, you know, real, real barrier, to develop small molecule drugs, and where exactly... So, so what was the, what was that barrier which, which, 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
I think 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, you know, if the anti-VEGF, VEGF, VGF, therapies have not been working for so long, why haven't, and, you know, kallikrein was the choice of target, for so long. And like, what makes kallikrein... Like, you know, what is the scientific rationale in thinking that kallikrein is the right target for, for DME?
Ryan, I'll give that one to you.
Yeah. 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 at its elevation in this disease from samples in 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 to 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's 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, you know, see if we have an effect on that contact activation system.... So those three things together give us a lot of confidence that this is, this is a different approach than what's been done before.
Got it. Thank you.
You're welcome. Bill, you gave me a lesson on diabetes and eye vessels, and so maybe you wanna just make a few comments on that front around-
Sure.
- validity of the target.
Sure. So the evidence for involvement—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 non-clinical and clinical. The non-clinical 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.
In the clinic, we see the same thing in terms of increased plasma kallikrein levels in the vitreous humor, which is the only compartment you can access and assay in a living human being. In addition, 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've described and make sure we're getting kallikrein into the right place in the eye.
Helen, you might wanna talk quickly about just, like, the speed at which we could move once we get into the clinic, 'cause you can't study this in healthy volunteers making injections in the eyes. You might wanna just briefly talk about numbers of patients that give us an idea of, is this drug working, and, and how quickly we can do that.
Yeah, one of the great things in 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 a sort of step forward into the development process. And our move from there is to understand, probably with one dose, a single dose in patients, what we see in the time frame after. So it's a sort of jump-start into being able to assess if this is going to help a patient.
Sorry, just to follow up.
Yes.
Are there biomarkers for these kind of studies? Or, like, how do you progress, how do you test the efficacy?
So-
Yeah, I can-
Do you wanna answer that?
Yeah. 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.
Got it.
Yeah.
Thank you.
Great. You're welcome. Serge?
Serge Belanger from Needham. Thanks for hosting us. 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 wanna have profitability, but you don't wanna just have it for a quarter and then not have it for the next quarter. And, and I think the key is to be very profitable ultimately. And with 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, and what we've told you repeatedly, I've said it, Anthony said it, is we're gonna 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.
Yeah. You know, 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, that from a valuation creation perspective, it 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, you know, potentially magnitude or orders of magnitude, as opposed to kind of eking it out and put some of these on the back burner, I think is the right approach for the company.
On the DME program, it's nice to see you have a real step back. I think another company has tried with a pKal inhibitor for DME and had mixed results. I'm sure you've seen the study, but just curious if you think it was 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.
Yeah, I mean, we are following what the field is doing, and again, we feel as though the combination of the three factors, especially now with the partnership with Clearside, gives us a distinct advantage combining with our molecule, which is very potent and has the right solubility properties. So we see 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
. ... Thank you. 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, 'cause you want it to stay there, 'cause you don't want to keep giving more and more injections, and then combine it with a delivery, the Clearside microinjector, to get it to the right spot. We're very excited about this. Seema?
Hi, this is Seema from Evercore ISI. I have a question on BCX10013. You have some dose-related observations in your non-clinical studies, and you wanted to figure out the, you know, efficacy and safety on the dose. So if you can provide any update on that, that would be great.
Helen?
Yeah, sure. 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.
I see. You're expected to finish those studies.
Mid next year.
Like the-
Mid 2024 .
I'm sorry. When are you supposed to finish those non-clinical studies?
The non-clinical studies will continue through this year.
Okay.
But I also want to say that the most important information will be coming from the patient studies mid next year.
I see. Thank you.
Others in the room? All right, looks like John's got some from the webcast.
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. I, you know, 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, you know, 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, that'll 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 it... 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 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 you know over the next several years as our portfolio evolves. So it's hard to say now, and but I am 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.
Yeah. 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. That we've all seen those experiences where the company you licensed to didn't move it as fast, didn't invest in it the right way. And so these are things that we discovered that we believe are gonna create crazy value because they're first in class and best in class.
But we will continue to have the right amount of discipline.
Yeah.
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 gonna 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.
No.
I think in that regard, that would be something that we'd be absolutely open to-
Yeah
... if it freed us up to do other things.
Yeah, 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.
Got this from a couple folks on the web. What dose range will you be studying in the BCX10013 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, 20 mg-160 mg. 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 mg. That's the plan. 100. 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, you can take, yeah. I mean, Anthony can take both, but-
Yeah, on the interest side of the house, we're, you know, 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. You know, it doesn't help in other areas around discount rates. It doesn't help in general, from a macro environment perspective, you know, funding. I'm glad we funded when we did. I'm glad we refinanced the debt that we did when we did. The market out there is not very receptive to whether it's equity financing or whether it's any other 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 capped and then the opportunity 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.
Charlie, you might, you might wanna just talk about the impact of the IRA in general to us. We don't see-
Yeah.
We don't see it being a big capital allocation issue-
No, I-
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, you know, if you get a drug that ultimately is subject to negotiation from CMS, that does not factor into our decisions. 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.
Another web?
This is 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? Then alongside that, would BCX10013 or the bifunctional molecule be a better fit for the IgAN nephropathy population?
Ryan, you wanna?
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, it 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 again, 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, we I think we'd want to get a FcRn inhibitor to all patients that could benefit, you know, if we prove that it's safe and effective in that population.
Bill, you wanna 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, other programs where patients—there's global need, we will bring it to patients globally.
And Charlie and I were in Tokyo two 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. All right. Well, listen, first off, again, to those of you that made the trek, 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.
But, you know, 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. Thank you and have a great weekend.