Great. Good morning, everyone. My name is Jess Fye. I'm a Senior Biotech Analyst with JP Morgan, and we're delighted to be continuing the 40th Annual Healthcare Conference today with BioCryst. I'm joined by the company's CEO, Jon Stonehouse. He's gonna give you a presentation, and then we're gonna go into some Q&A after that. If you wanna ask a question, there's a blue Ask a Question button on your screen. You can click that. It'll send me a question to ask management during the Q&A session. With that out of the way, let me turn it over to Jon. Thanks, Jess, and thanks for inviting us to this year's JP Morgan Healthcare Conference. Before I start, I'd like to remind you that I'll be making some forward-looking statements, and those statements have risks, and the risk factors can be found on our website. Not sure anyone's ever started a JP Morgan presentation with a zero on the first slide, but a little more than a year ago, that's what we had from our rare disease oral drug portfolio. Well, then in December of 2020, we got the approval of ORLADEYO, and everything changed. I share this with you to show you how far we've come, but more importantly, how far we'll go. We are creating and growing tremendous value in the marketplace right now with ORLADEYO. By all measures, the launch is a huge success. Even a global pandemic couldn't slow it down. This morning in our press release, we announced preliminary net revenue for last year, and the result is our first-year sales are $122 million, and we are just getting started. What's even more exciting is what's ahead. Given this great start, we're now able to give guidance for 2022, and that guidance is no less than $250 million of ORLADEYO net revenue for the year. That's more than a doubling of a very strong first year of sales. Several factors will drive the strong growth. First, it's a chronic therapy, and we start the year with a substantial base of patients to build on. Second, all the major payers and PBMs are now covering ORLADEYO, so we have a full year of many more paid patients in the U.S. Third, there are several things we started implementing late last year that we expect will have an impact this year. This includes patient activation. To this point, physicians have been driving the conversation with patients regarding ORLADEYO. We believe once patients engage with each other and their physicians, this will be another important driver of growth. What we're hearing from patients is having a treatment option with a profile like the one we have with ORLADEYO is so much more than a minor convenience improvement. It's life-changing for them. My name is Kissa, and I have hereditary angioedema. I have been taking ORLADEYO as a preventative medication since 2018. Early on, when I started on the intravenous and the other injectables, I hoped and I prayed for one day a pill, and then I found ORLADEYO. I love ORLADEYO. It has truly been a godsend for me and my life. Another important message we've been communicating since late last year is ORLADEYO works. As we see from our pivotal trial at 96 weeks, the attack rate in patients treated with ORLADEYO was reduced by 86% compared to baseline, and many experienced attack-free months. In 16 of the last 17 months, at least half the patients were attack free. No wonder patients are switching from their injectable therapy to ORLADEYO even when they've been controlled on that therapy. It doesn't matter what injectable therapy they've been on, as you can see from the bar chart on the right. Close to 80% of the patients switching from injectables in the first half of last year have stayed on ORLADEYO at least six months. No matter what your prior injectable therapy is, the conclusion is the same. You're controlled on your injectable therapy, and you switch to ORLADEYO, it's highly likely you'll continue to be stay controlled. Why wouldn't you switch? Now, no drug's perfect, and ORLADEYO is not for everyone living with HAE. What we're seeing in the first year of launch is an overall patient retention rate of 70%. With this profile, we believe we can build on an already strong market share. The final input is what physicians are telling us. Late last summer, we surveyed 60 physicians who are big treaters of HAE patients. What they told us is in the next 12 months, ORLADEYO will be their number one prescribed prophylactic therapy. Now, we know physicians sometimes overstate things in these surveys, so it could very well take more than a year. Our market research has been very predictive of this market thus far. We believe this survey will be predictive too. When you add it all up, you can see how we can double revenue year-over-year, and you can see how ORLADEYO will be the market leader. Now we've adjusted our peak sales number, and we believe we will reach $1 billion in global peak sales. That's real value. This is just the beginning. At BioCryst, we have the ability to compound this value with the world-class discovery team and platform we've been perfecting for decades. Our drug discovery platform at BioCryst is based on structure-based drug design, meaning we design drugs based on what we see, the shape and charge of a target enzyme active site. We aren't the only company that has this capability, but what makes us different is how we perfected our approach over decades, having built over 10,000 molecules. With this experience, our team is able to apply the art, like molding clay, to this scientific approach. The platform enables us to go after difficult targets like serine proteases and kinases. These are hard targets because as in the case of serine proteases, there are 300 in the human genome, and the challenge is blocking one without blocking the others. We're able to overcome this challenge because our scientists know how to build these molecules to not only be potent but also selective and bioavailable. I've talked in the past about the experienced team we have in Birmingham, Alabama, and how they work together, structural biology, medicinal chemistry, and the biology teams working collaboratively to build these oral drugs. Today I'm gonna show you how they took a challenging target, a serine protease, plasma kallikrein, and made a potent, selective, orally bioavailable once-daily capsule, ORLADEYO, to prevent HAE attacks. Let's take a look at the enzyme active site of plasma kallikrein. It starts with an understanding of this site. Our scientists see it divided into four sections labeled S1 through S4, as you see here. S1 is the key to potency. This is a deep pocket which allows us to fit an anchor to our molecule. We tried multiple ring anchors to securely fit this site and figured out a six-member ring gives the best fit. S2 through four are unique to plasma kallikrein and what differentiates it from other serine proteases. This is the key to developing an inhibitor that binds the plasma kallikrein and not the others. We need to figure out how to build a molecule to bind tightly to these parts of the active site while maintaining the potency. Some additions to the molecule can cause a loss in potency while others maintain it. By going through a cycle of understanding the structure, making the molecule at the chemistry bench, and then testing it in a biologic assay, and then repeating this cycle is a critical part to the process. Knowing what to try and persisting to improve until you get the best molecule is where we're experts. Lastly, bioavailability. To have an oral drug, one capsule once a day, that gives the same effect as an injectable is the last and most difficult piece. Part of the solution in this case is a fluorine group seen here in green. It's not just adding the group, but more importantly, where to add it to maintain a close and potent fit while giving it better bioavailability. You can see the final molecule has a perfect fit. Fits like a glove. The charges match blue to red, gray to gray, and the contour fits into the space perfectly into the active site. Sounds simple, right? In practice, it's very challenging, as evidenced by the fact that no one else has achieved this when many have tried. What's the benefit of our platform? Our platform is what allows us to deliver oral drugs to patients when others struggle. Our platform is how we'll be able to repeat this over again and again and again. Our platform is what will compound our value. Imagine the value that can be created if we go beyond ORLADEYO. Well, that's exactly what we have with our oral factor D inhibitor, BCX9930. What's even better is this is one molecule to treat many, many patients with rare diseases. A pipeline in one molecule. Factor D is another example of a challenging target, another serine protease, and BCX9930 is another example of how far we've come and again, how far we'll go. Let's take a look at one of the many rare diseases BCX9930 will be able to address, PNH. A year ago, we had proof-of-concept data with four patients in PNH. Today, we have data from 15 patients with many on BCX9930 for well over a year. That data has led us to start two pivotal studies in PNH. The data from these 15 patients give us great confidence we'll be successful in these pivotal studies as we see meaningful improvement in their anemia, with increases in hemoglobin and reduction or elimination of the need for transfusions. We're recruiting our pivotal studies as we speak, which will grow our data set to over 100 patients and ultimately lead to approval where we can reach many, many patients with PNH around the world. All of this with an oral therapy. Guess what? The value of an oral therapy is life-changing for these patients too. Take a listen to how a PNH patient describes the burden of their injectable therapy and what an oral would mean to him. I wish I didn't have to do it. It didn't take so long to administer. What I would like to see in the future is like something like I could do daily or I'd rather just like take a pill daily than go every eight weeks to get an infusion because that would just I would just take it with my vitamins. You know, it just takes, you know, I get there at eight o'clock and just the process of getting set up and getting stuck and then mixing the drug, having the right blood work done, get the results back and then getting it. It's just that's cumbersome. That takes forever. I wish it wasn't that long. I wish it was a little bit easier than that, but it's not. Honestly, that's exactly the kind of thing that I'd be looking for is something like this. This would be my like pie in the sky dream scenario is taking a pill twice a day rather than going and getting any kind of sticks and infusions. I would much rather do this, especially when it improves my quality of life, which is paramount to me. That all that stuff. This would be my dream scenario is what we're describing right here. I'd switch in a heartbeat. I just take like something orally, like take a pill every day? I'd be in so quick. Yes. As I mentioned earlier, there are many more rare diseases to treat with our oral factor D inhibitor. In addition to PNH, we've started a proof of concept basket study in three rare renal diseases, IgAN, C3G, and PMN. These are diseases where the unmet need is huge and a targeted oral therapy would be a game changer. Fast-forward two years from now and what do we expect? ORLADEYO is either at or on its way to becoming the market leader. With 9930, we expect to have data from pivotal studies and begin the process of preparing to file for approval in PNH. We expect to have data and proof of concept in more rare diseases and starting to prepare for pivotal studies in those diseases. We expect to be running more proof of concept studies in more rare diseases. Hopefully, you can see how we reach more and more rare disease patients with our oral therapies, and we layer on more and more value. We also have the capital now to invest and execute our plan. With the successful start of the launch of ORLADEYO and the rapid advancement of our pipeline, you can see how we're able to allocate this capital and successfully execute our plan. We have all the ingredients, the platform, the capital, the team, and the strategy to build the next great biotech company. That creates meaningful value, and that value is being created now. Everything changed a little more than a year ago when we got the approval of ORLADEYO. The great news is, there is so much more to come. Thank you. Great. Thanks, Jon, for that presentation. Just as a reminder, if you'd like to ask a question, you can ask it using the blue button on your screen. Maybe we can just start out with some of my questions, though. The ORLADEYO launch got off to a very strong start. What were the ingredients that led to that strong initial uptake? Charlie, you wanna take that? Well, Jess, hi. Thanks for the question. I think the ingredients start with a great product that patients wanted, and we recognized that early by doing a lot of market research, and then we really prepared. We got a great team, a very experienced commercial team on board early so that they'd be ready to launch. That's the start that they got off to at the beginning of late 2020, beginning of 2021, continued all the way through 2021. That's something I'm really pleased about. We've seen no decrease in patient or physician demand throughout the year. I think it's all because of the product plus the preparation. Okay. You mentioned coverage during the presentation. Have you completed your goal of having the vast majority of patients under insurance coverage by the end of 2021? Can you remind us of the tier status you achieved in different formularies? Yeah. We have achieved our goal in terms of getting major payers, all the major payers and PBMs to establish coverage policies for ORLADEYO. What our goal was, is to get parity access. We want patients and physicians to be able to choose the right product for them, and we've been successful in doing that. ORLADEYO is at parity or better across the board. It's really important to patients and physicians because this gives them confidence that the payers are gonna reimburse for ORLADEYO. That gives them even more confidence in trying ORLADEYO, and I think will serve us well in 2022. Okay. You talked about the same number of patients, I think, starting ORLADEYO in 1Q, 2Q, and 3Q of 2021. Obviously, there was different revenue associated with each quarter as patients continued on therapy and also converted to paid drug. Can you walk us through how the patient adds the move to paid drug and the quarterly revenue line up? Maybe now that we have Q4, was that sort of on the same pace as the other quarters? Yeah. Q4 was a very similar number of patient adds again as Q3 and the other quarters in the year. The trends have been very consistent as well. In each quarter and for the whole year, more than half the patients switching to ORLADEYO switched from other prophylaxis therapies, mostly injectable prophy therapies. Then the rest of the patients, most of the rest of the patients switched from acute only. The fact that we've got the better reimbursement situation, constantly improving reimbursement situation, means those patients are just moving to paid drug more quickly and will continue to do so in early 2022. Okay. Got it. We've got a question on the portal here, and thanks for asking questions. Reminder, you can just hit that blue button. How should we think about the ramp to your peak ORLADEYO sales of $1 billion? How many years will it take you to get there? One thing you can start with is just the market research that Jon showed in his presentation. The U.S. is gonna be the majority of that $1 billion. You can make it pretty easy. You can say what we need is about 2,000 patients in the U.S. gets you to close to $800 million. You see from the market research, physicians already believe that ORLADEYO will be their most prescribed prophy drug within the next 12 months. They sometimes get a little bit ahead of themselves, but we think that this will go quickly over the next few years, and then long-term, international sales will add about 20%-30% of that $1 billion. Okay, got it. I guess relative to your thinking before when you said it would be north of $500 million, is the source of the upside, is it geography? Is it different assumptions on penetration or persistency or something else? I think that, Charlie, I'll try to start the answer, and then you can. If I don't get it complete, you can finish. I think it's the first year of success of the market unfolding like we thought it would. We always had the plus. We always emphasized the plus. Now seeing the switching that's going on, seeing the retention of patients that we're maintaining, and recognizing that there's still so much more in the U.S. alone to get. You know, more physicians getting patients to interact with each other and their physicians and go into the office and ask to try ORLADEYO. All that stuff, you know, leads us to believe that it's the plus is way bigger and really a doubling of what the peak sales was before. Jon, the only other thing I'd add is the data that Jon showed, the 96-week data. Over two years ago when we said $500 million+, we didn't have the long-term data. Having the long-term data showing how well patients do after two years on therapy just gives us, and we believe physicians and patients, that much more confidence in the percentage of patients who will use ORLADEYO. Okay, got it. What's the current composition of ORLADEYO patients in terms of new to prophylaxis patients versus switchers? Well, that's why I'm really pleased with the consistency of what we've seen since launch, Jess. It's been consistently over half switching from other prophy therapies. As I said, most of that is switching from injectable prophylaxis. Most of the rest are coming from acute only. Then, as you saw in Jon's slides, across the board, these patients are having a really good experience. They're staying close to 80% of them are staying on for six months plus, and regardless of where they came from. It's bigger picture. Would you consider some newer injectable therapies with either monthly or even every eight-week injection schedules that are in phase III now to be serious competitors to ORLADEYO? We take every competitor seriously and, you know, our view is what's the incremental benefit that they offer compared to what we offer. If you're controlled on a once daily oral, why would you switch, right? You know, if the difference is 86% versus 90% efficacy, you know. None of these drugs are perfect. I don't expect that the new ones will be perfect. There'll be an occasional breakthrough attack here and there. Charlie's job is to get that market share as fast as possible, get these people locked in. Then whoever comes to the market after us, and it will take a while, right? These guys got a ways to go. They're gonna have to show some meaningful benefit to get people to switch off our drug. Got it. Great. We have a investor question here. How this is kind of related. How are you factoring in competition in that new long-term ORLADEYO guidance? Well, the beauty and Charlie said this earlier is that to get to the $1 billion, you can get there with 2,000 patients in the U.S. Remember that about two and a half years ago, Charlie told you that there are 7,500 treated and diagnosed patients in the U.S. You don't need over 50% market share to get there. In fact, you don't need over 30% market share to get there. You know, we're factoring in that competition may come in. Maybe some people are interested in that, but I think it's gonna be really hard for these folks to show a benefit to get people to switch. Okay. Maybe turning to BCX9930. What's the status of the phase III REDEEM-1 and REDEEM-2 studies? Hi, Jess. I'll take that. Thank you. We are proud to say that we have enrolled in both studies. REDEEM-1 and REDEEM-2 have now each enrolled, and we're expanding globally with continuing activation of sites. What you'll see with those over the next two years, we'll complete enrollment. We anticipate having top-line data and proceeding with that data to planning for submission of market approval applications. Sorry. When can we expect enrollment to be completed? I didn't say. We would complete enrollment and have top-line data and proceed to preparations for regulatory approval filings within two years. It's hard for us to predict just 'cause, you know, we're just starting the study, and we really don't have a sense of the pace yet of enrollment. We're pretty confident that within two years we'll get to the point Helen just described. Got it. Is there any expectation that COVID is gonna affect enrollment? Bill, you wanna take that one? Because you've been in recruiting trials in COVID for a while now. Sure. COVID has affected all clinical research for everybody all around the world. Nevertheless, we were able to complete our proof of concept study in PNH during the initial year of the pandemic, and complete that enrollment and have people continue on the study. It's definitely a challenge. We've learned you know some of the tactics that you'd have to implement in order to continue your research. As we've all seen recently with the huge surge in Omicron affecting staffing in every industry, I mean you can expect that it's going to impact sites. With multiple sites in multiple countries, that's the best way we can move forward in dealing with it. Bill, one of the examples we've seen is, you know, the use of telemedicine in trials, right? Yeah. that helps with study visits and things like that. That's right. To the extent that regulators and sites are allowing and capable of doing that, especially in the longer term follow up that will be required for the filing, you know, we'll take advantage of those tools, where we can in order to minimize travel and maximize our ability to recruit and have patients continue on the trials. Got it. Besides PNH, what are the additional indications you're planning to pursue with BCX9930? When could we expect to see initial data from some of the nephrology indications you're pursuing? Helen, you wanna take that? We are in that nephrology basket. We have a basket trial that is screening now, up and running. That's the three indications that we're pursuing next: C3G, IgAN, and PMN. We expect to continue with that trial. It's open enrollment. We have 14 patient cohorts for each of those diseases, and we will be talking about data once we have reached proof of concept for each of those. Again, that's another one within the next two years we expect to be getting to proof of concept and initiating planning for pivotal trials of those indications. Beyond that, we are also looking at indications where the alternative pathway is critical to the disease, and there are many outside of hematology, within hematology and nephrology, but also outside. Those indications where there's more being learned about the role of the alternative pathway, and it may be critical or perhaps significantly contributing, even if it's not critical to disease. What you'll see is more information from us about proof of concept, readiness to start with new medications going forward. The capital that we brought into the company at the tail end of last year allows us to go pretty broad and we're scaling and, you know, we're gonna be moving into other indications in the not too distant future. Great. How do you think about differentiation for BCX9930 from competing products like iptacopan from Novartis or danicopan from Alexion, or I guess now AstraZeneca. What's your strategy to compete in the future if we envision a time when all of these products are approved? Charlie, you wanna tackle that one? Sure. Well, you know, I think the first thing is the clinical trials for all these products are early, so we have to see what the clinical profile is. We feel like we can compete. Rare disease in particular is perfect for a company like ours. We're showing we can do it in HAE. We don't need huge teams, and we're getting really good at, you know, switching patients from injectable drugs. We expect to do the same in PNH. We're gonna apply all of our learnings from HAE to those future launches and do the same thing that we did with HAE, which is to really prepare and really understand the markets better than anyone else. I'll put our team up against anyone. I think we can compete very effectively with the type of profile that we see coming out for BCX9930. I'd add, you know, on the danicopan, you know, a twice daily oral that you can dose to levels that you can control disease is way more effective than a three times a day that has challenges in dosing up and having to be used in combination. So monotherapy is gonna be the offering here, and if you don't have that, it's gonna be really hard to compete. The last thing I would say is, if you were going into an injectable market where you had to understand the patient burden and in order to get switching, what company would you choose? What sales force would you choose to—who's recently demonstrated their effectiveness in doing that in another market? You know, I'd put my money on Charlie and his team. Got it. You maybe kind of answered this question, but would you consider partnering BCX9930 just given the competitive landscape and the potential, you know, size of that product? Yeah. We've always said if somebody can show us how they can do it better or broader, we'd certainly be open to it. We haven't found that yet. I think we can do it pretty well, both from a development and regulatory perspective and from a launch perspective. We have the capital. You're welcome. welcome. You know, we're expecting to generate no less than $250 million in revenue this year with ORLADEYO, and we've got a really solid balance sheet. We're gonna be making some big investments in the 9930 program. I don't see a need at this point in time, but I'm always open if somebody can show us that they can do better or bigger. Got it. Maybe switching to BCX9250, can you remind us where this program stands right now, and should we expect any updates on it in 2022? Yeah. Let me start, Helen, and then you can jump in. This program, you know, we're still in drug manufacturing and supply build-up, and then, you know, next will be tox and then moving into treating patients. We made a lot of progress on the drug front last year in terms of supply. But this program goes slow. As you've seen in the market or in the clinical space, there've been a lot of challenges with these programs and a lot of steps backwards that companies have taken. I don't think anybody's going very fast, but the unmet need is massive in this disease. You know, we hope to make really good progress over the course of this year, and then shortly thereafter, start to look to get into patient studies. You know, FOP, it just appears to have been a tough indication with some setbacks for, you know, other companies in their attempts. Do you think BCX9250 can succeed where others have failed and why? Bill or Helen? I'll take that. That's. So we do. This is going back to what Jon was describing in the presentation earlier. We have a specific ability to design molecules that are good for tough targets. This is a difficult disease. It's also a tough target. Our ability to design a molecule that's potent but specific, which is important with a kinase, and is one that can be bioavailable, and that's our strength. That really is our strength. We'll have to see the data as we go, but what we like with the data so far, our phase I data has been excellent. We think we're in an excellent position to advance this molecule and to have a molecule that may differentiate for FOP. Great. Couple more questions coming in here. You provided top line guidance for the year. Should we expect you to provide operating expense guidance, maybe when we get to Q4 results? Anthony? Yeah. I think when we get into late February, at that point, we'll give an indication of investment and, you know, like the team have said at this point in time, I think from a cash perspective, you know, best position the company has been in by a stretch, and from an investment perspective, really making sure that we are investing in the globalization of ORLADEYO and then investing in the programs that Helen talked about. You know, versus where we were, yes, we will continue to invest in those programs. But the revenue as well that we're generating in ORLADEYO makes it a hell of a lot more palatable. The areas that we're investing in, whether it be BCX9930, BCX9250, you know, the potential for value creation further down the road is phenomenal. Got it. What about gross to nets? Where do they stand now with ORLADEYO, and where will they go? Yeah. You know, Charlie's team has done a great job of getting payers and PBMs up and running and confirmed that the vast majority are now that all the big payers and PBMs are covered. I think if we exclude free product, then that 15%-20% that we've talked about and guided to is pretty much there. You know, the free product in terms of the Quick Start program, which has been a huge success as we get to our peak, overall our gross-to-net will be up 15%-20%, but when we just look at the paid component, the reimbursed component, that 15%-20% is already there. Okay. Got it. Let's see here. No more questions from the portal, so I think we can wrap it up there. Thanks so much, guys, for the presentation and the helpful Q&A. Thanks, Jess. Thanks for having us.