BioCryst Pharmaceuticals, Inc. (BCRX) Earnings Call Transcript

Good morning, and thank you for joining us for BioCryst's first virtual R&D Day. I'm John Bluth, Head of Investor Relations at BioCryst. And over the next 2 hours, we'll highlight for you how our unique approach and expertise in developing oral medicines for rare diseases has produced a full pipeline of molecules. Today, we'll also focus on the exciting new data we've just announced with one of those molecules, our oral Factor D inhibitor, BCX9930, which we are now advancing into pivotal trials as a monotherapy for complement-mediated diseases. I do want to remind you that we will be making forward-looking statements, so please refer to the cautionary statement in the accompanying presentation slides and review the risk factors in our SEC filings, including in our most recent annual report on Form 10-K. These risk factors could cause actual results to be materially different from those experienced or implied in the forward-looking statements. Throughout the program today, we will introduce you to members of the BioCryst team, and a panel of physician and patient experts in complement-mediated diseases. You can find bios on all of our speakers on the program website by clicking on the speaker bio button, which is the green the right-hand button at the bottom of your screen. The BioCryst team and our panel of experts will be available for a Q&A session with you at the end of the presentation. [Operator Instructions] So let's get started. [Presentation]

Why is it that BioCryst has been able to discover, develop oral drugs for patients suffered from rare diseases when very few others have tried and even fewer have succeeded. Everybody has the same tools, same software, the same equipment, heck, even many of the protein crystals can be found on the internet, but not everybody is able to do what we do. Today, you'll not only walk away with the why, but you will also get to experience the why. And by answering the question, you will better understand what this means for the future and value of our company. As you saw on the video, it all started with a small group of accomplished scientists coming together, Dr. Charlie Bug, Dr. John Montgomery, Dr. Bennett and Dr. Babu. The team and the scientific platform of structure-based drug design were and are the foundation of our company. In fact, BioCryst founders and scientists were some of the early pioneers of this intersection of art and science in drug discovery. Babu was the first employee at BioCryst. He did his post-doc training at Oxford, which at that time was one of the leading crystallography research centers in the world and included luminaries in the field like Nobel Laureate, Dorothy Hodgkin. As Charlie said in the video, Babu quickly rose to one of the bright young stars at Oxford. And this was the start of him becoming a world expert in crystallography and structural biology. I remember doing my own diligence over 14 years ago before joining BioCryst. I spoke to 2 leading drug discoverers from large pharma companies, who had done diligence on BioCryst for a large investor at the time. One of them told me, Babu can do with 10 people what he wasn't able to accomplish with 300 chemists. And the other said, Babu is one of the few people on the planet he's met that can place atoms in 3-dimensional space in his head. These are not individuals that passed out praise easily. Babu's brilliance and the team he'd built is one of the main reasons I joined BioCryst. The team led by Dr. Babu at BioCryst has been working for old over 30-plus years, perfecting our ability to discover drugs using structure-based drug design. Not surprisingly, how well the team works together is another key component to success. Having a group that's worked together for decades helps. How our computational chemistry, medicinal chemistry and biology teams work to solve problems together is key and quite unique. Instead of working in silos, we're melding our expertise. Instead of just building a department, we built a capability. So remember this, when you see the building of Orladeyo today. It is experience and these groups working to solve complex problems that allows us to build drugs 1 atom at a time. But that's not the end of the story. We all know great science doesn't always translate in the clinic. Many mice have been cured of cancer. But turning that to a science into drugs on the market is a whole lot harder and has significant risk. So choosing where to take the risk is another important piece to the story. This is where our strategy of focusing on oral drugs for patients suffering from rare diseases comes in. It's starts with the enzyme target that causes the rare disease. We don't go after disease targets unless there is clear and abundant scientific evidence that the target plays a key role in the disease. For example, plasma kallikrein is the critical enzyme in the pathway that leads to HAE. The same thing goes for Factor D and PNH and ALK2 and FOP. So if we're able to block these targets, we should be able to affect disease in patients and thus, have a better shot at success in the clinic. Where we are willing to take risk is where you need potent binding and selectivity to the specific enzyme. Many of the rare disease enzymes are part of large family, like serine proteases for plasma, kallikrein and Factor D and kinases was out, too. The reason we could take this risk is because of our expertise and structure-based drug design. The capability allows us to build molecules that bind tightly to that 1 specific enzyme and not others in the family. So when you combine it all together, the expertise, the people working together and the focused strategy. You do see great signs translated into the clinic. And that's when you see the transformation and success follows. BioCryst is now undergoing a major transformation. We have shown that we can take great science and translate successful outcomes that lead to products, patients' want and need. The evidence is Orladeyo. In a matter of weeks, we expect approval in the EU. This will be our third of 3 of the largest territories in the world. And the beauty of this strategy is we will do it again and again and again, applying the same approach in everything we learned in HAE to 9930 in complement-mediated diseases, a pipeline in a molecule. We'll continue to go fast with drugs in our pipeline and continue on to the next discovery of a drug for another rare disease. This is no longer aspirational. This is happening right now. And today, we'll show you the evidence. This is how we're building our company, and this is how we will build greater value. So today, we're focusing on Factor D and one of our most exciting molecules, BCX9930. You'll hear from thought leaders on what's important to them in the treatment of complement-mediated diseases. You'll hear from a patient directly, and gain insight from our market research on what's important to them. And you will see the data from our clinical trial in PNH with BCX9930, and why we are so excited about this program. But before we do that, we wanted to give you more of a feel and understanding of our drug discovery capability. Under normal circumstances, we could have invited you to join us at our facility in Birmingham. But nothing's normal in COVID. And so we put together a video to bring to you. Take a look. [Presentation]

Babu is the leader of our team in Birmingham. He doesn't venture out of the lab and on to Wall Street very often. But we thought today, it was important for you to see how we do what we do. So we've asked Babu to show you how we built Orladeyo. He will explain how the goal is not only potent binding, but it needs to be highly be selective and bio available as well to become a viable drug candidate.

My name is Babu Yarlagadda. I'm the Head of the Direct Discovery at BioCryst. I have been with the company from the beginning of the company. And this morning, I'll be walking you through the discovery of Orladeyo, a potent small molecule plasma kallikrein inhibitor as an example of the drug discovery capabilities at BioCryst, which could be applied to many other similar proteins. The goal of any drug discovery process is to identify novel molecules that have interactions with the therapeutic target. Plasma kallikrein is a serine protease. It belongs to serine protease family of serine protease members of about 200 to 300 enzymes. Some of them are very close to the plasma kallikrein. The -- an ideal plasma kallikrein inhibitor will be potent, highly selective to reduce the off-target toxicity and at the same time, highly bioavailable. The features that improve the potency may or may not work for the other 2 and vice versa. The way to welcome this challenge is through structured-based discovery approach where we know in greater detail, the 3D structure of the protein and the structural features help us to design a molecule that give us the potency, selectivity and the bioavailability. And the first step in the structured-based drug discovery approach is the identification of the target and the 3D structure of the protein. The 3D structure of the protein is given by the protein crystallization and expect this tomography . And in this representation, you're seeing all the 3,000 -- 2,000 to 3,000 add protein atoms of the plasma kallikrein, each one of them is represented by a point atom, color-coded by the type of atom. The red color represents the oxygen, the blue represents the nitrogen and the gray represents the carbon atoms. It may not show very well the final features of the protein, but it explains the function and the mechanism of the protein. Another presentation could be a bare-bones representation of the backbone of the protein, which see the second structure fold of the protein. Again, shows the secondary structure for, which are the protein. Again, that doesn't help us much in terms of the business discovery, that kind of representation. The best representation is the space-filling model, where each atom is represented by a sphere that is the size of which is proportional to the radius of the atom. And you can see you already, already, start seeing and the cavities on the surface of the protein and some of these fissures are very important for the enzymatic activity of the plasma kallikrein. The long stretch here that you're seeing, like a trench going from the left side to the top of the -- top right-hand corner is where the high molecule weight kinin then would bind. And the active set of the enzyme would clear that into 2 parts, generating the bradykinin, which is the bad actor in HAE. As we zoom into the active site, you can see in much greater detail the features of the active site. The active site is the business end of the enzyme. That is where the reaction takes place. That is where the hyperactivity of the enzyme is contributed by the active site. The best analogy to describe the active site and the enzyme goes back to about 100 years, the lock and key approach -- the lock and key analogy. Here, the lock is plasma kallikrein enzyme. The key is the substrate or the drug molecule that fits into the key, and the key hole is the active site. So if you know the key hole looks like, we can design a key that perfectly matches the key hole. In the same fashion, if you know how the active site looks like, you can design a molecule that fits the active site and binds to it very tightly. The active site is represented in 4 different subsites here, the S1, S2 and S3 and S4. Each one of these subsite is critical to the binding of the inhibitor. The Orladeyo molecule has been built 1 small fragment at a time by optimizing each fragment to bind in that particular subsite. As you can see, the first subsite, what we have gone after in terms of the fragment design is the S1 subsite. It has well-defined features, and it has a deep cavity. And we have substituted, we have designed a fragment that binds very well in that subsite S1 with a 6-membered ring. Anything smaller than this one would be very loose. Anything bigger than the 6-membered ring would be hysterically clashing with the protein. And a 6-membered ring is the perfect size to fit into that one. We are still in the cavity of the S1 site. To get out of the cavity, we have identified another smaller fragment that attaches to the 6-membered ring that brings us out of the cavity. And with that -- with those 2 fragments joined together, we have ideally filled the space with the shape and the space with this fragment here. To access the rest of the active site, we have used this atom here as a point of attachment and access the rest of the active site. We designed this flat ring to lie on top of the relatively flat surface here and attach that front with a peptide bond and avoiding the reach here. As you can see here, we can still have the S4 site and the S2 site, and by attaching a different ring structure, we were able to position that ring in this crevice, between these 2 walls and at the same time, going deep into the cavity. Finally, the molecule is finalized with a final fragment that goes and binds into the S4 site at the active site. The combination of all those 5 fragments joining them together there is what gives rise to the Orladeyo molecule, filling the active site completely, not only the shape complementarity but also the charge complementarity. So if you replace these point atoms by the appropriate size spheres, again, you would see very clearly, the tightness of the fit between the enzyme active site and the drug molecule. The golden arrow, what you're seeing here is the drug molecule bound and the design to fit in the active site. And the contours of the protein active site and the contours of the drug molecule, they perfectly match each other, not only at disposition, but also a disposition. The shape complementarity and the charge complementarity is very good between the 2. And that gives rise to a potent and selective molecule. And that resulted in the Orladeyo. The credit goes to the drug discovery team at BioCryst, the Medicinal Chemistry Group, the Structural Biology Group, and the Research Biology Group. They have been working together on many similar projects over the last 20 years using the same approach. And they were able to come up with a potent molecule like this 1 in under 2 years, 12 months to 18 months. And this molecule has been advanced into the IND-enabling studies in 2014. And at the end of 2020, we got the approval for -- by the FDA in U.S. That's a remarkable achievement to all the teams in BioCryst, and we are all very proud of that one. Thank you.

Thanks, Babu. What you just saw about who do with Orladeyo, it's also how we approach 9930. And how we approach every molecule we build at BioCryst. This amazing team will keep going after more targets because we know patients suffering from rare diseases are waiting for more oral therapies. Now I'm going to ask Dr. Bill Sheridan, our Chief Medical Officer, to join us. And as he does, let me say that Bill was the principal architect in getting us to focus our strategy on oral drug in rare diseases. Bill came to us from Amgen almost 13 years ago. And after he had a chance to really take a look at what we had, Bill got feedback from outside experts that led us to the target plasma kallikrein, and the rest is history. So Bill, my first question is it's one thing to discover a molecule like or Orladeyo in less than 2 years. But to go from Phase I to file for approval in less than 5 is also amazing. Tell us what you learned from that program, and what capability you and your team have built? And how it will help us with programs like PNH and nephritis with 9930?

Jon, I think we learned 3 key things from the HAE program in -- for Orladeyo and we can apply those to every rare disease program, every project of the company. So number one, the importance of active listening to regulators to top experts to patient advocates to clinical sites. And the reason is to get the strategy and the execution right. Number two, the importance of establishing and maintaining great relationships. We had picked boutique CROs we have our clinical and medical staff partnered with the CROs to maintain direct site interactions and be as responsive as possible to what's going on at the clinical sites. A really important piece of the story is that patients are enthusiastic about access to an oral drug. The patient advocacy organizations helped us immensely in encouraging enrollment. So throughout the whole thing, we keep our external experts fully engaged and informed, and that's can only be to our benefit. The third thing is that applying these concepts with an attractive opportunity to change medical practice like Orladeyo or like BCX9930 in rare disease programs of no more than a few hundred patients really enables us to compete effectively. So I think all of that, the adolescence. Our goal for the 9930 program is to do it all over again, 1 indication after another, and strive to be the sponsor of choice for everybody involved in these diseases.

Thanks, Bill. As I mentioned, Babu was our first employee, but now I'd like to introduce our newest employee, Dr. Helen Thackray, whose first day is today at BioCryst. Helen has been a member of our Board of Directors since 2019, and we are so excited that she's chosen to join us as our Chief Research and Development Officer. As a Board member serving on the Science and Commercial Committee, she's seen firsthand the progress we've made in building our company. To give you a little bit of background on Helen, she's a pediatrician, who served for over a decade on the research ethics review board of the National Center for Health Care Statistics, which is part of CDC, and she serves on the faculty of the Children's National Medical Center, and George Washington University School of Medicine and Health Sciences. Helen's combined experience as a leader, scientist and clinician will be a great addition to our company. So Helen, welcome to day one, what a way to start. Maybe you could say a few words about what you've seen regarding our approach to R&D from the Board perspective, and why you chose to join your company?

Good morning, Jon, thank you. And I am delighted to join BioCryst. I'd be happy to share a few points as to why. First, I've seen what BioCryst can do. I've had the advantage of sitting on the Board, interacting with the company's management team and hearing how the company conceptualizes plans and executes on the programs. As a member of the Board's Science Committee, I have come to know the extent of the scientific program and pipeline, the commercial committee. I've had a front-row seat to observe and appreciate the carefully planned and orchestrated commercial strategy, which has led to the launch, now proceeding globally. Second, with the benefit of this perspective, I have great respect for the BioCryst management team and for the company, I'll speak about discovery and development. In discovery, the creative thinking and expert application of a structure-based approach to novel drug design at BioCryst is unparalleled. Understanding the key molecular relationships, leveraging these to design a better drug and achieving that with oral bioavailability is not easy. And yet the molecules, Dr. Babu and his team are delivering have excellent potential to be transformative drugs for their intended patient populations. The recent launch of Orladeyo is just the beginning. Oral delivery is hard to achieve. And BioCryst has done it and is doing so repeatedly with best-in-class qualities, potency, selectivity and bioavailability. This is precision drug discovery. The existing pipeline and the future potential for continuing advancement of new best-in-class molecules is just tremendous in my view. In development, strategic planning and execution for drug development in rare disease is a specialty unto itself. And Dr. Sheridan, Bill, and the BioCryst team are expert and accomplished at this. They are thoughtful, and they put patients first in their planning, which is critical. BioCryst understands what it takes to approach drug development for small populations, complex diseases and in areas of unmet need, both medical need and need for improving quality of life for patients. And the company builds this into the programs with great impact. BioCryst is nimble in execution and highly effective. The company has not only achieved registration for Orladeyo, as you said, but has simultaneously pursued it across the globe with global launch, accordingly. Third, on a personal level, this is a natural fit for me as a physician. I'm a pediatrician, as you noted, and a hospitalist with medical genetics training. Working with rare, complicated serious disorders is my own medical specialty. So to me, this is a natural obvious fit, BioCryst. So for all these reasons, I'm inspired by the opportunity to join BioCryst. I think the company holds great promise for continued success that will transform available therapies for the rare disease patient community, and I'm honored to have a chance to be part of that.

Thanks, Helen. So Babu, a question for you. I know it's not fair to ask who your favorite child is. But I've seen you talk about 9930 in a way that's different from the way you talk about others. Can you tell us what it is about 9930 that's special?

Yes. Sure, Jon. First of all, thank you. You're correct, in a way, both Orladeyo and 9930 are special molecules to all of us. Both are serine protease inhibitors and both have promised to be great medicines. So it is really difficult to pick 1 or the other. Coming back to 9930. 9930 or Factor D Inhibitor is the most recent molecule from the discovery team. As you know, we have long interest in complement. And along with our colleagues at UAB, we were the very first one to describe the 3D Factor D and it is active site in atomic detail. Factor D is an interesting molecule. It normally separates in the blood in the inactive form, and it becomes fully active only when it binds to Factor B and C3b complex. It's matched to a substrate. What we have done is after careful consideration, we have decided to go after the inactive form for the drug discovery approach. This approach has both advantages and disadvantages to go after the inactive form. First, on the plus side, the inactive form has a unique active site, structurally very different from most of the other serine proteases. So that gave us an opportunity to minimize the risk of target toxicity by going after the inactive form. On the other hand, the same unique active site in the inactive form is not very well defined. So it presented some challenges to come up with a potent molecule to the active site. But our discovery team with the experience from the plasma collected program was able to dispose 9930 in a relatively short period of time. In fact, it was less than 1 year. That was a commendable achievement by the team, definitely. That is the structural point of view. The other aspect of 9930, as you will see from the rest of the program today, both Factor D and the alternative pathway play an important role in many complement-mediated diseases. And we have a chance here with 9930 have, really, an impact on the patient's lives. So both from a structural point of view and also its impact on the patients, 9930 is definitely turning out to be an interesting molecule for us.

Thanks, Babu. Bill, I've interviewed candidates after they've spoken to you, and one of them said to me, he never saw a CMOs to be so effusive about a program before when you were talking about 9930. Now I'm pretty sure most investors who know you pretty well would never accuse you of being effusive. So what is it about 9930 that gets you excited?

So Jon, it's a combination of the inherent quality of the compound coming out of the discovery group, combined with its track record in early development and add to that the number of indications we can go after a lot. So here we have a serine protease inhibitor that targets an absolutely unique confirmation of the active site of an enzyme, in this case, Factor D, that really helps drive specificity and lowers the risk of unwanted off-target effects. So that's really important. On top of that, all of the rich in vivo biomarker and in vitro target potency results that we gained during its preclinical development told us we should have a drug that could perform in the clinic. And that is exactly what we saw from the first evidence emerging from the PNH study. So there are just so many serious and life-threatening rare diseases driven by the alternative pathway and so I thought to myself this is an opportunity to help patients and revolutionize medical practice. So that's why I'm excited.

Great. Thank you. Well, that wraps up this section of our program. I'll turn it over to Bill, and he's going to do a deeper dive on our Factor D program.

Thanks. Thanks, Jon. Now it's my pleasure to introduce our panelists for today before we get into the rest of the program. First off, Dr. Austin Kulasekararaj, MD, practices as a consultant hematologist at King's College Hospital in London. And Austin's a leading expert and active researcher in PNH. Mr. Barry Katsof is the founder and President of the PNH, Patients Association of Canada and the founder of the PNH Global Alliance and, in fact, has PNH. Dr. Brad Rovin is professor of Medicine and Pathology in the division of nephrology at The Ohio State University Wexner Medical Center. So first off, we thought it would be helpful to ask them to explain what this disease, PNH, is all about. And what matters to physicians, its treatment. So Austin please join, and we'd love to hear, what you have to say about this disease.

Okay. I hope you guys can hear me. So what I'll do in the next 5 minutes is take you through some basics of this disease, which I'm obviously passionate about, this disease of paroxysmal nocturnal hemoglobinuria. As you obviously know, it's an ultra-orphan or a rare disease where patients get a triad of significant complications, including chronic hemolytic anemias with paroxysmal attacks, and also have a propensity to get thromboembolisms and also have an underlying bone marrow failure. So it is an extremely rare disease. We think the incidence of this disease is around 0.5 to 1 per year with the prevalence being higher because of the improvements in the therapy with complement inhibitors since the first clinical trials of -- this will complement inhibitors i.e., C5 inhibitors. So people always used to say, if you understand PNH, you understand a lot about hematology and medicine because it's a disease, although it's rare, and most patients could be stable. It can be associated with the number of life-threatening complications, which lead on to mortality and morbidity. And one of the key things is this thromboembolic manifestation or having complications with clots in different parts of their body, including cerebral hepatic and other parts. And historically, prior to that vent of complement therapy, the mortality for patients with PNH was close to, at 5 years, nearly 1/3 of patients were -- had life-threatening complications, predominantly related to thrombosis. And this intriguing relationship with an underlying bone marrow failure was also seen in this. So if we move on to the next slide. So this is -- if you look at if you look at the lifespan of red cells, we all know that the bone marrow is a factory which produces, but we are -- probably not -- most of us are not aware that 84% of the cells in the human body or red cells, which are 20 trillion to 30 trillion. And if you have a human adult, healthy human adult producing around 2.4 million new erythrocytes per second, think of it in the context of PNH. And I know this is a bit of a technical slide, but I just wanted to take you through this slide where normal red lifespan is around 90 to 120 days, i.e., circulates in the system for 3 to 4 months. If you have a patient who's 100% of the cells are composed of PNH, i.e., they are affected with PNH, you can see that each of these individual trillions of cells, instead of living for 120 days will only live for 10 days, which, again, means that these patients get significant hemolysis due to the lifespan of these cells not being sufficient or not living. And not only that, once these cells lysis and die off, which live after 8 to 10 days, your bone marrow produces more and more of the same red cells, and they have the same PNH defect, and they continuously have hemolysis or destruction of their red cells. So essentially, what is involved in the pathophysiology of hemolysis in the context of PNH? So red cells, white cells and platelets or any cellular population, which comes out of the bone marrow, i.e., stem cells, will have complement regulators, which are protecting the red cells, i.e., I call them as shields around the red cells. And we know complement is one system, which is part of the innate immune system, which is always active in everybody's body. As we are all sitting here in different places you have a background complement activation at all time. So what happens is this complement activation does not do anything to the intact red cells. But if you imagine a patient who's got PNH, these red cells will be naked without complement activating molecules on the surface of the cell. And when you have complement activation, this leads on to hemolysis of the PNH red cells, leaving onto all the complication symptoms associated in PNH patients, which significantly impact the quality of life seen in this group of patients. So it is important that this complement activation, because we know that we unless a patient undergoes a cell transplant, we are not able to stop the production of these big a mutant cells or complement sensitive cells. So the only possibility of treating this patient is to stop the complement activation pathway, thereby allowing these red cells to live for a longer duration of time and thereby stopping the hemolysis. And another way to pictorially depict this using this cartoon, where the complement pathway is lined up horizontally rather than vertically with alternate classical and lectin pathway, indicating a domino effect of activating the downstream pathways with C5/C5d activation and the terminal complement activation of membrane attack complex inducing red cell lysis. So what happens is this is what normally happens. But if you inhibited the terminal complement pathway at C5, this hemolysis, intravascular hemolysis is abolished. But what continues to happen is there -- and there are rare patients who have mutated C5, which stops binding of eculizumab. But for patients who are on terminal complement pathway inhibitors, the proximal pathway is still active with the alternate pathway and the tick over hemolysis with amplification look or continuously going on that it leads on the position of C3d fragments on the surface of the red cells. And these the cells need to be cleared in the reticular endothelial system, i.e., in the liver and in the spleen, and thereby inducing what is the concept of called as C3D-mediated extravascular hemolysis which happens in the liver and the spleen leading on to hemolysis of the cell. So we've changed a disease with significant intravascular hemolysis due to the proximal complement pathway activation with C3d deposition into a component of C3d-mediated hemolysis, and that is where compounds which broke the proximal pathways, more particularly targeted compounds rather than broad C3 inhibitor, i.e., blocking Factor B, Factor D and other molecules, specifically in the proximal pathways, could be significantly interesting and, more important, from a patient perspective, if these compounds are oral, and they induce better quality of life with improvement of hemoglobin and transfusion independence. So I think I'll stop there just trying to go over the landscape of PNH treatment, and hand it over to Bill.

Yes. Thanks, Austin. So clearly, the C5 inhibitors were a big step, and they basically changed the nature of the disease in the clinic. What are the problems left to solve from the medical perspective?

So I think the first thing is, as you rightly said, the C5 inhibitors have been a major change for these patients with improvement in the mortality and morbidity associated with this condition. So these patients do not have the thrombotic complications associated with the activation of the complement system. But obviously, couple of things from a physician perspective is, these patients -- quite a number of these patients continue to remain anemic due to the extravascular hemolysis component. And the proportion of these patients are quite symptomatic from their anemia, and also a proportion of these patients will also need significant blood transfusions with need for transfusions at regular intervals. And obviously, from a perspective from patient as well, this is a disease, I say, a lifelong or a long-term treatment. And sometimes if you have 2 weekly injections for a period of years and decades together, that is having a significant impact on the patients, and it is better to have choices out for our patients so that they can use the agents available.

Okay. Thanks very much, Austin. I think that's a great grounding. So now let's move on to discussing the results of that study. So it's my pleasure, of course, to be able to do this today. And with that background, as we discuss the results from our Phase I proof-of-concept study with 9930, what should we focus on, and I think that with the remaining medical challenges, we should focus on the relief of anemia and the avoidance of transfusions as key outcomes related to control of both intravascular hemolysis and extravascular hemolysis with increases in PNH red cell clone size as a key measure of control of hemolysis. And as Austin explained, that's all to do with improving the life span of the PNH red cells. The objectives of this study were typical of dose-ranging proof-of-concept studies of a new investigational drug. A really important goal was to identify, therapeutically, active dose regimens. And we, therefore, selected patients who are anemic with a hemoglobin less than 10 or else transfusion-dependent. And that applied to both the naive patient population who had never had a complement inhibitor and to the inadequate response population. So the main difference in our legibility criteria between the untreated PNH patients and those who had inadequate response to C5 inhibitors was it -- we required evidence of ongoing intravascular hemolysis in the C5 inhibitor-naive group. With lactate dehydrogenase or LDH, for sure, more than 2x the upper end is normal. PNH is a serious illness and very rare, as Austin explained. So we designed a dose-ranging scheme to maximize efficiency and minimize the duration of dosing at low doses that might prove suboptimal. Each patient enrolled had the dose increase from the starting dose at day 15. Patients who benefited from treatment entered the extension phase after day 28, and the treating investigator could titrate the dose up to 500 milligrams twice a day. We also increased the starting dose as we learned about the drug's activity and progressed through the cohorts. 9930 was dosed as a single agent in previously untreated patients. Remember, our goal in this program is monotherapy for this disease. In this first study of 9930 in PNH, we added 9930 to C5 inhibitor treatment in the C5-inhibitor inadequate response patients. We plan to transition responding patients off their C5 inhibitor after the responses are stable. All told, 16 patients were enrolled with C5 inhibitor-naive patients coming on first in sites in South Africa. A C5 inhibitor inadequate response to patients were enrolled later in the study in the U.K. and Austria when the COVID-19 restrictions eased later last year in the year. Since our last presentation in September, the C5 inhibitor-naive patients have continued with BID dosing. We completed enrollment, and the average duration of exposure is 6 months. The 9 patients dosed at either 400 milligrams or 500 milligrams twice a day were very ill from their disease with a baseline hemoglobin of 8.3, several with evidence of bone marrow failure and a high incidence of transfusion dependence. Laboratory biomarkers showed active hemolysis, of course, with high bilirubin, AST and LDH. The patients enrolled earliest in the study are now approaching a year on therapy, which is really gratifying to see and the duration of treatment, the doses that matter is now a median of 22 weeks. In the C5 inhibitor-naive group, follow-up has confirmed our early findings from last September. Anemia was relieved with hemoglobin going up by 3.5 grams per deciliter from a mean of 8.3 at baseline to a mean of 11.8 of the last [ study ] visit. And a remarkable increase in red cell client size, we've seen a 40 percentage point increase associated with a large and clinically meaningful reduction in all of the hemolysis biomarkers, bilirubin, AST, LDH and reticulocyte count. So a key remaining challenge, as we discussed earlier, is the need for continued transfusions, especially in the context of extravascular hemolysis, but also obviously, in people who are naive to complement inhibitors as this group is. And a really important and dramatic result from this study is that no transfusions were needed at the doses of 400 and 500 milligrams twice a day. The rate of transfusions dropped to 0. So if 100% of patients were transfusion free, by any measure, this is a great result for patients with PNH. The only transfusion in this group was very early on. We discussed that last year. It was after the first 2 weeks of dosing in patient B in the first cohort. Here's a quick summary of that patient. Updated from last year with now nearly a year of follow-up. In the year prior to study, patient B had 13 units of red cells transfused. We've indicated when the doses of 400 milligrams and then 500 milligrams were introduced with the arrows in the left-hand panel at about weeks 20 and 28, respectively. As the dose was escalated, we gained control of hemolysis, the hemoglobin continued to rise throughout the year on study, in fact, doubling from 6.7 to 13.8 over 50 weeks. Red cell client sites reached almost 100%, more than 99%. We can also see the clinical chemistry biomarkers, AST and LDH, stabilize, and the reticulocyte count settled down as the anemia was corrected. As you mentioned last year, in the discussion in September, the investigator reported rapid symptomatic relief. You can imagine the difference of hemoglobin of 12 to 14 and avoidance of transfusions makes to well-being compared to a hemoglobin of 6 to 7 and repeated transfusions. These dramatic responses in this patient were reflected in an improvement from baseline of 8 points in the FACIT Fatigue score. These are great results from monotherapy with an oral drug. Another example of patient H is also very instructive. This patient started at 200 milligrams twice a day and showed a prompt response in every measure. With continued dosing at 400 milligrams twice a day from day 15 through week 20, the clone size got to 100%. We can see that in this patient, stability in the various biomarkers took some time to be evident. With no transfusions on study, hemoglobin rising from just under 10 to nearly 15 and fatigues scores improving from baseline by 9 points, these are great results for this patient. As we'll see in the next few slides, the outcome for the C5 inhibitor inadequate response patients were very similar. So we have 6 patients. They all came on study in late 2020. And for the 405-milligram dose levels, the median duration of dosing is now about 13 weeks. These 6 patients were very ill, 3 had bone marrow failure and 3 had prior blood clots, 5 were transfusion-dependent and their baseline hemoglobin was 8.9. Four were being treated with eculizumab with an average dose of 1,200 milligrams every 2 weeks, which is obviously higher than the approved dose, and 2 are on ravulizumab. The baseline laboratory profile shows extravascular hemolysis with high bilirubin, circulating C3 oxygenized PNH red blood cells and higher reticulocyte counts. Adding oral 9930 treatment increased the hemoglobin by 3.2 grams per deciliter and the red cell clone size by 30 percentage points and reduced the lab markers of extravascular hemolysis. Remember, this is a shorter follow-up. So these results are strikingly similar nevertheless to those in the C5 inhibitor naive subjects, indicating that proximal compound inhibition with targeting Factor D can control both intravascular hemolysis and extravascular hemolysis. So even though follow-up is much shorter than in the C5 inhibitor-naive group, the story with red cell opsonization with complement component C3, that Austin discussed earlier, is pretty interesting. And in 5 out of 6 subjects, these levels have fallen dramatically even in the first 8 weeks of treatment, and the hemoglobin has risen quickly as a result. Just like in the naive population, we have a dramatic outcome in transfusion rate. So it's gone to 0 in 5 of 6 patients. In the other patient, the transfusion rate was halved. So all total, we have 5 or 6 patients now transfusion free. Again, this is a really great result. Patient N is one of Austin's patients and demonstrates the effects of adding 9930 on top of 1,200 milligrams of eculizumab every 2 weeks. So this person was still not getting control, was still anemic. And after trailing 12 weeks of adding 9930, we're seeing a gratifying response with continued rise in hemoglobin, and rise in the PNH red cell clone size, fall in the reticulocyte count and fall in the C3-opsonized cells. So as you saw before, it can take longer than this for the whole picture to stabilize. But already, this patient has done really, really well. So overall, the outcomes on anemia transfusions and control of hemolysis have been very encouraging. But so does the safety and tolerability profile we've seen so far, we haven't really seen any safety signals. And of course, with any new investigational medicine, we're very careful about safety monitoring the clinic and in the laboratory with thorough investigations. No patient has stopped or interrupted dosing due to related AEs. And like in all trials of complement inhibitors, we've seen instances to hemolysis. These has resolved without changing the dose and the patients have continued on study. As we discussed last year, we have seen a benign drug ration some patients that goes away without any intervention or change in dosing of 9930. We've also seen transient headache more commonly in the C5 inhibitor-naive group. This is an expected effect of complement inhibitors and happens due to resetting of nitric oxide homeostasis with control of intravascular hemolysis. In essence, it's confirmation of the on-target effect of the drug. We couldn't be more pleased with the responses we've seen so far. Anemia was relieved, transfusions avoided, and both intravascular and extravascular hemolysis brought under control. The consistent effects in both C5 inhibitor naive and C5 inhibitor inadequate response patients provide confidence for the next steps in this program and also provide confidence for focusing on monotherapy with 9930. We even chat about it today, that the PK and PD of PNH and laboratory assays were similar to healthy subjects. Importantly, we've got a very good dose range to select pivotal studies in PNH and also to apply to our broader program in other alternative pathway dysregulation diseases. So we look forward to finalizing dose switch after discussion with regulators. All told, these findings, plus the safety and tolerability profile in their seriously old patient population, strongly support our pivotal study program in PNH and the expansion to studying selected nephritis indications. So that's the review of the data. I'd now like to in invite Austin and Barry to join us. And we'll, in a minute, get to -- getting a perspective on the data coming out of our Phase I dose-ranging study but -- Barry, it would be really important just to spend a few minutes to educate everybody about what it's like to experience natures of patients. So please go ahead.

Thank you. It's not a good experience, to be very frank and open about it. First of all, the journey starts when typically, most patients wake up one morning and see that the urine is red blood colored. That's pretty frightening in itself. So what do you do? You end up going to your GP, and they end up sending to our urologist. In my case, we went through all the workups, and the doctor kept saying, don't find anything, don't worry about it. That's fine for them to say. Meanwhile, every morning when you enter the washroom, you kind of had 1 eye open, 1 eye closed because you didn't know what you were going to see. Very frightening. Went to another urologists, head of the university, and did all the work ups again, nothing was found. Came back, did all the work ups again. To make a long story short, we ended up going to an nephrologists, kidney doctor, because I was very insistent on wanting to know what was upstream from the bladder. And when you put the blood -- or you're in an essential field, what ends up happening is the blood will settle and the hemoglobin won't. And that's how we determined that I had something other than blood in my urine. And that whole process took nearly 2 years. Then going to the hematologist with these findings, they were able to quickly do some tests and determine that I had PNH. That was great. But the treatments at that time weren't available. And then when they were available in '07, the C5 inhibitors, as was stated, hemoglobin never gets to an optimal level. You end up becoming transfusion dependent. Life with PNH is dependent or revolves around how you feel. Fortunately, I have a very supportive network, family and friends. And you can never make plans. It's always, yes, we'll go for dinner, but it's really going to depend on how I physically feel. Low hemoglobin severely restricts what you can do in your daily life, forget about active -- activity, because in most cases, your hemoglobin doesn't allow you to do that. Climbing a set of stairs becomes an issue or a challenge.

Thank you. It's not a good experience, to be very frank and open about it. First of all, the journey starts when typically, most patients wake up 1 morning and see that the urine is red blood colored. That's pretty frightening in itself. So what do you do? You end up going to your GP, and they end up sending you to your urologist. In my case, we went through all the workups, and the doctor kept saying, "don't find anything, don't worry about it." That's fine for them to say. Meanwhile, every morning when you enter the washroom, you kind of have 1 eye open, 1 eye closed because you didn't know what you were going to see. Very frightening. Went to another urologist, head of the university, and did all the work ups again, nothing was found. Came back, did all the work ups again. To make a long story short, we ended up going to an nephrologist, kidney doctor, because I was very insistent on wanting to know what was upstream from the bladder. And when you put blood -- or urine in a centrifuge, what ends up happening is the blood will settle and the hemoglobin won't. And that's how we determine that I had something other than blood in my urine. And that whole process took nearly 2 years. Then going to the hematologist with these findings, they were able to quickly do some tests and determine that I had PNH. That was great. But the treatments at that time weren't available. And then when they were available in '07, the C5 inhibitors, as was stated, hemoglobin never gets to an optimal level, you end up becoming transfusion dependent. Life with PNH is dependent or revolves around how you feel. Fortunately, I have a very supportive network, family and friends. And you can never make plans. It's always, yes, we'll go for dinner, but it's really going to depend on how I physically feel. Low hemoglobin severely restricts what you can do in your daily life. Forget about active activity because in most cases, your hemoglobin doesn't allow you to do that. Climbing a set of stairs becomes an issue or a challenge. Then you start to develop the need for transfusions. Transfusions in themselves are very problematic. You just don't go into a blood bank and say, you need 2 units of type A. It doesn't work that way. You get your blood tests. You then -- your doctor determines that you need a top-up, if you want to call it that, then you have to go back for a cross match. They -- after lots of transfusions, you end up building up antibodies, and that -- they have to get you a proper blood to match what you have or what the patient has. All told, besides feeling very sluggish and not well before you need the transfusion with the hemoglobin in the 70s, it could take several days until you actually get the transfusion. Then once you get the transfusion, you just don't walk out of the clinic and feel 100%. It takes another couple of days until your body adapts to the transfusion. So again, it's very time-consuming, and plays upon patient's lifestyle, the sequence, everything depends upon when you're going to need a transfusion. If you're a student or if you're working, you have to take time off. It becomes very burdensome on the patient and their lifestyle being tied to an infusion schedule of every few weeks or every few months. Again, you have to run your life and manage your life around your infusion schedules and your transfusion schedules. Far from optimal. Granted, it's eliminating some of the uglier aspects of PNH, but it is still not an optimal lifestyle. Having options, as Austin said, for patients to be able to improve their hemoglobin to normal levels to lead an active lifestyle that is representative of your age group or demographic is great. Being able to eliminate the need for transfusions is more than great. Transfusions bring with themselves -- sure, it makes you feel better, but there's other medical side effects. Patients typically become -- either overload with iron. They need iron chelation pills to reduce the iron in their body. Some of these medications have severe side effects with them. So having the option of a treatment that will allow a patient to have, a, an acceptable hemoglobin and reduce or eliminate the need for transfusions, as they say, in the advertisement's prices.

Okay. I think that really explains it perfectly. Austin, can we get your reactions to the results of our study? And maybe you can frame it as to what are you looking for from proximal complement inhibitors?

So thanks, Bill. So Barry did sum it up, is it? Because we -- I think of it as a sort of going through different eras. Because in the pre-eculizumab era, the main goal of therapy was to prevent end organ damage, prevent the thrombosis and the complications associated with it, which is obviously life-threatening leading on to mortality and morbidity. And I think -- which we were all very pleased about, and that is what the C5 inhibitors, mainly eculizumab did in that. So switching gears. I think once you see these patients coming into the clinic where you tell them, you're prevented from thrombosis, but still their quality of life is not significantly great because they still continue to remain anemic and transfusion dependent. And you accumulate this group of patients over a period of years. Because these are patients who have remained on C5 inhibitors, but continue to have -- continue to remain anemic, continue to remain symptomatic, continue to have significant impact on their -- impact on their quality of life. So -- which is where I think the proximal complement inhibitors do significantly play a role. And I think it doesn't make sense when somebody is on an intravenous every 2 weekly to give them another subcutaneous or another intravenous. So patients, once you say that there is a proximal complement inhibitor, which is an oral compound with -- then patients were extremely keen to participate in these studies. And more pleasing for a trial list and the patient to see is this group of patients, as you showed, having a significant improvement in the hemoglobin because you showed 1 of the patients, the other patient jumped from a hemoglobin of 7to 14. That's nearly doubling of the hemoglobin level. And sometimes I jokingly say that you come to a stage of needing vivisections, which is coming to Barry's point of increased ferritin and you take our inclination, you don't need it. You might even let out a bit of blood to control. So I think this is a significantly important step forward for this group of patients where oral therapy is important to improve their quality of life, and continue to keep the thrombosis at bay as well and let them lead a lifestyle where you're not attached to the hospital for too long.

Okay. So this is a complicated disease with lots of measures. So we've talked about transfusions, hemoglobin and a bunch of biomarkers, including LDH. In terms of measuring outcomes, how would you rank those in order of importance and what matters to you?

I think we -- again, we are going through a shifting and a changing landscape as well. So LDH for all right purposes because it's a marker of intravascular hemolysis was always -- and it's important to measure LDH because that's a simple, cheap test to monitor intravascular hemolysis to see what the LDH is doing, be it 1.5x, be it 2x, upper limit of normal. But I always say this, patients don't see LDH. Patients see their quality of life. You can tell them what their LDH is. But patients might say, "but I'm still feeling tired. I'm still needing transfusions." So at the end of the day, I keep saying this to all my patients as well, I'm not treating numbers. I'm treating you. And that is what is important, if a patient's quality of life improved. I'm not belittling LDH as all. LDH is important. It's an important biomarker to look at the ability of the complement inhibitor. But in a larger scale, transfusions and hemoglobin are extremely important for patient's well-being and quality of life.

Thank you. So that was super. I think I'd like to move on to 1 slide that sort of sets up what else we might be able to do with complement inhibitors. And also invite Dr. Roven to join us. So there have been an explosion of knowledge about the effect of the alternative pathway in different diseases. Dr. Roven, could you maybe expand on this? And from the point of view of the nephrology world, what makes you excited about these investigational new drugs and BCX9930 and Factor D inhibitors?

So thanks, Bill, and thanks for having me. It's been well-known in nephrology circles for a really long time that certain diseases that affect the filtering units of the kidney, glomerular diseases or glomerulonephritis, such as lupus, systemic lupus erythematosus, activate the complement pathway. And so early on in my investigational career, I had hoped we could look to complement inhibitor in lupus nephritis. Over the last decade, however, with molecular biology techniques, we've really discovered that complement is involved in a whole variety of our glomerular diseases. And I'd like to think about them as diseases in which complement is positive. And these are the C3 glomerulopathies, where the alternative pathway is disregulated and overactivated. And these caused direct damage to the filtering units of the kidney and can progress to end-stage kidney disease requiring dialysis and transplantation. Atypical hemolytic uremic syndrome is a thrombotic microangiopathy where patients get clotting. And this is also a disregulation of the alternative complement pathway. So these 2 categories of diseases, which are really manifested in several ways clinically, show you where an alternative pathway inhibitor target would be absolutely perfect. Then you have diseases like systemic lupus, which consumes complement. And we know that complement in disease like this can be helpful. Because if you have early complement pathway loss, you actually get manifestations of lupus. But when you get down to the alternative pathway, that's an effector pathway that we believe causes end organ damage. And especially in the kidney, we see complement deposited in the kidney within the glomeruli, and that's generally associated with considerable inflammation. When we -- our own group has looked at the transcripts that are elevated within the kidney in patients with lupus nephritis. We do this by micro dissecting out from the kidney biopsy that we take clinically. One of the complement components that's really elevated is Factor D. And we've shown in our own laboratory that the alternative pathway is really the pathway that's doing the damage in the kidney during lupus. You can have another example in which the complement pathway is pro-inflammatory within the kidney. And also a very good example for the audience is ANCA vasculitis. ANCA vasculitis is not associated with systemic complement consumption like lupus is and when we look at the kidney, we don't see a lot of complement, just at the sort of gross level of the kidney biopsy. But experimental animals suggested that this was important and a complement C5a inhibitor has now been shown to really reduce inflammation in patients with ANCA vasculitis. So those are 2 really good examples of where complement is really driving inflammation. I'll give you 3 other examples within the kidney world, which are really important. And that is IgA nephropathy and membranous nephropathy, where we think that, at least, in IgA nephropathy, the alternative pathway is activated, but it's action in the kidney is going to be -- where it comes into the, of course, into the common pathway, which will be the end of starting with Factor D and beyond, C3 and beyond. So that's being targeted right now in patients with IgA nephropathy, and also in patients with membranous nephropathy, another rare glomerular disease. And I'm going to just throw this out there because I think this is important for people to consider. When we've done a proteomic analysis of micro dissected kidney biopsies. One of the things we find in diabetic kidney disease, which, of course, is the most common cause of end-stage kidney disease requiring dialysis or transplantation. One of the surprising findings we consistently see is C3 and other distal complement components. And sort of one of my pet hypothesis is that even though this complement probably doesn't have anything to do with the pathogenesis of diabetic kidney disease, it may be responsible for the progression once the disease is up and running -- the progression -- the slow progression of kidney injury towards end-stage disease which really suggests or begs the question of whether a complement inhibitor in a disease that's not rare could actually slow the progression towards end-stage disease or possibly prevent it. So in my opinion, in summary, blocking at Factor D or beyond is really sort of target that we want to pursue and in fact are pursuing in several different kidney diseases. Having a Factor D complement inhibitor which takes out both the membrane attack complex down the line as well as the anaphylactic toxins because inflammation such as C5a is really -- could be a benefit in treating and managing these kidney diseases.

Thanks, Fred. That was great. Barry, before we hand it over to Charlie to talk about market research that they're conducting, would you mind just giving us your reaction to the study results that we shared today? What does it mean to you?

Freedom. Freedom from needing transfusions, freedom to be able to go out and do the things I like to do, cycle, hike in the woods, go shoot, that because my hemoglobin levels will be at an acceptable level to allow me to do that. I won't need transfusions, I won't have to worry about the iron overload, I won't have to judge my or manage my travel schedules about when I need infusions in the clinic and so on. So these numbers are, from a patient's point of view, very, very encouraging. It gives the quality of life back to the patients that we've lost for so many years and as Austin said, he's treating the patients and not the numbers. If the patient has a very acceptable quality of life, sort of you're happy H, but if it's not affecting what you do and how you live and not allowing you to do certain things, to sum up, freedom.

Okay. Well, with that, I'd like to thank all our panelists today. That was really super to have you hear. And now we're going to hand it over to Charlie Gayer who's Head of Commercial today to talk about our market research.

Thanks, Phil. It's my pleasure to introduce Jinky Rosselli. Jinky is Vice President of Global Business Analysis and Operations here, and she's been with BioCryst since 2015. The breadth and depth of customer insight research from Jinky and her team was fundamental to shaping our strategy for oral of AO on HAE. Her research uncovered pent-up demand for an oral prophylactic therapy across a broad range of patients and we were really thrilled to see that demand coming to life in the early days of the Orladeyo launch. addition in to her work at BioCryst, Jinky has extensive experience in other competitive rare disease categories like pulmonary hypertension and alpha Alpha-1 antitrypsin deficiency. I'll turn it over to Jinky to describe the specific insights about PNH patients and physicians that will help shape our strategy for BCX9930. Jinky?

Well, thank you, Charlie. Well, let's move to the next slide. Great. So first of all, just so great to hear from Bill, Austin, and Barry. These conversations wherever they -- and whenever they happen is just so critical as we build up our base of insights for PNH. So thank you so much for that conversation. You mentioned a bit about my experiences with Alpha-1, pulmonary hypertension, and most recently, with HAE and there's just a lot of really good learnings there but we do recognize that every condition is unique. Early in our work with PNH, it's really been about understanding that journey that Barry is describing of the patient and also the physician with a certain level of depth, and it's really listening intently for the what and most importantly, digging for the whys. We started with some secondary work, really sort of building up our anecdotes, library vantages, but there really is no substitute for hearing directly from our patients and actively treating physicians and gaining some additional confidence from those insights. So what we did is we conducted structured interviews with 25 PNH specialists and 23 PNH patients, all currently receiving C5 inhibitor therapy. So all these patients were either on Soliris or ULTOMIRIS and all based in the U.S.. Some additional context for the patients in this study, only 3 of the 23 patients were still getting transfusions regularly. So by today's standards, majority of our patient sample could be considered fairly well controlled. As I walk through the results of this study, I'll be referencing 2 patients. The main difference between these 2 patients is one was transfusion-dependent and the other transfusion free. Both gave their current C5s high marks for satisfaction. So consistent with what Barry was describing, for most of these patients, their journey towards a diagnosis of PNH was quite frustrating. 40% of the patients stated that they were misdiagnosed, mainly because of the rarity of the condition and its ability to really masquerade as other conditions. Imagine going from frustrations with misdiagnosis to the fear of the actual diagnosis, lack of therapeutic options, potentially then finally getting into a C5. So when we ask the patients directly about their -- directly about their experiences with C5 treatment, these patients are very grateful and generally very satisfied. And it makes perfect sense given the journey they have been on. These therapies are really life-changing for them. But as you can see from the scatter plot on the slide, there were also a wide range of satisfaction scores from these patients, most likely due to some of them having ongoing symptoms like Austin is describing, anemia, fatigue and transfusions. To help better describe how these patients feel about their C5, here are a couple of clips from the 2 patients I described earlier, patient a, who's transfusion-dependent and patient B who is transfusion free. [Presentation]

So as you just heard in the audio clips, these patients are coping and as in the case of many rare diseases, these patients become expert copers. Again, they are grateful for the benefits of these advancements in therapies and relatively satisfied. But despite this general satisfaction, the majority of patients are still looking for something more. They're looking for more convenient options and more efficacy. When we probe deeper with these patients, we uncovered a couple of points that provide some additional color to these unmet needs. The first point, many patients are still managing the overall disease and symptoms. I'd like to share clips again from these 2 patients. First from patient A on how he's dealing with his symptoms, and then from patient B, who speaks about what he desires in terms of incremental benefits from a future therapy. [Presentation]

So now we turn to our 25 PNH treating physicians. Compared to the patient, physician satisfaction is slightly higher when asked about current treatment. This is not unexpected, especially as these physicians are looking to gain a relatively acceptable level of stability with these patients. And it's really a judgment call for them, what that level of stability is. Keep in mind for the 23 patients who've participated in our research, the mean hemoglobin for the group is around 9.3, ranging from about 7 to 12. So with the tools these physicians currently have, they're really shooting to take these patients from bad to okay. While these physicians are generally satisfied, they do recognize that there's still room for improvement as they are very much aware that these patients are still experiencing symptoms. So when we ask about their desires for future therapies, physicians indicate on an unaided basis, greater efficacy, really centered around hemoglobin, which echoes what we heard from Austin and Barry, and having an oral option. These physicians are doing their best, but do desire more for the patients. They recognize that their patients are continuing to experience burden, whether it's disease-related or treatment-related. A core exercise in the research was really showing patients and physicians an early profile of 9930, which we called Product X. Just for some additional context. The product profile we showed them was very similar to the profile that Bill described earlier in his presentation. Reactions to the profile were overwhelmingly positive. 91% of patients indicate an interest in switching to 9930 after reviewing the profile. And this is across all the patients in our research, regardless of whether the patient was stable, transfusion-free or not. Physicians were also enthusiastic about the profile with some signs of hesitation to switching their well-controlled patients. But this is fairly common at this stage with many of our diseases. In addition, these physicians indicate from their research that if asked by their patient, they would prescribe. This is a very similar to what we saw in HAE, and what I've seen in other rare diseases. So for patients, what really drives their desire to switch is, one, the availability of the oral; two, the potential improved hemoglobin; and three, symptom control. When we did some additional maps into the data, we did see that there is really no correlation between their satisfaction with current treatment that I discussed earlier and patients' desire to switch to 9930. I'm now at the end of my presentation. So I just wanted to thank you all for your attention and time today, and hope you found the presentation helpful. I would like to end, however, with a final clip from patient B. If you remember, he is transfusion-free and very satisfied with the C5. This clip is a reaction when we showed him the early profile of 9930. [Presentation]

Thank you, Jinky. At BioCryst, this is why we do what we do . We hear these heartfelt expressions all the time from people with HAE, PNH, people with serious life-threating diseases. They're happy for any drug that helps them, makes their lives better, maybe even keeps them alive. But to be able to do that with an effective oral drug, for so many of these people with rare diseases, that is truly their dream. You heard today from Dr. Babu, and our discovery team in Birmingham. You heard their passion and saw their skill. You heard Bill's excitement about the clinical results for BCX9930 at this stage. You heard expert opinions from Austin, Barry and Brad about the opportunities for 9930, and what a difference a drug like this could make for people living with PNH, rare kidney diseases and beyond. We have a commercial team out there right now working hard to bring Orladeyo to people living with HAE. We can't wait to bring more oral medicines like 9930 to other people who have the same dream. This is why we do what we do. I'd like to invite my colleagues back now for the Q&A session.

[Operator Instructions] First question we have for you, Bill. Now that you have more data, what dose do you plan to use in your PNH pivotals? And have you considered a higher dose? And will the dose in the PNH pivotals be the same dose for the renal proof-of-concept trial?

Thanks, John. So we'll finalize the first selection with the regulators. So the way we work it out is based on PK/PD modeling. And that evidence supports what we've seen -- what we show today is that a 400 to 500-milligram dose level looks like the right dose level to go forward. So one of the really useful things about typing Factor D is that it's not the mutated protein in PNH, or for that matter, in any of the real diseases. So we can translate the dose directly over to the other indications, and that's what we intend to do.

Great. Thanks, Bill. And another one for you. Can you explain why the relative PNH clone size is an important metric?

It's something it's been written about by academics in the literature. And the proportion of the bone marrow production that is PNH production, you can measure with the white cell clone size with a granular-size clone size. And so if the red cell clone size poses only a fraction of that, that's telling you that the red cells have a very short lifespan and cost to explant. So if we can get that number, that relative number to look just like the white cell clone size, then we've normalized the red cell lifespan is what it's telling us. So it's an interesting metric, and it's something that we should look at more.

Great. And another one for you. Have you withdrawn the C5 inhibitor in any patients? And what are your plans to do so and report data?

Yes. So I'll ask Austin to comment on this as well. So the protocol absolutely plans to do that. And it's -- the data in the naive patient population from our perspective, strongly supports that strategy because it's monotherapy and naive. And fundamentally, the disease is the same basis. I mean, whether or not you've had a good response or a poor response to C5 inhibitor. So our objective is to get things stable and then withdraw the C5 inhibitor. We haven't done it yet. We look forward to seeing that later. Hopefully, later in the year. Austin, would you like to comment about -- I mean, you're an investigator on a study with several patients. So interested to hear your perspective?

Yes. So I agree with you, Bill, because the protocol map allows us to withdraw the baseline C5 inhibitor and just leave them on 9930. And the couple of reassuring things for me or the good data coming out from the naive study from South Africa saying that these patients are continuing to remain stable with a hemoglobin improvement as well. So that is a very reassuring aspect. And the second thing is, obviously, all our patients or 3 out of my 4 patients are on a higher dose, 1,200 and 1,500-milligram of eculizumab. So there is a possibility of gradually and slowly withdrawing drawing these patients rather than abruptly stopping them as well. So there is a potential of doing that. And going forward, that's probably what it's going to be because we don't want patients to be on multiple different complement inhibitors at the same time, or am I wrong? Is that going to be what it's going to be in the future? I don't know. But from the cost perspective and every perspective, I think a single drug is going to be better specifically for patients and economically makes sense as well.

Great. Well, I'll follow-up with another question sort of in that category for you and Bill, and the panel also. How do you feel the data supports monotherapy for 9930?

I think it does. Obviously, it's a rare disease, but smaller numbers are always going to be a problem, even if it's rare disease. But the confidence and the additional data from the add-on therapy and the ability to use it in our patients makes -- gives us a bit more confidence. The patients need, having a stability in their hemoglobin also gives an added reassurance as well. And I always say that as well, the reassurance that these patients have not developed thrombosis with significant disease activity during the course of the disease is also important because we should not forget about it. So all in all, it looks very promising. Obviously, we need to talk about the slightly higher LDH than expected in all the other programs and what is the reasoning. But as I said, if you ask a patient, and obviously varies here, whether you have a normal LDH or a transfusion independency with a good hemoglobin probably will take the -- later rather than the earliest, I think so.

Yes. Barry, we've gotten that question for you, too. From a patient perspective, what do you find most important?

Hemoglobin and transfusion independence. All the other numbers really to most patients don't anything. And more they delve into them, the more nervous they may get. The patient wants to know that they don't need transfusions and their hemoglobin is at a very acceptable, if not a near-normal level, to allow them to have a great quality of life.

Great. Thank you. Bill, I'll start with you on this one. Given the excellent results around transfusions in hemoglobin, why did LDH only go to 2x upper limit of normal?

Yes. I think it's an interesting question. And I think we're learning about what happens when the hemoglobins get really high, and they're all made up of PNH cells. And this is a massive transformation. As a couple of the subjects we talked about today, doubling the hemoglobin from 7 to 14. And all of the cells are PNH cells now. So even a slight bit of trauma in taking a blood sample or a little bit of analysis will put the LDH out. What does it mean? I think that it may mean nothing, actually. And one of the interesting discussions we've been having with our advisers is where did the target level of LDH come from in the first place. And it's actually pretty obscure when you delve into the literature. But Austin, maybe you'd like to answer that question because clearly, hemoglobin is what most hematologists care about more.

I think the LDH baseline, LDH level comes from South African -- sorry, South Korean registry data, where they looked at the -- this is all pre-eculizumab, where they looked at the baseline LDH and abdominal pain in chest pain and predicting the risk of thrombosis, and end-organ damage. And that is where the cutoff of 1.5x upper limit of normal comes. And it's a gradated view of 1.5 to 3 and more than 3 and going up, I think so. But there is no data post the complement therapy era, i.e., both in C5 and C3 inhibitors in the context of correlating LDH with the clinical response from the patient perspective. And secondly, just to add a point as well. It is -- even if it's 2x upper limit of normal of LDH, this is definitely not in the range of when patients get proper breakthrough hemolysis when the LDH goes up to 4x to 6x upper limit of normal with significant symptoms. So this is again something to look up. And there was 1 additional question, Jon, on that as well, whether -- are we sure that all the LDH is coming from the red cells? Or are there going to be other sources of LDH as well. So potential.